maternal fetal evidence based guidlines ed 2007

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26

Venous Thromboembolism and anticoagulation

James Airoldi

Key Points

Venous thromboembolism (VTE) is the leading cause of pregnancy-related maternalmorbidity and mortality in the developed world.

Risk factors for VTE are listed in Table 28.1, and include pregnancy,priorthromboembolism, age of 35 years or more, increased parity, increased

maternal weight,instrument-assisted deliveries or cesarean section, prolonged

immobilization, smoking, and the presence of an acquired or inherited

thrombophilia.

Compressive ultrasonography is the primary modality for the diagnosis of deep veinthrombosis (DVT) in pregnancy.

T h e ventilation/perfusion (V/Q) scan or a computerized tomography pulmonaryangiography (CTPA) are fairly equivalent first-line imaging tests for the diagnosis of

pulmonary embolism in pregnant patients although some experts favor V/Q scans.

The three anticoagulant typically used are unfractionated heparin (UFH), low-molecularweight heparin (LMWH), and warfarin.

Platelet counts should be checked five days after initiation of UFH, and periodically forthe first three weeks ofheparin therapy.

LMWH is at least as effective and safe as UFH for the treatment of patients with acuteDVT, and for the prevention of DVT. LMWH and UFH do not cross the placenta, and

are safe for the fetus. The incidences of bleeding, osteopenia, and heparin-induced

thrombocytopenia with LMWH are probably decreased compared to UFH in pregnant

patients. Pregnant women may require higher doses and these risks could be dose related.

The dosing of LMWH in pregnancy remains controversial.

Warfarin derivatives cross the placenta and have the potential to cause both bleeding inthe fetus and teratogenicity. Warfarin use is believed to be safe in the first six weeks of


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gestation, but has been associated with warfarin embryopathy in 4% to 5% of fetuses

when maternal exposure occurs between six and nine weeks' gestation.

In the pregnant patient with acute VTE, either therapeutic LMWH throughoutpregnancy or intravenous UFH for at least five days, followed by therapeutic UFH or

LMWH for a

minimum of six months, is the recommended approach. Anticoagulants should beadministered for at least six weeks postpartum.

There are three general approaches to the antepartum management of pregnant patientswith previous VTE: UFH, LMWH, or close surveillance.

Among women with a nonrecurring cause for the prior VTE and no thrombophilia,the risk of recurrent antepartum VTE is low, and therefore routine antepartum

prophylaxis with heparin is not warranted. However, postpartum low-dose

prophylaxis is still recommended.

If there is a potential recurring cause, prophylactic anticoagulation isrecommended.

In pregnant women with a prior VTE with history of a low-risk thrombophilia(heterozygous factor V or prothrombin gene, protein C or S), prophylactic

anticoagulation is recommended.

Therapeutic anticoagulation is recommended for prior VTE and high-riskthrombophilia (ATIII deficiency, homozygous factor V or prothrombin gene, or

compound heterozygote).

Therapeutic anticoagulation should be used in pregnant women if the woman has hadrecurrent VTE episodes, life-threatening thrombosis, or thrombosis while receiving

chronic anticoagulation. Filters in the inferior vena cava should be considered in this

situation as well.

It is recommended that pregnant patients with recurrent early pregnancy losses andantiphospholipid syndrome (APS) who do not have a history of venous thrombosis

receive a prophylactic regimen of heparin (and low-dose aspirin), and that those with

previous thrombosis and APS receive a similar prophylactic dose regimen of heparin (see

chap. 26).


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The antepartum management of pregnant women with known thrombophilia and noprior VTE remains controversial because of our limited knowledge of the natural

histories of various

thrombophilias and a lack of trials of VTE prophylaxis. Currently, there is no evidence tosuggest prophylactic anticoagulation (see chap. 27).

In pregnant women with mechanical heart valves, it appears reasonable to use one ofthe following four regimens: (i) therapeutic LMWH or UFH between 6 and 12 weeks and

close to term only, and vitamin K antagonists (VKAs) at other times; ( ii) careful

therapeutic UFH throughout pregnancy; (iii) careful therapeutic LMWH throughout

pregnancy; or (iv) VKAs throughout pregnancy.

DEFINITION

Venous thromboembolism (VTE) includes any thromboembolic event in a vein, including deep

vein thrombosis (DVT) and pulmonary embolism (PE), which are the most common, and others

[cerebrovascular event (CVA or stroke), etc.].

SYMPTOMP

DVT can present with leg swelling, erythema, pain and calor, with about 25% of patients with

these symptoms having DVT. PE is not detected clinically in 70% to 80% of patients in whom it

is detected postmortem. Most patients who die of PE do so within 30 minutes of the event,

reinforcing the need for rapid and accurate diagnosis

EPIDEMIOLOGY/INCIDENCE

VTE is the leading cause of pregnancy-related maternal morbidity and mortality in the

developed world (2). Fatal PE remains the leading cause of maternal mortality, accounting for

19.6 % of all maternal deaths. Interestingly, hemorrhage is the second leading cause of maternal

deaths (about 17%), thus signifying the delicate balance between coagulation and anticoagulation

in pregnancy. The incidence of all thromboembolic events averages about 1.3 (range 0.53) per


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1000 pregnancies (3), and about an equal number are identified antepartum and in the

puerperium (4).

There is an equal frequency in all three trimesters. Pulmonary emboli are more frequent

postpartum (4). During pregnancy and postpartum, women in general have a fivefold increased

risk of VTE compared with nonpregnant women (4). The risk is increased approximately

twofold during the antepartun period, and 14-fold in the postpartum period, especially after

cesarean delivery. DVT is more common in the left than the right leg. PE occurs in 15% of

untreated DVTs, with a mortality rate

of 15%. PE occurs in 4.5% of treated DVTs, with a mortality rate of 1% ( 5). Death from PE

occurs about every 1.1 to 1.5 per 100,000 pregnancies (6).

GENETICS

About 50% of patients with thrombosis have an identifiable underlying genetic disorder (7).

Moreover, approximately 50% to 60% of patients with a hereditary basis for thrombosis, or a

thrombophilia, do not experience a thrombotic event until one other risk factor is present (4) (see

chap. 27)

ETHIOLOGY/BASIC PATOPHISIOLOGY

The coagulation cascade is briefly and schematically shown in Figure 28.1. Pregnancy is

associated with marked alterations in the proteins of the coagulation and fibrinolytic systems (8,

9) (see chap. 3, Obstetric Evidence Based Guidelines). A tendency for excessive clotting seems

to be an adaptive mechanism to prevent excessive bleeding at delivery. At delivery, about 120

spiral arteries are denuded while carrying about 12% of the woman's cardiac output every

minute. Much of the prevention in bleeding is due to myometrial contraction, but there are alsomarked increased clotting capacity, impaired fibrinolysis, and decreased natural anticoagulant

activity in pregnancy. Three main factors, those in Virchow's triad, contribute to the increased

risk of VTE in pregnancy:


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FIGURE 28.1

Hypercoagulable blood: The levels of coagulation factors II, V, VII, VIII, IX, X, and XII

increase substantially by the middle of pregnancy. The generation of fibrin also increases

markedly. Levels of the anticoagulant protein S appear to decrease about 40% throughout

pregnancy, although levels of protein C remain normal. The fibrinolytic system is also inhibited,

most substantially in the third trimester. These clotting factor changes occur very early in

pregnancy, and thus anticoagulation should be started early in pregnancy if it is going to be

started.

Stasis: compression of iliac veins; hormonally mediated vein dilation; immobilization.

Vascular damage: vascular compression at delivery; assisted or operative delivery.

RISK FACTOR/ASSOCIATION

Hypercoagulable blood: The levels of coagulation factors II, V, VII, VIII, IX, X, and XII

increase substantially by the middle of pregnancy. The generation of fibrin also increases

markedly. Levels of the anticoagulant protein S appear to decrease about 40% throughout

pregnancy, although levels of protein C remain normal. The fibrinolytic system is also inhibited,


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most substantially in the third trimester. These clotting factor changes occur very early in

pregnancy, and thus anticoagulation should be started early in pregnancy if it is going to be

started.

Stasis: compression of iliac veins; hormonally mediated vein dilation; immobilization.

Vascular damage: vascular compression at delivery; assisted or operative delivery.

TABLE 28.1

COMPLICATIONS


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VTE in general: risk of recurrence is about 7% to 12% DVT: risk of PE, postthrombotic syndrome PE: risk of death, pulmonary hypertension

MANAGENENT

Principles

Given the paucity of data regarding diagnosis and treatment in pregnancy, most data are derived

from the nonpregnant general population.

DIAGNOSIS

To diagnose VTE, clinical suspicion must remain high. Clinical evaluation alone cannot confirm

or refute a diagnosis of VTE in the nonpregnant state, and diagnosing VTE in pregnancy is even

more challenging. Epidemiologic studies have shown that exposure to radiation of less than a

total cumulative dose of 5 rads has not been associated with significant risk for fetal injury ( 13).

The diagnostic tests shown in Table 28.2 are all below the safe limit, and most combinations of

these tests are also below the 5 rads limit, although they may increase the risks for childhoodcancers (14, 15).


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FIGURE 28.2

During pregnancy, thrombosis most frequently begins in the veins of the calf or in theiliofemoral segment of the deep venous system and has a striking predilection for the left leg

(1618) (8590%), possibly because of the compressive effects on the left iliac vein by the right

iliac artery where they cross (19). Only about 25% of symptomatic patients have a thrombus, and

thus the physical exam has low predictability.

Compressive ultrasonography is now the primary modality for the diagnosis of DVT in


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pregnancy. It has a sensitivity of 97% and a specificity of 94% for the diagnosis of proximal

DVT in the nonpregnant population (15, 20). It is less accurate for symptomatic calf DVTs ( 21).

It is inadequate for iliac vein thrombosis for which only magnetic resonance imaging (MRI) has

shown a high degree of sensitivity and specificity (20).

Venography was widely held to be the standard for establishing a diagnosis of DVT (22).

However, exposure to radiation and the invasive nature of the test has led to its replacement by

compressive ultrasound.

D-dimer testing has been noted to have a role in diagnosing VTE in nonpregnant patients and

may be useful during pregnancy. D-dimer is a measurement of the degradation products of

crosslinked fibrin. Pregnancy itself may increase D-dimer levels, increasing with gestational age.

Preterm labor, preeclampsia, and placental abruption also can elevate levels significantly (23).

Sensitivities vary widely with different assays, ranging from 80% to 100% (24), but the main use

is derived from a high negative predictive value. The approach using D-dimer is not validated in

pregnancy. Patients who, on clinical evidence, are likely to have thrombosis but whose initial test

results are negative, should undergo either venography or serial noninvasive testing. Diagnosis of

pelvic vein and internal iliac thrombosis is difficult, and may require MRI.

The ventilation/perfusion (V/Q) scan is one of the two primary tools for the diagnosis of PE in

pregnant patients. If a perfusion defect is seen in a patient with symptoms of PE, this finding can

be considered diagnostic. The ventilation portion of the test is useful to distinguish matched

defects from unmatched defects if a perfusion defect is not clearly caused by a PE. About 40% to

60% of V/Q scans are diagnostic (either high probability or normal). For nondiagnostic tests,

further studies are necessary (26). Given lower radiation exposure, high proportion of normal or

near-normal perfusion scans, and uncertainty regarding finding of subsegmental PE on

computerized tomography pulmonary angiography (CTPA), V/Q scan is often preferred by

experts as the first-line radiologic diagnosticstudy (27).

CTPA has provided an additional first-line imaging test and has become the most widespread

imaging test in nonpregnant adults (25). The sensitivity varies from 57% to 100% and the

specificity varies between 64% and 100% (20, 24, 28). The location of the embolus affects the

sensitivity andspecificity of CTPA. CTPA scanning is more sensitive for detecting emboli in the

central arteries andis less sensitive for detecting subsegmental emboli (29). With CTPA, the

thrombus is directly visualized, and both mediastinal and parenchymal structures are evaluated,


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which may provide important alternative or additional diagnoses. CTPA is associated with a

higher risk of maternal breast cancer than V/Q scanning.

Pulmonary angiography remains the gold standard for ruling out PE. The test requires expertise

for performance and interpretation and is invasive. Thus, this test is held in reserve for patients in

whom the diagnosis cannot be made or excluded on the basis of less invasive testing.

THERAPY

Agents

Given the paucity of data regarding the efficacy ofanticoagulants during pregnancy,

recommendations about their use during pregnancy are based largely on data from nonpregnant

patients. The three anticoagulant typically used are unfractionated heparin (UFH), low-

molecularweight heparin (LMWH), and warfarin. Heparin (UFH or LMWH) is the

anticoagulant most often used given its safety and efficacy during pregnancy (3043). Warfarin

is also an alternative anticoagulant in certain situations. All three choices are safe during breast-

feeding. These anticoagulants can be used either as a low-dose prophylactic dose (Table 28.3)

or as a (sometimes weight-adjusted) therapeutic dose (usually with monitoring, Table 28.4).

Unf ractionated heparin. The word heparin derives from the Greek hepar, liver, the organ

where it was first isolated from. UFH exerts its anticoagulation action by two mechanisms of

action:

(i) stimulation of antithrombin III (ATIII) activity, which is an inhibitor of factors 2, 9, 10

(especially), and 11; (ii) direct factor 10 inhibition (Fig. 28.1). UFH half-life is about 1.5 hours.

Approximately 3% of nonpregnant patients receiving UFH acquire immune-mediated (IgG)

thrombocytopenia (heparin-induced thrombocytopenia, HIT), which is frequently complicated

by extension of preexisting VTE or new arterial thrombosis (44). HIT is diagnosed by antibodies

to heparin, fall in platelet count >50%, skin lesions at the injection site, and systemic reactions

after IV injection (45). HIT encompasses a range of presentations, from asymptomatic antibodies

without thrombocytopenia, to thrombocytopenia, to thrombocytopenia with thrombosis. The

mortality rate from untreated HIT and new thrombotic complications is 20% to 30% (46). This

should be


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differentiated from an early, benign, transient thrombocytopenia that can occur with initiation of

UFH due primarily to platelet clumping. It should be suspected when the platelet count falls to

100 109/L or 50% of the baseline value 5 to 15 days after commencing heparin, or sooner with

recent heparin exposure (44) . Platelet counts should be checked about five days after

initiation of UFH, and periodically for the first two weeks of UFH therapy. In pregnant

women who acquire HIT and require ongoing anticoagulant therapy, use of the heparinoid

danaparoid sodium is recommended because it is an effective antithrombotic agent (40), does

not cross the placenta, has much less crossreactivity with UFH, and therefore, has less potential

to produce recurrent HIT than LMWH (47).

Alternatives may include fondaparinox or lepirudin (45). LMWH treatment for VTE has in

general been associated with decrease in the incidence of HIT (44, 47), but not in all studies (38).

Heparin therapy has been associated with osteopenia in pregnant women. Long-term

prophylactic UFH therapy during pregnancy is associated with a 2.2% incidence of vertebral

fracture (49). The mean bone loss is about 5%, with unclear reversibility. LMWHs have a lower

risk of osteopenia than UFH. UFH and dalteparin for thromboprophylaxis in pregnancy are

associated with similar bone mineral density in the lumbar spine for up to three years after

delivery between healthy control subjects and the dalteparin group (50). Bone mineral density

was significantly lower in the UFH group when compared to both control subjects and

dalteparin-treated women in this trial.

Multiple logistic regressions found that the type of heparin therapy was the only independent

factor associated with reduced bone mass. Cohort studies (51) have also reported no association

with osteopenia and LMWH therapy. Given that UFH does not cross the placenta, there is no

risk of teratogenicity. The rate of major maternal bleeding in pregnant patients treated with

UFH therapy is about 2%, which is consistent with the reported rates of bleeding associated with

heparin therapy in nonpregnant patients (52) and with warfarin therapy (53) when used for the

treatment of DVT. There is insufficient evidence to assess whether UFH is associated with

different incidence of bleeding complications compared to LMWH in RCTs ( 54). Bleeding at

the uteroplacental junction is still possible. The short half-life makes UFH the optimal

anticoagulation around the time of delivery or surgery. The anticoagulant effect lasts for about 8

to 12 hours. Protamine sulfate can be used to reverse the effects of UFH. Recent UFH


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administration is not a contraindication to regional anesthesia as long as the\ partial

thromboplastin time (PTT) is not prolonged.

Low-molecular-weight heparin. LMWH exerts its anticoagulation action by stimulation of ATIII

activity, inhibiting in particular factor 10 (not factor 2). There is accumulating experience with

the use of LMWHs, both in pregnant and nonpregnant patients, for the prevention and treatment

of VTE\ (3641). On the basis of the results of large clinical trials in nonpregnant patients,

LMWH is at least as effective and safe as UFH for the treatment of patients with acute

proximal DVT (38, 40), and for the prevention of DVT in patients who undergo surgery (41).

LMWH does not cross the placenta, and LMWH is safe for the fetus (37, 51). The half-life is

usually about four to seven hours (e.g., enoxaparin).

Bleeding complications appear to be very uncommon with LMWH. LMWH might have fewer

associated risks for bleeding, HIT, and osteoporotic fractures than UFH ( 44, 48), but the

incidence ofthese complications have not been well established for LMWH use in pregnant

patients. Pregnant\ women may require higher doses and these risks could be dose related.

The dosing of LMWH remains controversial. The anticoagulant effect of LMWH lasts for 18

to 24 hours. Pregnant women may require increases in dalteparin dose of 10% to 20% compared

with doses of nonpregnant women to reach the target anti-Xa levels (5557). Anticoagulation

with LMWH may need to be monitored in pregnant women and the dose adjusted to reach the

target Xa level, which decreases the logistical and financial benefits of LMWH. The therapeutic

anti-Xa level for adjusted-dose therapy is 0.5 to 1.2 U/mL. The target anti-Xa level for

prophylactic dose therapy is 0.2 to 0.4 U/mL. To achieve these levels, often dosing every 12

hours is necessary even forprophylaxis in pregnancy. Twice-daily dosing of enoxaparin may

be necessary to maintain antifactor Xa activity above 0.1 IU/mL throughout a 24-hour period in

pregnant women (6, 56, 58).

Enoxaparin 40 mg every 12 hours (instead of once daily) has been suggested for prophylactic

anticoagulation in women at or above 90 kg (6). It is not known whether a specific minimum

level of antifactor Xa activity is necessary throughout the day to prevent thrombosis in

pregnancy or whether maintaining a specific minimum level of antifactor Xa activity for only a

portion of the day is sufficient. Anti-Xa levels may be used especially for obese and for renal

disease patients (6).

Warfarin(Coumadin). Warfarin derivatives are vitamin K antagonists (VKAs). Vitamin K


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derives its name from the German word koagulation. Warfarin inhibits the effects of vitamin

K, and

hence vitamin Kdependent factors (factors 2,7,9, and 10) (Fig. 28.1). Consequently, warfarin

decreases levels of proteins C and S. Warfarin derivatives cross the placenta and have the

potential

to cause both bleeding in the fetus and teratogenicity (58, 59). Warfarin use is believed to be

safe

in the first six weeks of gestation, but has been associated with warfarin embryopathy in 4%

to 5%

of fetuses when maternal exposure occurs between six and nine weeks gestation . First-

trimester

warfarin embryopathy includes skeletal, (involving stippled epiphyses), nasal, and limb

(hypoplasia)

involvement. Bleeding in the fetus can occur during any trimester. Some recommend the use of

warfarin during pregnancy anyway for specific patients, such as women with mechanical heart

valves, those who have a recurrence while receiving heparin, and those with contraindications to

heparin therapy. If warfarin is used during pregnancy, patients must be fully informed about the

potential adverse effects on the fetus. Warfarin does not induce an anticoagulant effect in the

breastfed

infant when the drug is given to a nursing mother (60, 61). Therefore, the use of warfarin in

breastfeeding

women who require postpartum anticoagulant therapy is safe.

Aspirin. Potential complications of aspirin use during the first trimester of pregnancy include

birth defects (e.g., gastroschisis) and bleeding in the neonate and in the mother. Low-dose (60 to

150

mg/day) aspirin therapy administered during the second and third trimesters of pregnancy in

women at

risk for hypertensive complications and/or FGR is safe for the mother and fetus (62, 63). The

safety

of higher doses of aspirin and/or aspirin ingestion during the first trimester remains uncertain.


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Table 28.5

There are no RCTs for treatment of DVT specific to pregnant women ( 64). There are now many

well-designed randomized trials and meta-analyses comparing IV UFH and SC LMWH for the


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treatment of acute DVT and PE in nonpregnant patients (38). They show that LMWH is at least

as safe

and effective as UFH. However, there are no trials comparing UFH to LMWH for the treatment

of

acute VTE in pregnancy. Therefore, in the pregnant patient with acute VTE, either (weight-

adjusted)

therapeutic doses of SC LMWH, or IV UFH [80 IU/kg bolus followed by a continuous

infusion (at

least 1300/hour) to maintain the aPTT in the therapeutic range] for at least five days, followed by

adjusted-dose UFH or LMWH for the remainder of the pregnancy, is the suggested approach

(Table

28.4). The therapeutic dose regimen of subcutaneous UFH was shown to have equal efficacy in

preventing recurrent VTE as compared to warfarin in the first three months after an acute VTE

(52).

Interestingly, three patients had recurrent VTE during therapy, but all were associated with

interruption of anticoagulation (52). Anticoagulants should be administered for about six

months in

adjusted dose (12), and at least six weeks postpartum as well. There is insufficient evidence to

assess if continuing adjusted-dose anticoagulation until six weeks postpartum is associated with

any

benefit or detriment. Women with antithrombin deficiency, antiphospholipid antibodies,

homozygous

or combined thrombophilias, or previous VTE may benefit from indefinite anticoagulation, but

this

should be decided by an internist after pregnancy (12). Long-term, low-intensity warfarin

therapy is

associated with an about 50% prevention of recurrent VTE, major hemorrhage, or death in

patients

with a prior idiopathic VTE (65).

Filters in the inferior vena cava have been used safely and effectively in pregnant women (66,


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67). Suprarenal placement is recommended. No important maternal or fetal morbidity associated

with

the filters has been reported. The indications for their use are the same as in nonpregnant

patients: any contraindication to anticoagulant therapy; serious complication of anticoagulation,

such

as HIT; and the recurrence of PE in patients with adequate anticoagulant therapy.

The use of thrombolytic agents during pregnancy has been limited to life-threatening situations

because of the risk of substantial maternal bleeding, especially at the time of delivery and

immediately postpartum (68). The risk of placental abruption and fetal death because of these

drugs is

currently unknown.

Embolectomy, another treatment option when conservative treatment fails, is indicated to

prevent death in patients who are hemodynamically unstable despite anticoagulation and

treatment

with vasopressors (69). Embolectomy has been associated with a 20% to 40% incidence of fetal

loss

(70), so this treatment must be restricted to cases in which the woman's life

Prevention of VTE in pregnancy

Avoidance of risk factors shown in Table 28.1 can provide important prevention of VTE and its

complications. Preconception counseling should review these preventive measures, as well as

review in detail any prior history of VTE and risk factors (see Table 27.2).

Women with a history of VTE (with or without thrombophilia) are believed to have a higherrisk

of recurrence in subsequent pregnancies. Estimates of the rate of recurrent venous thrombosis

duringpregnancy in women with a history of VTE have varied between 1% and 10% (7174). The

higher

of these estimates has prompted recommendation for anticoagulant prophylaxis during

pregnancy and


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the postpartum period in women with a history of VTE. However, the risk is likely to be lower

than

has been suggested by some of these studies because they were retrospective, with the possibility

of

significant bias. The risk is dramatically influenced by risk factors, in particular the presence of

thrombophilias (see Table 27.2).

There are very few trials for the prevention of VTE in pregnancy (both antepartum and

postpartum). The sample sizes of all trials are small and cannot be combined. There is

insufficient

evidence on which to base recommendations for thromboprophylaxis during pregnancy and the

early

postnatal period, because of limited data, especially regarding rare outcomes such as death and

thromboembolic disease and osteoporosis. In general, care must be individualized according to

risk

factors (Table 28.5).

Antenatal prophylactic anticoagulation (usually for prior VTE) (Table 28.5). Compared to

UFH, LMWH is associated with a 72% decrease in bleeding episodes; however, all other

outcome

variables showed no significant differences (75, 76).

Compared to aspirin alone, in pregnant women with recurrent miscarriage associated with

antiphospholipid antibodies, aspirin plus heparin appears to be associated with a 70% lower

risk of

fetal loss (77).

Compared to UFH only postpartum, UFH antepartum and postpartum is associated with similar

results in one very small (n = 40) trial, which could not possibly detect significant differences

given

the sample size (78).

In summary, there is insufficient evidence on which to base recommendations for VTE

prophylaxis during pregnancy and the early postnatal period (79). In general, in pregnant women

with


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a prior history of VTE, prophylactic anticoagulation can be used. This may be modified on

the

basis of the cause of the first VTE and the presence of a thrombophilia. If the prior VTE was

related

to a nonrecurrent cause (i.e., broken bone and immobilization) and the thrombophilia

workup is

negative, the risk of recurrence is very low, and prophylaxis may be avoided, especially in

women

without other risk factors except pregnancy. In fact, the risk of recurrence was 0% in such 44

women

followed without antepartum anticoagulation (80). Postpartum prophylaxis is suggested in all

women

with prior VTE. Both antepartum and postpartum prophylaxis may be suggested to the woman

with

prior VTE and thrombophilia, prior unexplained VTE, or a current major risk factor. There are

two

general therapies for management of pregnant patients with previous VTE who require

prophylaxis:

UFH or LMWH. For low-dose prophylaxis of VTE during pregnancy, see Table 28.3.

Approximately 50% to 80% of gestational VTEs are associated with heritable thrombophilia

(see chap. 27). Given that the background rate of VTE during pregnancy is approximately

1:1000, the

absolute risk of VTE remains modest for majority of these thrombophilias, except antithrombin

deficiency, homozygosity for factor V Leiden mutation and for prothrombin mutation, and

combined

defects. The absolute risk of pregnancy-associated VTE has been reported to range from 9% to

16%

in homozygotes for the factor V Leiden mutation (8184). Double heterozygosity for the factor

V

Leiden and prothrombin gene mutations has been reported to have an absolute risk of

pregnancyassociated


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VTE of 4.0% (95% CI, 1.416.9%) (79). These data suggest that women with

antithrombin deficiency, homozygosity for factor V Leiden mutation or the prothrombin

mutation as

well as double heterozygotes should be managed more aggressively than those with other low-

risk

inherited thrombophilias; thus, adjusted-dose therapeutic anticoagulation is recommended

for

prior DVT and a high-risk thrombophilia (ATIII deficiency, homozygous factor V or

prothrombin

gene mutation, or double heterozygote). Therapeutic anticoagulation may also be used in

pregnant

women if the woman has had recurrent VTE episodes, life-threatening thrombosis, or thrombosis

while receiving chronic anticoagulation. Filters in the inferior vena cava should be considered in

this

situation as well. In pregnant women with prior VTE with a history of low-risk thrombophilia

(heterozygous factor V or prothrombin gene, protein C or S), prophylactic anticoagulation is

recommended. Persistent antiphospholipid antibodies are associated with an increased risk of

VTE

during pregnancy and the puerperium (48). It has been suggested that pregnant patients with the

antiphospholipid syndrome who do not have a history of venous thrombosis receive a low-dose

prophylactic regimen of heparin, as well as those with previous thrombosis (48) (see also chap.

26).

The antepartum management of pregnant women with known thrombophilia and no prior VTE

remains

controversial because of our limited knowledge of the natural histories of various thrombophilias

and

a lack of trials of VTE prophylaxis. Prospective data are lacking regarding the issue of the

incidence

of VTE in a large group of pregnant women with known thrombophilia and no prior VTE.

Currently,


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there is no evidence to suggest prophylactic, low-dose anticoagulation in this group. If there is a

very

strong family history of VTE (especially at young ages), consideration can be made for low-dose

prophylactic anticoagulation. Individualized risk assessment should be performed in this

situation.

Postnatal prophylaxis after cesarean delivery. Available data suggest that the risk of VTE is

higher aftercesarean section (especially emergent surgery) than after vaginal delivery (3). The

presence of additional risk factors for pregnancy-associated VTE (e.g., prior VTE,

thrombophilia,

age > 35 years, obesity, prolonged bed rest, and concomitant acute medical illness) may

exacerbate

this risk. Clinical judgment should be used to decide on anticoagulation after cesarean section,

taking

into account all of the patients risk factors.

Evidence from small trials revealed that for postcesarean delivery VTE prophylaxis, the

following are observed: Compared to placebo, heparin (either UFH or LMWH) is associated

with

similar outcomes in two trials (85, 86). Compared to UFH, LMWH is associated with similar

outcomes in one trial (87). Compared to UFH, hydroxyethyl starch is associated with similar

outcomes in one trial (88).

It has been recommended that graduated compression stockings or intermittent pneumatic

compression devices be used during and after cesarean section in patients considered to be at

moderate risk of VTE and that LMWH or UFH prophylaxisbe added in those thought to be

at

high risk (6, 89). However, there are no RCTs on this subject (see chap. 13, Obstetric

Evidence

Based Guidelines).

Prophylaxis in women with mechanical heart valves. Women who anticipate ultimately needing

valve replacement surgery should be encouraged to complete childbearing before valve

replacement.


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The highest risk for VTE is with first-generation mechanical valves (StarrEdwards, Bjork

Shiley)

in the mitral position, followed by second-generation valves (St. Jude) in the aortic position (see

also

chap. 2). These women need to be therapeutically anticoagulated throughout pregnancy and

postpartum, with blood levels frequently (usually weekly) checked to ensure therapeutic

levels

of anticoagulation. Pregnant women with prosthetic heart valves pose a problem because of the

lack

of trials regarding the efficacy and safety of antithrombotic therapy during pregnancy. There are

insufficient data to make definitive recommendations about optimal anticoagulation in pregnant

patients with mechanical heart valves.

There are in general four regimens that can be considered: (i) VKAs throughout pregnancy; (ii)

either therapeutic LMWH or UFH between 6 and 12 weeks and close to term only, and VKAs at

other

times; (iii) careful therapeutic UFH throughout pregnancy; (iv) careful therapeutic LMWH

throughout

pregnancy. Before any of these approaches is used, it is crucial to explain the risks/benefits

carefully

to the patient.

In a review, VKAs throughout pregnancy was the regimen associated with the lowest risk of

valve thrombosis/systemic embolism (3.9%); using UFH only between 6 and 12weeks

gestation was

associated with an increased risk of valve thrombosis (9.2%) (90). This analysis suggests that

VKAs

are more efficacious than UFH for thromboembolic prophylaxis of women with mechanical heart

valves in pregnancy; however, coumarins increase the risk of embryopathy. In the first

trimester,

coumarin is associated with a 10% to 15% teratogenic risk (nasal hypoplasia, optic atrophy,

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anomalies, mental impairment). European experts have recommended warfarin therapy

throughout

pregnancy in view of the reports of poor maternal outcomes with heparin and their impression

that the

risk of embryopathy with coumarin derivatives has been overstated (91). If coumarin is used, the

dose

should be adjusted to attain a target INR of 3.0 (range, 2.53.5).

A common option utilizes UFH during the first trimester to minimize teratogenesis,

warfarin

for the majority of pregnancy (1236 weeks), and UFH again in the last month to prepare

for

delivery and allow for epidural anesthesia. While this may be efficacious, fetal risk is not

completely eliminated. Substituting VKAs with heparin between 6 and 12 weeks reduces the

risk

of fetopathic effects but possibly subjects the woman to an increased risk of thromboembolic

complications. The reported high rates of thromboembolism with UFH might be explained by

inadequate dosing and/or the use of an inappropriate target therapeutic range.

The use ofweight-adjusted therapeutic UFH warrants careful monitoring and appropriate

dose adjustment. A target aPTT ratio of at least twice the control should be attained (92). If used,

SC

UFH should be initiated in high doses, usually every eight hours, and adjusted to prolong a six-

hour

postinjection aPTT into the therapeutic range (usually 6080 seconds); strong efforts should be

made

to ensure an adequate anticoagulant effect.

LMWH use in pregnant women with prosthetic heart valves (9399) has been associated with

treatment failures (9699), and the use of LMWH for this indication has recently become

controversial because of a warning from a LMWH manufacturer regarding their safety in this

situation

(100). If used, LMWH should be administered twice daily and dosed to achieve anti-Xa levels of

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to 1.2 U/mL four to six hours (peak) after SC injection, with trough 0.6 to 0.7.

Extrapolating from data in nonpregnant patients with mechanical valves receiving warfarin

therapy (101), for some high-risk women, the addition of low-dose aspirin, 75 to 162mg/day,

can be

considered in an attempt to reduce the risk of thrombosis, recognizing that it increases the risk of

bleeding.

ANTEPARTUM TESTING

No specific resommendation

DELIVERY

In order to avoid an unwanted anticoagulant effect during delivery (and also for allowing

neuroaxial anesthesia) in women receiving therapeutic UFH (9, 102) or LMWH (3039), it is

suggested that heparin be discontinued about 24 hour prior to planned induction of labor or

cesarean

section. If spontaneous labor occurs in women receiving therapeutic LMWH or UFH, careful

monitoring of the aPTT may be necessary. If it is markedly prolonged near delivery, protamine

sulfate

may be required to reduce the risk of bleeding. Therapeutic heparin can be restarted about 6 to 12

hours after delivery, and warfarin restarted in an overlapping fashion (to avoid paradoxical

thrombosis) 24 to 36 hours after delivery (the night after delivery).

In women with mechanical heart valves, therapeutic anticoagulation can be continued IV

(halflife:

1 hour) until active labor, and then stopped during active labor and for delivery, with

therapeutic heparin restarted about 6 to 12hours after delivery, and warfarin restarted in anoverlapping fashion (to avoid paradoxical thrombosis) 24 to 36 hours after delivery (the night

after

delivery). Extensive counseling on all these options and risks is required.

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UFH 5000 IU twice a day does not pose a risk for spinal hematoma. Low-dose prophylactic

UFH and LMWH probably do not cause a risk for spinal hematoma (1). For precaution, women

on

low-dose prophylactic LMWH should not receive regional anesthesia sooner than 12 hours after

the

last dose. Women on therapeutic LMWH should not receive regional anesthesia sooner than 24

hours

after the last dose (6, 103).

POSTPARTUM/BREASTFEEDING

For women necessitating low-dose prophylactic anticoagulation, UFH or LMWH can be

restarted

12 to 24 hours postpartum, after removal of epidural catheter, depending on risk. For women

necessitating therapeutic adjusted-dose anticoagulation, heparin can be restarted (either UFH or

LMWH) 6 to 12hours postpartum, with warfarin also started about 24 to 36hours later,

overlapping

for the first five to seven days until warfarin is therapeutic (INR 2.03.0). In general, postpartum

anticoagulation should be at levels at or higher those antepartum (Table 28.5). Graduated

compression stockings should also be used while not fully able to mobilize. Breast-feeding is

safe

while on anticoagulation (with UFH, LMWH, or warfarin). Estrogen-containing hormonal

contraception should be avoided in women remaining at high risk for VTE, such as those with

prior

VTE and/or thrombophilias.

maternal fetal evidence based guidlines ed 2007

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