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Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) FREE TO VIEW

Shannon M. Bates, MDCM, MSc, Chair; Ian A. Greer, MD; Ingrid Pabinger, MD; Shoshanna Sofaer, DrPh; Jack Hirsh, CM, MD, FCCP
Author and Funding Information

*From the Department of Medicine (Dr. Bates), McMaster University and Henderson Research Centre, Hamilton, ON, Canada; Hull York Medical School (Dr. Greer), The University of York, York, UK; Department of Internal Medicine (Dr. Pabinger), Medical University of Vienna, Vienna, Austria; School of Public Affairs, Baruch College (Dr. Sofaer), New York, NY; and Henderson Research Centre (Dr. Hirsh), Hamilton, ON, Canada.

Correspondence to: Shannon M. Bates, MDCM, FRCP(C), HSC 3W11, McMaster University Medical Centre, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada; e-mail: batesm@mcmaster.ca



Chest. 2008;133(6_suppl):844S-886S. doi:10.1378/chest.08-0761
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This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C.

Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C].

For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C).

We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A].

For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).

When describing the various regimens of UFH and LMWH, we will use the following short forms:

  • –Prophylactic UFH: UFH 5,000 U subcutaneously q12h.

  • –Intermediate-dose UFH: UFH subcutaneously q12h in doses adjusted to target an anti-Xa level of 0.1 to 0.3 U/mL.

  • –Adjusted-dose UFH: UFH subcutaneously q12h in doses adjusted to target a mid-interval activated partial thromboplastin time (aPTT) into the therapeutic range.

  • –Prophylactic LMWH: eg, dalteparin 5,000 U subcutaneously q24h, tinzaparin 4,500 U subcutaneously q24h, or enoxaparin 40 mg subcutaneously q24h (although at extremes of body weight modification of dose may be required).

  • –Intermediate-dose LMWH: eg, dalteparin 5,000 U subcutaneously q12h or enoxaparin 40 mg subcutaneously q12h.

  • –Adjusted-dose LMWH: weight-adjusted, full treatment doses of LMWH, given once or twice daily (eg, dalteparin 200 U/kg or tinzaparin 175 U/kg qd or dalteparin 100 U/kg q12h or enoxaparin 1 mg/kg q12h).

  • –Postpartum anticoagulants: vitamin K antagonists for 4 to 6 weeks with a target INR of 2.0 to 3.0, with initial UFH or LMWH overlap until the INR is ≥ 2.0, or prophylactic LMWH for 4 to 6 weeks.

  • –In addition, the term surveillance refers to clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep vein thrombosis (DVT) or pulmonary embolism (PE).

2.1 Vitamin K Antagonist Exposure In Utero

2.1.1. For women receiving anticoagulation for the management of VTE who become pregnant, we recommend that vitamin K antagonists be substituted with UFH or LMWH (Grade 1A).

2.1.2. For women with mechanical valves who become pregnant, we suggest either adjusted-dose bid LMWH or UFH throughout pregnancy or adjusted-dose bid LMWH or UFH until the thirteenth week with substitution by vitamin K antagonists until LMWH or UFH are resumed close to delivery (Grade 1C). In pregnant women with high-risk mechanical valves (eg, older generation valve in the mitral position or history of thromboembolism), we suggest the use of oral anticoagulants over heparin (Grade 2C).

Underlying values and preferences: The suggestion to utilize vitamin K antagonists during the first 12 weeks of pregnancy places similar value on avoiding maternal thromboembolic complications as on avoiding fetal risks.

2.2 Management of Women Receiving Long-term Vitamin K Antagonists Who Are Considering Pregnancy

2.2.1. For women requiring long-term vitamin K antagonists who are attempting pregnancy and are candidates for UFH or LMWH substitution, we suggest performing frequent pregnancy tests and substituting UFH or LMWH for vitamin K antagonists when pregnancy is achieved (Grade 2C).

Underlying values and preferences: This recommendation places a higher value on avoiding the risks, inconvenience, and costs of UFH or LMWH therapy of uncertain duration while awaiting pregnancy compared to minimizing the risks of early miscarriage associated with vitamin K antagonist therapy.

3.0 Use of Anticoagulants in Nursing Women

3.0.1. For lactating women using warfarin or UFH who wish to breastfeed, we recommend continuing these medications (Grade 1A).

3.0.2. For lactating women using LMWH, danaparoid, or r-hirudin who wish to breastfeed, we suggest continuing these medications (Grade 2C).

3.0.3. For breast-feeding women, we suggest alternative anticoagulants rather than pentasaccharides (Grade 2C).

4.2 LMWH Therapy

4.2.1. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C).

5.1 Risk of VTE Following Cesarean Section

5.1.1. We suggest that a thrombosis risk assessment be carried out in all women undergoing cesarean section to determine the need for thromboprophylaxis (Grade 2C).

5.1.2. In patients without additional thrombosis risk factors undergoing cesarean section, we recommend against the use of specific thromboprophylaxis other than early mobilization (Grade 1B).

5.2 Thromboprophylaxis Following Cesarean Section

5.2.1. For women considered at increased risk of VTE after cesarean section because of the presence of at least one risk factor in addition to pregnancy and cesarean section, we suggest pharmacologic thromboprophylaxis (prophylactic LMWH or UFH) or mechanical prophylaxis (graduated compression stockings or intermittent pneumatic compression) while in hospital following delivery (Grade 2C).

5.2.2. For women with multiple additional risk factors for thromboembolism who are undergoing cesarean section and are considered to be at very high risk of VTE, we suggest that pharmacologic prophylaxis be combined with the use of graduated compression stockings and/or intermittent pneumatic compression (Grade 2C).

5.2.3. For selected high-risk patients in whom significant risk factors persist following delivery, we suggest extended prophylaxis (up to 4 to 6 after delivery) following discharge from the hospital (Grade 2C).

6.1 Treatment of VTE During Pregnancy

6.1.1. For pregnant women with acute VTE, we recommend initial therapy with either adjusted-dose subcutaneous LMWH or adjusted-dose UFH (IV bolus, followed by a continuous infusion to maintain the aPTT within the therapeutic range or subcutaneous therapy adjusted to maintain the aPTT 6 h after injection into the therapeutic aPTT range) for at least 5 days (Grade 1A).

6.1.2. For pregnant women with acute VTE, after initial therapy, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B).

6.1.3. For pregnant women with acute VTE, we suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 6 months) [Grade 2C].

6.1.4. For pregnant women receiving adjusted-dose LMWH or UFH therapy, we recommend discontinuation of the heparin at least 24 h prior to elective induction of labor (Grade 1C).

7.2 Prevention of Recurrent VTE in Pregnant Women

7.2.1. For pregnant women with a single episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C).

7.2.2. If the transient risk factor associated with a previous VTE event is pregnancy or estrogen related, we suggest antepartum clinical surveillance or prophylaxis (prophylactic LMWH/UFH or intermediate-dose LMWH/UFH) plus postpartum prophylaxis, rather than routine care (Grade 2C).

7.2.3. For pregnant women with a single idiopathic episode of VTE but without thrombophilia and who are not receiving long-term anticoagulants, we recommend one of the following, rather than routine care or adjusted-dose anticoagulation: prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C).

7.2.4. For pregnant women with thrombophilia (confirmed laboratory abnormality) who have had a single prior episode of VTE and are not receiving long-term anticoagulants, we recommend one of the following, rather than routine care or adjusted-dose anticoagulation: antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH or clinical surveillance throughout pregnancy; plus post-partum anticoagulants (Grade 1C).

7.2.5. For women with “higher risk” thrombophilias (eg, antithrombin deficiency, persistent positivity for the presence of antiphospholipid antibodies; compound heterozygosity for prothrombin G20210A variant and factor V Leiden or homozygosity for these conditions) who have had a single prior episode of VTE and are not receiving long-term anticoagulants, we suggest, in addition to postpartum prophylaxis, antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C).

7.2.6. For pregnant women with multiple (≥ 2) episodes of VTE not receiving long-term anticoagulants, we suggest antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or prophylactic, intermediate or adjusted-dose UFH followed by postpartum anticoagulants rather than clinical surveillance (Grade 2C).

7.2.7. For pregnant women receiving long-term anticoagulants for prior VTE, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C).

7.2.8. For all pregnant women with previous DVT, we suggest the use of graduated elastic compression stockings both antepartum and postpartum (Grade 2C).

Underlying values and preferences: This recommendation places a high value on uncertain incremental benefit with stockings, and a low value on avoiding discomfort and inconvenience.

8.1 Risk of Pregnancy-Related VTE in Women With Thrombophilia

8.1.1. For pregnant patients with thrombophilia but no prior VTE, we recommend that physicians do not use routine pharmacologic antepartum prophylaxis but instead perform an individualized risk assessment (Grade 1C).

8.2 Prevention of Pregnancy-Related VTE in Women With Thrombophilia

8.2.1. For pregnant women with no history of VTE but antithrombin deficiency, we suggest antepartum and postpartum prophylaxis (Grade 2C).

8.2.2. For all other pregnant women with thrombophilia and no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants (Grade 2C).

9.1 Risk of Pregnancy Complications in Women With Thrombophilia

9.1.1. For women with recurrent early pregnancy loss (three or more miscarriages) or unexplained late pregnancy loss, we recommend screening for APLAs (Grade 1A).

9.1.2. For women with severe or recurrent preeclampsia or IUGR, we suggest screening for APLAs (Grade 2C).

9.2 Prevention of Pregnancy Complications in Women With Thrombophilia

9.2.1. For women with APLAs and recurrent (three or more) pregnancy loss or late pregnancy loss and no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B).

10.1 Prevention of Recurrent Pre-eclampsia in Women With No Thrombophilia

10.1.1. For women considered high risk for preeclampsia, we recommend low-dose aspirin therapy throughout pregnancy (Grade 1B).

10.1.2. For women with a history of preeclampsia, we suggest that UFH and LMWH should not be used as prophylaxis in subsequent pregnancies (Grade 2C).

11.1 Anticoagulant Management of Mechanical Prosthetic Valves in Pregnant Women

11.1.1. For pregnant women with mechanical heart valves, we recommend that the decision about anticoagulant management during pregnancy include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism, and that the decision should also be influenced strongly by patient preferences (Grade 1C).

11.1.2. For pregnant women with mechanical heart valves, we recommend one of the following anticoagulant regimens in preference to no anticoagulation:

(a) adjusted-dose bid LMWH throughout pregnancy (Grade 1C). We suggest that doses be adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h after subcutaneous injection, (Grade 2C) or

(b) adjusted-dose UFH throughout pregnancy administered subcutaneously q12h in doses adjusted to keep the mid-interval aPTT at least twice control or attain an anti-Xa heparin level of 0.35 to 0.70 U/mL (Grade 1C), or

(c) UFH or LMWH (as above) until the thirteenth week with warfarin substitution until close to delivery when UFH or LMWH is resumed (Grade 1C).

In women judged to be at very high risk of thromboembolism in whom concerns exist about the efficacy and safety of UFH or LMWH as dosed above (eg, older-generation prosthesis in the mitral position or history of thromboembolism), we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH (as above) close to delivery, rather than one of the regimens above, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).

Underlying values and preferences: In contrast to our other recommendations, which place a high value on avoiding fetal risk, the recommendation for women at very high risk of thromboembolism places equal value on avoiding maternal complications.

Remark: For all the recommendations above, usual long-term anticoagulants should be resumed postpartum.

11.1.3 For pregnant women with prosthetic valves at high risk of thromboembolism, we recommend the addition of low-dose aspirin, 75 to 100 mg/d (Grade 2C).

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of venous thromboembolism (VTE), for the prevention and treatment of systemic embolism in patients with mechanical heart valves and, in combination with aspirin, for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies (APLAs). The use of anticoagulation for prevention of pregnancy complications in women with hereditary thrombophilia is becoming more frequent. The use of anticoagulant therapy during pregnancy is challenging because of the potential for fetal, as well as maternal, complications. Given the paucity of data regarding the efficacy of anticoagulants during pregnancy, recommendations about their use in pregnant women are based largely on extrapolations from data from nonpregnant patients, from case reports, and from case series of pregnant patients.

Since our last review, investigators have published new information concerning the risk of VTE in pregnant women with thrombophilia, management of pregnant women with prior VTE, the treatment of VTE in pregnancy, the safety of low-molecular-weight heparin (LMWH) during pregnancy, the difficulties of managing pregnant women with mechanical heart valves, as well as the relation between thrombophilia and pregnancy complications and the use of anticoagulant therapy in this setting. Unfortunately, the additional publications have not achieved a dramatic improvement in the quality of available evidence.

In this chapter, we will review the management of thrombophilia, thromboembolic complications, and anticoagulant therapy during pregnancy, with particular emphasis on important new studies. Table 1 describes the search and eligibility criteria for the studies considered in each section of the recommendations that follow. Recommendations are based on the revised American College of Chest Physicians grades of recommendation.1

In considering women’s choices regarding risks and benefits of antithrombotic therapy in pregnancy, two special considerations are of particular importance. First, treatment decisions during pregnancy and nursing have implications not only for the health and life of the mother but for the health and life of the fetus. Second, many women prefer to see pregnancy as a normal part of a healthy life course, rather than as a medical condition. On the background of these considerations, many factors—including the frequency and type of medication administration; pain, discomfort and possible side effects; and the need, frequency and type of testing associated with a given regimen—will affect choices.

While we are unaware of any research specifically addressing women’s preferences regarding antithrombotic therapy in pregnancy, anecdotal evidence suggests that many, though not all women, give higher priority to the impact of any treatment on the health of their unborn baby than to effects on themselves. For example, consider the decision regarding heparin, typically administered through injection, vs coumarin derivatives, administered orally, as antithrombotic therapy during pregnancy. Our recommendations reflect a belief that most women will place a low value on avoiding the pain, cost, and inconvenience of heparin therapy in order to avoid the small risk of even a minor abnormality in their child.

Recommendations in this chapter, therefore, reflect our belief that although average women considering antithrombotic therapy will also want to avoid medicalizing their pregnancy, they will put an extremely high value on avoiding fetal risk. For women who do not share these values, even some of the strong recommendations in this chapter may not apply. For most recommendations, optimal decision making will require that physicians educate patients about their treatment options, including their relative effectiveness, the consequences for both mother and baby, the method of administration and monitoring, the likely side effects, and the uncertainty associated with the estimates of all these effects. Once educated, women can participate in the selection of the treatment regimen that best matches their preferences and values.

The antithrombotics currently available for the prevention and treatment of venous and arterial thromboembolism include heparin and heparin-like compounds (unfractionated heparin [UFH], LMWH, pentasaccharides, and heparinoids), coumarin derivatives, direct thrombin inhibitors, and antiplatelet agents. When considering antithrombotic use during pregnancy, the risks of fetal teratogenicity and bleeding should be borne in mind.

2.1 Vitamin K Antagonist Exposure In Utero

Vitamin K antagonists cross the placenta and have the potential to cause fetal wastage, bleeding in the fetus, and teratogenicity.24 In a systematic review of the literature examining fetal and maternal outcomes of pregnant women with prosthetic valves,4 Chan and colleagues provided pooled estimates of risks associated with the following commonly used approaches: (1) use of vitamin K antagonists throughout pregnancy, (2) replacement of vitamin K antagonists with UFH from 6 to 12 weeks; and (3) UFH use throughout pregnancy. The authors found that the use of vitamin K antagonists throughout pregnancy was associated with congenital anomalies in 35 of 549 live births (6.4%; 95% confidence interval [CI], 4.6–8.9%) [Table 2 ].,4The most common fetal anomaly seen was characteristic coumarin embryopathy, consisting of nasal hypoplasia and/or stippled epiphyses. Limb hypoplasia has been reported in up to one third of cases of embryopathy.5 Embryopathy typically occurs after in utero exposure to vitamin K antagonists during the first trimester of pregnancy.,3 The magnitude of this risk varies widely among reports with estimates ranging from 0%611 up to 29.6%.12Although the latter estimate is from a relatively large prospective study, it is likely to represent an overestimate because only two infants (5.7%) were described as having classic features of warfarin embryopathy, while the others had minor facial defects or facial bone features suggestive of embryopathy. The results of a recently published multicenter European study in which the pregnancies of 666 consenting women who contacted one of 12 Teratology Information Services between 1988 and 2004 seeking advice about gestational exposure to vitamin K antagonists were prospectively followed up also suggests that the risk of coumarin embryopathy is not high.13 Although the frequency of major birth defects after any first trimester exposure was increased compared to that seen in a control group of women counseled during pregnancy about exposures known to be nonteratogenic (4.8% vs 1.4%, respectively; odds ratio [OR], 3.86, 95% CI, 1.86–8.00), there were only two cases of embryopathy among 356 live births (0.6%). Both of these cases involved exposure to phenprocoumon until at least the end of the first trimester. The substitution of heparin at or prior to 6 weeks appears to eliminate the risk of embryopathy,4 raising the possibility that vitamin K antagonists are safe with regard to embryopathy during the first 6 weeks of gestation, although there is a definite risk of embryopathy if coumarin derivatives are taken between 6 and 12 weeks of gestation.3 Interestingly, in the European multicenter Teratology Information Services study, there were no cases of embryopathy in which vitamin K antagonists were discontinued before week 8 after the first day of the last menstrual period.13

Vitamin K antagonists have also been associated with CNS abnormalities after exposure during any trimester.3 Two patterns of CNS damage have been described: dorsal midline dysplasia (agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy) and ventral-midline dysplasia leading to optic atrophy.3 These complications are likely rare.34 Although one cohort study reported that the use of coumarins during the second and third trimesters was not associated with major risks for abnormalities in growth and long-term development of offspring, the authors noted increased risk of minor neurodevelopmental problems (OR, 1.9; 95% CI, 1.1–3.4) in children exposed to coumarins in the second and third trimesters of pregnancy.14However, the clinical importance of these minor neurodevelopmental problems is uncertain because there were no differences in mean intelligence quotient or performance on tests for reading, spelling, and arithmetic between exposed and nonexposed children.15

In addition, vitamin K antagonists have been associated with fetal wastage4,16 and can cause fetal hemorrhagic complications, likely because the fetal liver is immature and fetal levels of vitamin K dependent coagulation factors are normally low. Fetal coagulopathy is of particular concern at the time of delivery, when the combination of the anticoagulant effect and trauma of delivery can lead to bleeding in the neonate. The risk of delivering an anticoagulated infant can be reduced by substituting UFH or LMWH for vitamin K antagonists approximately 3 weeks prior to planned delivery16and discontinuing these medications shortly before delivery. Others have advocated the use of planned cesarean section at 38 weeks with only a brief (2- to 3-day) interruption of anticoagulant therapy.17 Although this strategy resulted in good neonatal and maternal outcomes, only thirty babies were delivered using this strategy. As well, it should be noted that cesarean section is not without risk and it not routinely recommended for other conditions associated with an increased risk of neonatal intracranial hemorrhage at the time of delivery (eg, immune thrombocytopenia purpura).

Given their potential for deleterious effects on the fetus, vitamin K antagonists should only be used during pregnancy when potential maternal benefits justify potential fetal risks. Although UFH and LMWH are as effective as vitamin K antagonists in the management of VTE (see section 6), vitamin K antagonists may be more effective than these agents in patients with mechanical prosthetic valves. Therefore, after discussing the risks and benefits with the patient, it would be reasonable to use vitamin K antagonists in pregnant women with high-risk valves (discussed in section 11).

Recommendations

2.1.1. For women receiving anticoagulation for the management of VTE who become pregnant, we recommend that vitamin K antagonists be substituted with UFH or LMWH (Grade 1A).

2.1.2. For women with mechanical valves who become pregnant, we suggest either adjusted-dose bid LMWH or UFH throughout pregnancy or adjusted-dose bid LMWH or UFH until the thirteenth week with substitution by vitamin K antagonists until LMWH or UFH are resumed close to delivery (Grade 1C). In pregnant women with high-risk mechanical valves (eg, older-generation valve in the mitral position or history of thromboembolism), in whom concerns exist about the efficacy and safety of UFH or LMWH, we suggest the vitamin K antagonists over heparin with replacement by adjusted-dose bid UFH or LMWH close to delivery (Grade 2C).

Underlying values and preferences: The suggestion to utilize vitamin K antagonists during the first 12 weeks of pregnancy places similar value on avoiding maternal thromboembolic complications as on avoiding fetal risks.

2.2 Management of Women Receiving Long-term Vitamin K Antagonists Who Are Considering Pregnancy

Physicians should counsel women receiving vitamin K antagonist therapy and contemplating pregnancy about the risks of vitamin K antagonist therapy before pregnancy occurs. If pregnancy is still desired, two options can reduce the risk of warfarin embryopathy: (1) performance of frequent pregnancy tests and substitution of adjusted-dose UFH or LMWH for warfarin when pregnancy is achieved; or (2) replacement of vitamin K antagonists with UFH or LMWH before conception is attempted.

Both approaches have limitations. The first assumes that vitamin K antagonists are safe during the first 4 to 6 weeks of gestation. The second increases the duration of exposure to heparin and, therefore, is costly and exposes the patient to a higher risk of complications related to the use of UFH and LMWH. We suggest the first approach because it is convenient and appears to be safe.

Recommendation

2.2.1. For women requiring long-term vitamin K antagonists who are attempting pregnancy and are candidates for UFH or LMWH substitution, we suggest performing frequent pregnancy tests and substituting UFH or LMWH for vitamin K antagonists when pregnancy is achieved (Grade 2C).

Underlying values and preferences: This recommendation places a higher value on avoiding the risks, inconvenience, and costs of UFH or LMWH therapy of uncertain duration while awaiting pregnancy, compared to minimizing the risks of early miscarriage associated with oral anticoagulant therapy.

2.3 UFH Exposure In Utero

UFH does not cross the placenta18 and, therefore, does not have the potential to cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction is possible. Several studies strongly suggest that UFH therapy is safe for the fetus2,19 and should be used as necessary for maternal indications.

2.4 LMWH Exposure in Utero

As determined by measurement of anti-Xa activity in fetal blood, LMWH also does not cross the placenta.2021 There is no evidence of teratogenicity or risk of fetal bleeding.22 Therefore, LMWH is safe anticoagulant choice for the fetus.

2.5 Aspirin Exposure in Utero

Although animal studies have shown that aspirin may increase the risk of congenital anomalies, data from human studies are conflicting. The most compelling data come from a metaanalysis of 14 randomized studies including a total of 12,416 women23 that reported that low-dose (50 to 150 mg/d) aspirin therapy administered during the second and third trimesters of pregnancy to women at risk for preeclampsia was safe for the mother and fetus. The authors of this meta-analysis also reviewed observational studies including > 96,000 pregnancies and found no evidence of teratogenicity or long-term adverse effects of aspirin during pregnancy.23

The safety of aspirin ingestion during the first trimester remains uncertain. Another metaanalysis of eight studies (seven observational and one randomized) that evaluated the risk of congenital anomalies with aspirin exposure during the first trimester found no evidence of an increase in the overall risk of congenital malformations associated with aspirin use, suggesting that aspirin is safe even when used early in pregnancy.24 In this study, however, aspirin use during the first trimester may have been associated with a two-fold increase in the risk for gastroschisis (OR, 2.37; 95% CI, 1.44–3.88), a rare anomaly that occurs in 3 to 6 of every 100,000 births in which the intestines herniate through a congenital defect in the abdominal wall on one side of the umbilical cord.24 However, the reliability of this risk estimate is questionable as the use of other drugs, the type of control subjects selected, and failure to definitively confirm the diagnosis in all patients could have biased these results.

Available evidence suggests that low-dose aspirin during the second and third trimester is safe for the fetus and clinicians should use this agent as necessary for maternal indications. Although the safety of aspirin ingestion during the first trimester remains uncertain, there is no clear evidence of harm to the fetus and, if fetal anomalies are caused by early aspirin exposure, they are very rare. If the indication for aspirin is clear and there is no satisfactory alternative agent, clinicians should offer first-trimester patients aspirin.

2.6 Danaparoid Exposure in Utero

Consistent with investigations of danaparoid placental transfer in pregnant guinea pigs that indicated negligible movement across the placenta,25two case reports in which clinicians used danaparoid to treat heparin-induced thrombocytopenia (HIT) in pregnancy reported no detectable anti-Xa activity in fetal cord plasma.2627 A review of 51 pregnancies in 49 danaparoid-treated patients reported three fetal deaths, but all were associated with maternal complications antedating danaparoid use.28 Thus, the available literature suggests that there is no demonstrable fetal toxicity with maternal danaparoid use. However, the quality of evidence available to support that claim is low.

2.7 Direct Thrombin Inhibitor Exposure in Utero

Investigations have documented placental transfer of r-hirudin in rabbits and rats.2930 Although small numbers of case reports of successful outcomes with r-hirudin use in pregnancy have been published,29,3132 there are insufficient data to evaluate its safety in this setting. The use of direct thrombin inhibitors in pregnant women should be limited to those with severe allergic reactions (including HIT) to heparin who cannot receive danaparoid.

2.8 Pentasaccharide Exposure in Utero

Although no placental passage of fondaparinux was demonstrated in an in vitro human cotyledon model,33anti-factor Xa activity (at approximately one tenth the concentration of maternal plasma) was found in the umbilical cord plasma in newborns of five mothers treated with fondaparinux.34Although there have been reports of the successful use of this agent in pregnant woman,3536 the quality of evidence supporting or recommending against the use of fondaparinux during pregnancy is weak and potential deleterious effects of fondaparinux on the fetus cannot be excluded. Thus, clinicians should avoid the use of fondaparinux during pregnancy whenever possible and reserve its use for those pregnant women with HIT or a history of HIT who cannot receive danaparoid.

2.9 Thrombolysis During Pregnancy

Investigations with 131 I-labeled streptokinase showed minimal transplacental passage37and placental transfer of tissue plasminogen activator, a finding consistent with their large molecular size. Concerns about the use of thrombolytic therapy during pregnancy center on its effect on the placenta (ie, premature labor, placental abruption, fetal demise). Although there have been several reports of successful thrombolysis in pregnancy with no harm to the fetus,39 its safety in this setting is unclear and the use of thrombolytic therapy in pregnancy is best reserved for life-threatening maternal thromboembolism.

Clinicians considering antithrombotic therapy in breast-feeding women must consider risks to the neonate. For most agents, research data are limited. In order for a drug to pose a risk to the breast-fed infant, not only must it be transferred and excreted into breast milk, it must also be absorbed from the infant’s gut. Drugs that are poorly absorbed orally are unlikely to affect the neonate. Lipid soluble drugs with a low molecular weight that are not highly protein bound are more likely to be transferred into breast milk.40

Despite a lack of data suggesting any harmful effect to breast-feeding infants, many obstetricians remain reluctant to prescribe warfarin to lactating women. These concerns might represent extrapolations from warfarin’s fetopathic effects and theoretical concerns that less polar, more lipophilic oral anticoagulants rarely utilized in North America (eg, phenindione and anisindione) might be excreted into breast milk.41Warfarin, the oral anticoagulant prescribed for most patients in North America is polar, nonlipophilic and highly protein-bound. There have been two convincing reports demonstrating that warfarin is not detected in breast milk and does not induce an anticoagulant effect in the breast-fed infant when nursing mothers consume the drug (Table 3 ).43 Therefore, the use of warfarin in women who require postpartum anticoagulant therapy is safe.

Because of its high molecular weight and strong negative charge, UFH does not pass into breast milk and can be safely given to nursing mothers.44In a case series of 15 women receiving 2,500 IU of LMWH after cesarean section, there was evidence of excretion of small amounts of LMWH into the breast milk in 11 patients (Table 3).45 However, given the very low bioavailability of heparin ingested orally, there is unlikely to be any clinically relevant effect on the nursing infant.

Very little is known about the passage of danaparoid into breast milk. A small number of case reports have reported no or very low anti-Xa activity in the breast milk of danaparoid-treated women.29 As danaparoid is not absorbed after oral intake, it is unlikely that any anticoagulanteffect would appear in breastfed infants.

In a single case report, no hirudin was detected in the breast milk of a nursing mother with a therapeutic plasma hirudin level.46 Enteral absorption of r-hirudin appears to be low.30 Therefore, it is unlikely that exposed infants would experience a significant anticoagulant effect, even if small amounts of hirudin appear in breast milk. It is not known whether or to what extent fondaparinux is excreted in breast milk.

Recommendations

3.0.1. For lactating women using warfarin or UFH who wish to breastfeed, we recommend continuing these medications (Grade 1A).

3.0.2. For lactating women using LMWH, danaparoid, or r-hirudin who wish to breastfeed, we suggest continuing these medications (Grade 2C).

3.0.3. For breastfeeding women, we suggest alternative anticoagulants rather than pentasaccharides (Grade 2C).

Maternal complications of anticoagulant therapy are similar to those seen in nonpregnant patients and include bleeding (for all anticoagulants), as well as HIT, heparin-associated osteoporosis, and pain at injection sites for heparin-related compounds.

4.1 UFH Therapy

During pregnancy, UFH is used for both prevention and treatment of thromboembolism. Prophylactic UFH is typically administered subcutaneously two to three times per day either in fixed doses or doses adjusted to a target a specific anti-Xa UFH level (prophylactic- or intermediate-dose UFH). When used in therapeutic doses, UFH is administered either IV by continuous infusion with dosage adjustment to achieve a target therapeutic activated partial thromboplastin time (aPTT) or by twice-daily subcutaneous injection in doses sufficient to achieve a therapeutic aPTT 6 h after injection. During pregnancy, the aPTT response to UFH is often attenuated, likely because of increased levels of heparin-binding proteins, factor VIII, and fibrinogen.47 This causes a “blunting” of the aPTT response relative to the heparin level and a resultant increased requirement for UFH. Consequently, the use of an aPTT range that corresponds to therapeutic heparin levels in nonpregnant patients might result in higher dosing (and heparin levels) in pregnant women than in nonpregnant patients. However, it is not clear whether this translates into excessive bleeding because the reported rates of bleeding using the standard aPTT range appear to be low. In a cohort study,19 the rate of major bleeding in pregnant women treated with UFH was 2%, which is consistent with reported rates of bleeding associated with heparin therapy in nonpregnant patients48and with warfarin therapy49when used for the treatment of deep vein thrombosis (DVT). Therapeutic doses of subcutaneous UFH can cause a persistent anticoagulant effect, which can complicate its use prior to delivery. In a small cohort study, prolongation of the aPTT persisted for up to 28 h after the last injection of adjusted-dose subcutaneous heparin.50 The mechanism for this prolonged effect is unclear. A prolonged anticoagulant effect with IV-administered UFH has not been noted in pregnant women; however, data with this method of administration in pregnancy are scarce.

Approximately 3% of nonpregnant patients receiving UFH have immune IgG-mediated thrombocytopenia (HIT), which may lead to extension of preexisting thrombosis or new onset of venous or arterial thrombosis.51Although it is reasonable to expect that the frequency of HIT in pregnant and postpartum women exposed to UFH would be similar, insufficient data exist to confirm or refute this observation. HIT should be differentiated from an early, benign, transient thrombocytopenia that can occur with initiation of UFH and from pregnancy-specific disorders including incidental thrombocytopenia of pregnancy52 and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Diagnosing HIT is often difficult because immune assays are nonspecific and the more specific platelet-activation assays are not widely available and turnaround times are slow. HIT 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.,51 The diagnosis, prevention, and treatment of HIT are described in the chapter “Treatment and Prevention of Heparin-Induced Thrombocytopenia.” In pregnant women who develop HIT and require ongoing anticoagulant therapy, use of the heparinoid, danaparoid sodium, is recommended because it is an effective antithrombotic agent53 that does not cross the placenta2527 and has low cross-reactivity with UFH54 and, therefore, rarely produces HIT.

Long-term treatment with UFH has been reported to cause osteoporosis in both laboratory animals and humans.5563 In animal studies, UFH causes a dose-dependent loss of cancellous bone through decreasing rates of bone formation and increased bone resorption.61 Animal models demonstrating that heparin is sequestered in the bone for extended periods also suggest that heparin-induced osteoporosis may not be rapidly reversible.63 A number of studies have attempted to quantify the risk of osteoporosis during prolonged treatment (> 1 month) with UFH. Symptomatic vertebral fractures have been reported to occur in approximately 2 to 3% of the patient population and significant reductions of bone density have been reported in up to 30%.5556 A small study (n = 40) reported an even higher percentage of fractures (15%) when older nonpregnant patients were treated with twice-daily subcutaneous injections of 10,000 U UFH for a period of 3 to 6 months.59

4.2 LMWH Therapy

Despite a paucity of supportive data from controlled trials or even large prospective observational studies, LMWH is now commonly used for prophylaxis and treatment of maternal thromboembolism. This change in practice is based largely on the results of large trials in nonpregnant patients showing that LMWHs are at least as safe and effective as UFH for the treatment of VTE6465 and acute coronary syndromes,6667 as well as for prophylaxis in high-risk patients.68 Retrospective analyses and systematic reviews suggest that the incidence of bleeding in pregnant women receiving LMWH is low.22,6970 A review of LMWH use in 486 pregnancies identified a frequency of minor bleeding of 2.7% and no major hemorrhagic events.69In a more recent systematic review of 64 studies reporting 2,777 pregnancies, the frequencies of significant bleeding were 0.43% (95% CI, 0.22–0.75%) for antepartum hemorrhage, 0.94% (95% CI, 0.61–1.37%) for postpartum hemorrhage, and 0.61% (95% CI, 0.36–0.98%) for wound hematoma; giving an overall frequency of 1.98% (95% CI, 1.50–2.57%).70 Although HIT can occur with LMWH therapy, the risk appears lower with LMWH than with UFH51 and no confirmed cases were identified in these two large reviews.6970

Several lines of evidence suggest that LMWHs have a lower risk of osteoporosis than UFH. When rats were treated with UFH or LMWH (tinzaparin), both treatments were associated with a dose-dependent decrease in cancellous bone volume but LMWH caused significantly less bone loss than UHF.62 In a study by Monreal and colleagues59in which 80 patients (men and women with a mean age of 68 years) with DVT were treated with either 5,000 U subcutaneously bid of dalteparin or 10,000 U subcutaneously bid of UFH for a period of 3 to 6 months, the risk of vertebral fractures was higher in those receiving UFH (6 of 40 patients [15%]; 95% CI, 6–30%) than in those receiving dalteparin (1 of 40 patients [3%]; 95% CI, 0–11%). In another randomized trial, 44 pregnant women were allocated to prophylactic doses of dalteparin (n = 21) or UFH (n = 23)60 and bone density in the lumbar spine was measured for up to 3 years after delivery. Bone density did not differ between women receiving dalteparin and untreated patients but was significantly lower in those receiving UFH compared to both those who were not treated and those who received dalteparin. On multiple logistic regression analysis, the type of heparin used was the only independent factor associated with reduced bone mass. Similar results were reported in a prospective observational study in which 55 pregnant women treated with prophylactic LMWH and aspirin and 20 pregnant untreated volunteers had dual energy radiograph absorptiometry scans of the lumbar spine performed within 6 months prior to conception and within 6 weeks of delivery.71 Both groups showed a loss in lumbar spine bone mineral density by the end of pregnancy, but there was no statistically significant difference in bone loss between the two patient populations, suggesting that bone loss associated with prophylactic LMWH therapy is not different from normal physiologic losses during pregnancy.

Recommendation

4.2.1. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C).

The frequency of cesarean delivery is increasing in developed countries and rates in excess of 30% are now commonplace. Available data suggest that this mode of delivery is associated with an increased relative risk of fatal and nonfatal VTE, with the risk being highest following emergency procedures.7274

5.1 Risk of VTE Following Cesarean Section

In a population-based study conducted before the implementation of guidelines for postpartum thromboprophylaxis in which outcome frequencies were based on routinely collected hospital record data, the incidence of DVT after cesarean section was reported to be 0.424/1,000 vs 0.173/1,000 following vaginal delivery.72 In the same study, the risk of pulmonary embolism (PE) was also higher after cesarean delivery, complicating almost 0.4/1,000 such deliveries.72 In a Swedish study that also utilized health record information, the adjusted relative risk (RR) of PE associated with cesarean section compared to that with vaginal delivery was 6.7 (95% CI, 4.5–10.0).75 These data are consistent with those from a retrospective review of objectively confirmed events in a hospital population in the United States in which the frequency of VTE was reported as 0.521/1,000 cesarean sections.74

When cesarean section is performed emergently, the risk of VTE is approximately double that of an elective procedure.72 Further, interaction between risk factors has been noted, with the combination of age > 35 years and emergency cesarean delivery being associated with an incidence of DVT of approximately 1.2/1,000 deliveries and that for PE of 1/1,000 deliveries.72 In a single-center Norwegian cohort study in which 5 of 1,067 women undergoing cesarean section had symptomatic, objectively confirmed VTE (0.47%), all the affected women had additional risk factors including twin pregnancy, obesity, severe preeclampsia, re-operation, immobilization, and placenta previa.76

Studies based on hospital records and disease coding have significant limitations77 that may result in an underestimation of the true incidence of VTE. Few studies have screened consecutive patients objectively for VTE postpartum. In the Norwegian study described above, 59 low-risk women undergoing elective cesarean section underwent screening for DVT using triplex ultrasonography (compression, color Doppler and spectral Doppler) 2 to 5 days after delivery and followed up for 6 weeks; none had symptomatic or asymptomatic VTE (95% CI, 0–6.1%).76

Others have suggested that pelvic MRI venography (MRV) is a better surrogate measure for DVT. A recent clinical trial of 15 women considered to be at moderate or high risk of DVT after cesarean section in which screening for DVT was performed using compression ultrasonography of the proximal veins and pelvic MRV reported that 46% (95% CI, 21–73%) had evidence of pelvic vein thrombosis, while none had a positive ultrasound assessment of the legs.78 None of the affected women were symptomatic. Although these data suggest that asymptomatic pelvic thrombosis may be common after cesarean section in women with additional risk factors, the clinical significance of these radiologic findings is not clear.

Although cesarean section is likely to be a risk factor for VTE, the level of risk for symptomatic events attributable to cesarean section itself appears very modest and similar to that seen in low-risk surgical patients for whom no routine thromboprophylaxis other than mobilization is recommended (ie, frequency of proximal DVT: 0.4%; frequency of symptomatic PE: 0.2%).79 Although data from MRV-based screening studies suggests a substantial risk of asymptomatic pelvic vein thrombosis, the data are limited to one study and the natural history of these types of thrombi is unknown. Based on the small number of associated clinically evident events, routine thromboprophylaxis is not justified and cannot be recommended on the basis of cesarean section alone.

Limited data do suggest that the presence of additional risk factors may increase the risk of VTE associated with cesarean section. The quantification of risk when multiple factors are combined is not clearly established. However, the addition of multiple other risk factors (ie, increased age, prior VTE, obesity, thrombophilia, lower limb paralysis, immobilization, extended surgery such as hysterectomy, preeclampsia, and comorbid medical conditions such as heart failure) is likely to place the patient at moderate to high risk of VTE.

Recommendations

5.1.1. We suggest that a thrombosis risk assessment be performed in all women undergoing cesarean section to determine the need for thromboprophylaxis (Grade 2C).

5.1.2. In patients without additional thrombosis risk factors undergoing cesarean section, we recommend against the use of specific thromboprophylaxis other than early mobilization (Grade 1B).

5.2. Thromboprophylaxis Following Cesarean Section

For many years, guidelines in the United Kingdom have advocated the use of prophylaxis following cesarean section in women with additional risk factors,8081 and the use of thromboprophylaxis with LMWH following cesarean section is now widespread in Europe. These recommendations however, are based on expert opinion and consensus rather than good quality clinical trials. To date, no adequately powered clinical trials of thromboprophylaxis following cesarean section have been conducted.82One prospective cohort83and six randomized studies8489 have been published (Tables 4, 5 ). Of the randomized trials, the primary outcome was VTE in four,8586,8889: two compared LMWH with placebo,8586 one evaluated UFH vs placebo,87one randomized patients to either LMWH or UFH,88and one compared hydroxyethyl starch (an intervention that is no longer utilized) with placebo.89 The sample sizes of all these trials were small. The trial evaluating UFH against placebo enrolled 50 patients,87while that comparing UFH and LMWH recruited < 20.88 One pilot study of 76 patients comparing LWMH vs placebo after cesarean section, reported a 26% recruitment rate and a DVT frequency of 1.3% (95% CI, 0.03–7.1%).85Although the authors of this pilot study concluded that a full study was feasible, the difficulties of conducting such a trial were highlighted in another pilot study of LMWH vs placebo in which recruitment was slow (141 women at eight hospitals over the course of two years) and the overall event rate was low (0.7%).86 Based on their pilot data, the authors of this second study calculated that approximately 8,000 hospital-months of recruitment would be required to demonstrate the effectiveness of LMWH prophylaxis after cesarean section.

In the absence of high-quality trial data evaluating optimal thromboprophylaxis after cesarean section, others have utilized decision analyses to determine optimal prophylactic strategies. Quiñones and colleagues modeled and compared four approaches: universal subcutaneous UFH prophylaxis, UFH prophylaxis for patients with genetic thrombophilia, pneumatic compression stockings, and no prophylaxis.90 Outcomes included VTE, HIT, HIT-related thrombosis, and major maternal bleeding. The use of pneumatic compression stockings was the strategy with the lowest number of adverse events, while universal prophylaxis with subcutaneous UFH was associated 13 cases of HIT-induced thrombosis and bleeding per VTE prevented. This model has substantial limitations. Data used to derive risk probability estimates were largely derived from studies that included nonpregnant patients, and a cost-analysis component was not included. A strategy utilizing LMWH prophylaxis was not evaluated, and the negligible risk of HIT associated with LMWH use in this population would be expected to impact on this model.70,91 Given the absence of data from controlled trials in this population, recommendations regarding thromboprophylaxis are by necessity based on extrapolation from other patient populations.

Recommendations

5.2.1. For women considered at increased risk of VTE after cesarean section because of the presence at least one risk factor in addition to pregnancy and cesarean section, we suggest pharmacologic thromboprophylaxis (prophylactic LMWH or UFH) or mechanical prophylaxis (graduated compression stockings or intermittent pneumatic compression) while in hospital following delivery (Grade 2C).

5.2.2. For women with multiple additional risk factors for thromboembolism who are undergoing cesarean section and are considered to be at very high risk of VTE, we suggest that pharmacologic prophylaxis be combined with the use of graduated compression stockings and/or intermittent pneumatic compression (Grade 2C).

5.2.3. For selected high-risk patients in whom important risk factors persist following delivery, we suggest extended prophylaxis (up to 4 to 6 weeks after delivery) following discharge from hospital (Grade 2C).

PE remains the major cause of maternal mortality in the Western world73,92and VTE in pregnancy is an important cause of maternal morbidity.93 Results from studies in which either all or most patients underwent accurate diagnostic testing for VTE report that the incidence of VTE ranges from 0.6 to 1.3 episodes per 1,000 deliveries.72,74,9396 Although these rates are low, they represent a fivefold to tenfold increase in risk compared to those reported for nonpregnant women of comparable age. A metaanalysis showed that two-thirds of DVT occur antepartum, with these events distributed relatively equally throughout all three trimesters.97 In contrast, 43 to 60% of pregnancy-related episodes of PE appear to occur in the 4 to 6 weeks after delivery.74,96 Since the antepartum period is substantially longer than the 6-week postpartum period, the daily risk of PE, as well as DVT, is considerably higher following delivery than antepartum.

6.1 Treatment of VTE During Pregnancy

Based on the safety data for both mother and fetus, LMWH is the preferred drug for the treatment of VTE during pregnancy. Metaanalyses of well-designed randomized trials comparing IV UFH and subcutaneous LMWH for the acute treatment of DVT64and PE65 in the nonpregnant population show that LMWH is at least as safe and effective as UFH. Additional studies in the nonpregnant population demonstrate that long-term LMWH (and UFH) are as effective and safe as vitamin K antagonists for the prevention of recurrent VTE.98100

Clinicians selecting UFH can use one of two alternatives: (1) initial IV therapy followed by adjusted-dose subcutaneous UFH given q12h or (2) twice-daily adjusted-dose subcutaneous UFH can be used for initial and long-term treatment. With subcutaneous therapy, UFH doses should be adjusted to prolong a mid-interval (6 h after injection) aPTT into therapeutic range. LMWH is the preferred option for most patients because of its better bioavailability, longer plasma-half-life, more predictable dose response, and improved safety profile with respect to osteoporosis and thrombocytopenia compared to UFH.68,70</