Thrombosis in Pregnancy thrombophilia increases the risk of recurrent venous events

Thrombosis in Pregnancy thrombophilia increases the risk of recurrent venous events

during pregnancy and the postpartum period. In a systematic Although there are no data on the risk factors for recurrent

review of the risk of recurrent venous thromboembolism in thrombosis in pregnancy, the risk factors are thought to be

individuals who were not pregnant, factor V Leiden and the the same as the overall risk factors for thrombosis. Aside from

prothrombin gene mutation were found to confer a slightly

a history of thrombosis, the most important risk factor for increased risk of recurrence with an OR for factor V Leiden of

Thromboembolism in pregnancy 169

Table 2 Medical Conditions and Complications of Pregnancy and Delivery Associated with an Increased Risk of Venous Thromboembolism in Pregnancy 9

Risk Factor

Odds Ratio

Confidence Interval

Medical conditions Heart disease

7.1 6.2, 8.3 Sickle cell disease

1.7 1.4, 2.1 Complications of pregnancy and delivery Multiple gestation

1.6 1.2, 2.1 Hyperemesis

2.5 2.0, 3.2 Fluid and electrolyte imbalance

4.9 4.1, 5.9 Antepartum hemorrhage

2.3 1.8, 2.8 Cesarean delivery

2.1 1.8, 2.4 Postpartum infection

4.1 2.9, 5.7 Postpartum hemorrhage

1.3 1.1, 1.6 Transfusion

1.41 (1.14, 1.75) and for the prothrombin gene mutation of

20 1.72 (1.27, 2.31). Evaluation of the Woman In a separate study, protein C and S

with a History of Thrombosis

deficiencies were found to confer only a slightly increased

Ideally, evaluation of the woman with a history of throm- deficiency was found to confer approximately a twofold in-

risk of recurrence [OR 1.4 (0.9, 2.2)], 21 but antithrombin

bosis should occur before conception, or at least early in

pregnancy. At the time of the evaluation, the clinician firmed the findings of Christiansen and coworkers who also

creased risk of recurrence [OR 1.9 (1.0, 3.9)]. 21 This con-

obtains a history, reviewing any pertinent discharge sum- found a twofold increased risk of recurrence with antithrom-

maries, reports of imaging studies and laboratory reports,

and makes recommendations. In most cases, women can for factor V Leiden, homozygosity for the prothrombin gene

bin deficiency [OR 1.8 (0.9, 3.7)]. 22 Although homozygosity

be counseled that, although their history puts them at an mutation, and combined heterozygosity for both factors are

increased risk for recurrent thrombosis and, if they have associated with a high risk of venous thromboembolism, it is

an underlying hypercoagulable state, an increased risk of not clear whether they also confer an increased risk of recur-

poor pregnancy outcome, these risks are manageable and rent thrombosis. Results are conflicting. 22-24

can be reduced with anticoagulation. Women with throm- boembolic conditions that place them at a high risk of

Brill-Edwards and coworkers 13 and Pabinger and co-

maternal mortality may be best served by avoiding preg- workers found that thrombophilia conferred an increased nancy. These conditions include mechanical heart risk of recurrent venous thromboembolism in pregnancy valves, 30 chronic thromboembolic pulmonary hyperten- and the postpartum period, but De Stefano and coworkers

sion, a history of recurrent thrombosis while fully antico- Nonetheless, any thrombophilic condition that

did not. 15

agulated, and a history of myocardial infarction. confers an increased risk of primary venous thromboem- Usually, women with a history of thrombosis will re- bolism above the background risk of recurrence in preg-

ceive anticoagulation during pregnancy. Women who are nancy of 2.4% to 12.2% will likely confer an increased risk

on lifelong anticoagulation will be continued on full anti- of recurrent thrombosis. This would be true for antithrom-

coagulation. They should be counseled about the terato- bin deficiency where the absolute risk of venous thrombo-

genic effects of warfarin and offered the opportunity to be embolism in pregnancy has been reported to be as high as

converted to low-molecular-weight heparin before con- the antiphospholipid syndrome where

40% to 68%, 25-27

ception. This can be done in collaboration with the phy- sician who prescribes the patient’s anticoagulation.

the absolute risk has been reported to be as high as 30%, 28

and homozygosity for factor V Leiden where the risk has Women who have not had a complete thrombophilia

workup should be offered appropriate testing. Whereas erozygosity, for the MTHFR C677T polymorphism does

been estimated to be 32%. 29 Homozygosity, let alone het-

the results of thrombophilia testing will not alter the gen- not confer any increased risk of venous thromboembolism

eral recommendation for anticoagulation in pregnancy, in pregnancy 29 and, therefore, would not be expected to

the results may alter the intensity of anticoagulation that is increase the risk of recurrent events.

prescribed.

A.H. James et al.

Testing for Thrombophilia

rent thrombosis in pregnancy, the risk of recurrent thrombo- embolism is significantly reduced in women who receive

Testing should include assays for both antiphospholipid an-

thromboprophylaxis. 13,14,16,17

tibodies and inherited thrombophilia. Tests for inherited Women with a history of recurrent thrombosis will likely thrombophilia should include assays for antithrombin (III),

be on lifelong anticoagulation and, because of warfarin’s ef- protein C and protein S deficiency, as well as tests for factor V

fects on the fetus, will require conversion from warfarin to Leiden and the prothrombin gene G20210A mutation. Since

unfractionated or low-molecular-weight heparin. protein S activity levels fall during pregnancy, a cutoff of 35%

is suggested. 31,32 Antithrombin (III) 33-38 and protein C 39-42 levels do not change significantly during pregnancy, so lab-

Options for

oratory reference values can be used. Hyperhomocysteine-

Anticoagulation

mia is associated with thrombosis and possibly with poor pregnancy outcome. Treatment of hyperhomocysteinemia is

during Pregnancy

Unique aspects of anticoagulation in pregnancy include both of adequate folate levels, the methylene tetrahydrofolate re-

with folic acid, vitamin B12, and vitamin B6. 32 In the absence

maternal and fetal issues. During pregnancy, there is an in- ductase (MTHFR) C677T polymorphism can result in ele-

43 crease in blood volume of 40% to 50% 46 vated homocysteine levels, and an increase in but testing for the MTHFR the volume of distribution. An increase in glomerular filtra- C677T polymorphism is not recommended, since even ho-

tion 46 results in increased renal excretion of drugs eliminated mozygosity for the polymorphism does not appear to be as-

by this route. Additionally, there is an increase in protein sociated with an increased risk of thrombosis or poor preg-

29 nancy outcome. binding of heparin. Since 45% of pregnancies are unin- There is insufficient information on other tended, 47 many women do not realize they are pregnant dur- polymorphisms for genes in the folate metabolism pathway

ing the critical period for organogenesis, which is the 4th to to make specific testing recommendations. Even if the poly-

8th weeks after conception. 48 Warfarin taken during this pe- morphism were present, the treatment for hyperhomocys-

riod is associated with a 14.6% to 56% reported risk of mis-

carriage, 49-55 and carries up to a 30% risk of congenital anom- can be adequately supplemented with prenatal vitamins. The

teinemia is folic acid, vitamin B12, and vitamin B6, 32 which

alies. 49-51,53,55-58 Placental transfer of warfarin later in 4G/5G PAI-1 polymorphism was associated with poor preg-

pregnancy can result in fetal bleeding 58,59 nancy outcome in one retrospective study, 44

or still-

birth. 49,51,53,54 Long-term sequelae include a 14% reported studied sufficiently to be included in testing.

but has not been

risk of adverse neurological outcome 60 and a 4% reported Tests for antiphospholipid antibodies include the lupus

risk of low intelligence quotient (IQ). 60 anticoagulant, anticardiolipin antibodies, and anti-␤2 glyco-

The preferred agents for anticoagulation in pregnancy are protein I antibodies. The addition of anti-␤2 glycoprotein I

heparin compounds. 61 Neither heparin 62-64 nor low-molecu- antibodies to the lupus anticoagulant and anticardiolipin an-

lar-weight heparin 63,64 crosses the placenta, and both are tibodies is recommended in an international consensus state-

considered safe in pregnancy. 17,65 Disadvantages of unfrac- ment to increase the sensitivity of the assays for the diagnosis

45 of the antiphospholipid syndrome. tionated heparin include the necessity of parenteral adminis- tration, a 2% risk of major bleeding, 65 a 2% to 36% risk of In summary, the recommended tests are:

reduced bone density, 66-68 a 2% risk of vertebral fracture, 69

● Lupus anticoagulant, and a risk of heparin-induced thrombocytopenia (HIT). ● Anticardiolipin antibodies,

Although the risk of HIT, a life- and limb-threatening com- ● Anti-␤2 glycoprotein I antibodies,

plication of heparin therapy, is low in pregnancy, and may be

● Activated protein C resistance with factor V Leiden if lower than in nonpregnant patients, the actual risk is un- known. abnormal, 61

● Prothrombin G20210A polymorphism, There are few comparative studies in pregnancy, but in ● Protein C,

nonpregnant patients, low-molecular-weight heparin has ● Protein S, and

been associated with fewer side effects than unfractionated

● Antithrombin (III). heparin. Although parenteral administration is still re- quired, potential advantages of low-molecular-weight hepa- rin over unfractionated heparin are less bleeding, a more

Rationale for

predictable response, a lower risk of HIT, a longer half-life,

Thromboprophylaxis in Women 61 and maybe less bone loss. However, in a recently completed

with a History of Thrombosis randomized trial of low-dose unfractionated heparin versus

enoxaparin for thromboprophylaxis in pregnancy, the inci-

Pregnancy increases the risk of thrombosis fourfold, 5 includ-

dence of clinically significant bone loss was 2% to 2.5% and

was no different in women who took unfractionated heparin are not on lifelong anticoagulation will likely require antico-

ing women who have a history of thrombosis. 11 Women who

compared with those who took enoxaparin. 68 Another study agulation during pregnancy, or, at a minimum, during the

found that bone loss in women who took low-molecular- postpartum period. Although there are no randomized trials

weight heparin was approximately 4%, no different than of anticoagulation versus placebo for the prevention of recur-

bone loss in controls. 71 A definite advantage of enoxaparin,

Thromboembolism in pregnancy 171

Table 3 Protocols for Thromboprophylaxis in Pregnancy 61,93

Bates et al., 2004 61 Duke Protocol 93

Unfractionated Heparin Mini-dose “low dose”

5000 U sc q 12 hrs

5000 U sc q 12hrs <8 weeks 7500 U sc q 12 hrs 8-28 weeks 10,000 U sc q 12 hrs >28 weeks

Moderate-dose “low dose”

q 12 hrs to target anti-factor Xa level of

q 8 or12 hrs to target mid-interval aPTT in

therapeutic range Adjusted dose “full dose”

0.1-0.3 U/ml

q12 hrs to target mid-interval aPTT in

therapeutic range

Low-Molecular-Weight Heparin Prophylactic dose “low dose”

Enoxaparin 40 mg qd

Enoxaparin 40 mg qd or 30 mg bid before

Dalteparin 5000 U qd

28 weeks then

Enoxaparin 40 mg bid after 28 weeks Weight-adjusted dose “full dose” Enoxaparin 1 mg/kg bid or 1.5 mg/kg qd

Tinzaparin 4500 U qd

Enoxaparin 1 mg/kg bid with target of

Dalteparin 100 U/kg q 12 hrs or 200 U/kg

antifactor Xa level of 0.5-1.0

1 24 hrs Tinzaparin 175 mg U/kg qd

and probably other low-molecular-weight heparins, over un- thrombosis. Although in one series women with transient fractionated heparin is less bruising at injection sites. 72 A risk factors had a rate of recurrence similar to that of other

disadvantage of low-molecular-weight heparin is that it is women with a history of thrombosis, 14 close observation (as- more expensive. Also, its longer half-life may be a problem at

sessment of signs and symptoms of thrombosis at routine the time of delivery.

prenatal visits) may be an option for women with a history of Long-term therapy with fondaparinux, a new selective fac-

thrombosis in the setting of transient risk factors such as tor Xa inhibitor, may result in less bone loss than either

injury or immobility. 61 Nonetheless, if these women do not

receive anticoagulation during pregnancy, they should be on the use of fondaparinux in pregnancy are limited. Al-

unfractionated or low-molecular-weight heparin, 73 but data

considered for thromboprophylaxis during the first 2 to 6

though Lagrange and coworkers 74 observed no transplacen-

weeks postpartum.

tal passage of fondaparinux using a perfused cotyledon There are few protocols for thromboprophylaxis of arterial

thromboembolism. Currently, there is no consensus regard- sage of fondaparinux in five women who took it for 1 to 101

model, Dempfle and coworkers 75 found transplacental pas-

ing the best protocol for women with a history of stroke 78 or days because of heparin allergy. Antifactor Xa levels in um-

myocardial infarction. Outside of pregnancy, most of these bilical cord plasma of newborns, however, were found to be

women are on an antiplatelet agent. It is our practice to dis- only one-tenth the concentration of maternal plasma, a con-

continue full-dose antiplatelet agents and prescribe aspirin centration well below that required for effective anticoagula-

81 mg per day along with low-dose unfractionated or low- tion. 75 Nonetheless, at the present time, there are insufficient

molecular-weight heparin to counteract the hypercoagulabil- data to justify the routine use of fondaparinux in pregnancy,

ity of pregnancy.

but fondaparinux is probably still the anticoagulant of choice in cases of severe cutaneous allergies or heparin-induced thrombocytopenia in pregnancy. 75,76

Initiating Anticoagulation during Pregnancy

Protocols for Anticoagulation

Normal pregnancy is accompanied by increased concentra-

in Pregnancy for Women

tions of factors VII, VIII, X, and von Willebrand factor and by

pronounced increases in fibrinogen. 1 with a History of Thrombosis Factors II, V, and IX are

relatively unchanged. 1 Free protein S, the active, unbound Protocols for prevention of recurrent venous thromboembo-

form, is decreased during pregnancy secondary to increased lism are presented in Table 3 . Full-dose (adjusted dose) an-

levels of its binding protein, the complement component ticoagulation is recommended 61,77 for women with either a

C4b. 1 Plasminogen activator inhibitor type 1 (PAI-1) levels need for life-long anticoagulation or antiphospholipid syn-

are increased fivefold. 1 Levels of PAI-2, produced by the pla- drome with a history of thrombosis. Full-dose (adjusted

centa, increase dramatically during the third trimester. 2 dose) or an intermediate or moderate dose is recom-

These changes, which may not return to baseline until more mended 61,77 for women with either antithrombin (III) defi-

than 8 weeks postpartum, 1 begin with conception. So does ciency or homozygosity for the factor V Leiden mutation, the

the risk of thrombosis. 10,14,79

prothrombin gene G20210A mutation, or compound het- Women on lifelong anticoagulation should be converted erozygosity for both mutations. Low-dose anticoagulation is

from warfarin to low-molecular-weight heparin before preg- recommended 32,61 for women with a history of unprovoked

nancy or as soon as possible after conception. The problem

A.H. James et al.

with conversion before pregnancy is the inconvenience and incision at the time of cesarean delivery. A vertical midline discomfort of parenteral administration of heparins and the

incision, which is made in a watershed area and does not risks associated with their long-term use. The problem with

involve dissection of the rectus muscles off of the fascia, may conversion after conception is that the half-life of warfarin is

be associated with less bleeding.

36 to 42 hours 80 and it may remain in the maternal circula- tion for several days, increasing the risk of miscarriage and congenital anomalies. Only a few women are candidates for

Postpartum Management

warfarin rather than heparins during pregnancy. Candidates Pneumatic compression devices are left in place until the

include women with mechanical heart valves 30 and certain

patient is ambulatory and until anticoagulation is restarted other unusual conditions. after delivery. To minimize bleeding complications, resump- Women who are not on lifelong anticoagulation, but are tion of anticoagulation should be postponed until 12 hours candidates for thromboprophylaxis in pregnancy, should after vaginal delivery, 12 hours after epidural removal, or 24 start soon after conception. An exception is women who will hours after cesarean delivery. After the risk of postpartum

be undergoing ovulation induction. Because hormone ther- hemorrhage has lessened (2 or more weeks after delivery), apy, including clomiphene, increases the risk of thrombo-

unless a woman prefers to remain on unfractionated or low- sis, 81 these women should begin anticoagulation at the time molecular-weight heparin, she may be bridged to warfarin they start ovulation induction.

for the remainder of the 6-week postpartum period. Women Because HIT manifests within the first 5 to 15 days of

82 exposure to heparins, who have had a thrombotic event during the current preg- platelet counts may be monitored for nancy should remain on warfarin for at least another 3 to 6

the first 2 to 3 weeks after initiation of therapy. Although

83 platelet counts usually drop by 10% in pregnancy months after delivery. Women on lifelong anticoagulation and

83 thrombocytopenia affects up to 10% of all pregnancies, will remain on warfarin indefinitely. Although warfarin is HIT contraindicated during pregnancy, it is not contraindicated

still must be considered in women who develop thrombocy- during breastfeeding. In a study of the transfer of warfarin topenia after starting heparin or low-molecular-weight hep-

into breast milk, less than 25 ng of warfarin was detected per arin.

mL. 86 The American Academy of Pediatrics Committee on Drugs supports breastfeeding for women who take

warfarin. Management 87

At the present time, since there are no data about whether

at the Time of Delivery

fondaparinux enters breast milk, fondaparinux should not be Women are often converted from low-molecular-weight hep-

used routinely in women who are breastfeeding, but arin to unfractionated heparin at 36 to 37 weeks of gestation

fondaparinux is an option for women who are not breastfeed- or sooner if there is preterm labor, preeclampsia, fetal (intra-

ing. Fondaparinux, a selective factor Xa inhibitor, may be uterine) growth restriction, oligohydramnios, or other evi-

used until a woman is bridged to warfarin. For women who dence of imminent delivery. The purpose of converting

have to be fully anticoagulated for only 6 weeks postpartum, women to the shorter-acting unfractionated heparin has less

an advantage of fondaparinux over warfarin is that it does not to do with any risk of bleeding at the time of delivery, but

require monitoring. In addition, it requires only daily, as rather the rare possibility of an epidural or spinal hematoma

opposed to twice-daily, dosing.

Women who are not breastfeeding and who will be on ologists usually will not place a regional anesthetic if a

with regional anesthesia. 84 Due to this possibility, anesthesi-

lifelong anticoagulation should be allowed to take estrogen- woman has received low-molecular-weight heparin within

containing contraceptives, but these are contraindicated for

12 to 24 hours. Because of the benefits of regional analgesia the woman who will discontinue anticoagulation at 6 weeks and anesthesia over other analgesia and anesthesia for labor

postpartum. Although progestins may increase the levels of and delivery, 84

certain coagulation factors, progestin-only contraceptives every effort should be made to ensure that a have not been found to increase the risk of thrombosis and woman has not received low-molecular-weight heparin

are, therefore, generally allowed. 88

within 12 to 24 hours of needing a regional anesthetic. De- pending on the risk of thrombosis, unfractionated heparin should be held for 6 to 24 hours before delivery. Should a

Fetal Surveillance

woman go into labor while taking unfractionated heparin, the heparin will usually clear within 6 hours. Reversal of

Hypercoagulability, as manifested by a history of thrombo- heparin is rarely required and is not indicated for low-dose

embolism, may alter normal hemostasis and increase the like- heparin. Although the use of pneumatic compression devices

lihood of poor pregnancy outcome, including abruption, for the prevention of pregnancy-related thrombosis has not

stillbirth, fetal growth restriction, and preeclampsia. 29 Al-

though anticoagulation may improve pregnancy outcome, 89 placement of pneumatic compression devices in labor or be-

been studied, extrapolating from perioperative data, 85 the

a plan for fetal surveillance should still be implemented. 90 fore cesarean delivery is recommended. In the woman who is

This would include periodic ultrasounds for fetal growth, being aggressively anticoagulated, consideration should be

fetal testing in the last month or two of pregnancy, and con- given to entering the abdomen through a vertical midline

sideration of delivery by 39 weeks gestation.

Thromboembolism in pregnancy 173

Implications for

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