Interesting link: ESC guidelines on cardiovascular diseases during pregnancy.
Background
Pregnancy is associated with higher occurrence of a prothrombotic status (1), due to: 1) increased levels of fibrinogen and coagulation factors VII, VIII, X, von Willebrand factor, plasminogen activator inhibitor type 1 (PAI-1), 2) decreased protein S levels, 3) high PAI-2 (produced by the placenta).
Furthermore, mechanical factors can intervene, as the gravid uterus compresses the inferior vena cava, leading to pelvic and lower body venous stasis (mainly on the left side).
Al these factors can explain the increased risk of both venous and arterial thrombosis in pregnancy (Table 1), with 11% of maternal deaths due to pulmonary embolism (2).
Furthermore, mechanical factors can intervene, as the gravid uterus compresses the inferior vena cava, leading to pelvic and lower body venous stasis (mainly on the left side).
Al these factors can explain the increased risk of both venous and arterial thrombosis in pregnancy (Table 1), with 11% of maternal deaths due to pulmonary embolism (2).
Table 1. Thrombotic risks in pregnancy (modified from (1))
| Thromboembolic condition | Risk in pregnancy |
|---|---|
| Venous thromboembolic disease | 4-5 higher risk vs non-pregnant VTE prevalence 1-2/1000 pregnancies 80% DVT, 20% PE 30-50% VTE - postpartum |
| Arterial thrombosis | 3-4 higher risk vs non-pregnant |
| Thrombophilia | 20-50% of pregnant/postpartum women with VTE associate thrombophilia |
| Mechanical valve prosthesis | Maternal mortality during pregnancy 1-4% Risks of embryopathy and valvular thrombosis |
I - Low-molecular weight heparin
Low-molecular weight heparin (LMWH) is preferred over adjusted-dose unfractionated heparin (UFH) during pregnancy due to adverse effects of long-term administration of UFH
Indeed, adverse effects of long-term administration of UFH are thrombocytopenia, osteoporosis and risk of bleeding due to pregnancy-related changes in aPTT values. However, the physiologic changes of pregnancy alter the metabolism of LMWH, resulting in lower peak levels and a higher rate of clearance - so a pregnant woman may need higher doses or more frequent dosing (3).
In terms of monitoring, while no definitive recommendations exist, peak anti-Xa activity can be measured at 4 hours after LMWH administration, with a target value of 0.7-1.2 iu/ml (4,5).
American College of Chest Physicians (ACCP) recommendations only consider this dose cost-efficient for patients with prosthetic heart valves, in other patients they advise a weight-adjusted dose to be correct. Weekly monitoring is indicated by the ESC pregnancy guidelines, while monthly monitoring is advocated by others.
Indeed, adverse effects of long-term administration of UFH are thrombocytopenia, osteoporosis and risk of bleeding due to pregnancy-related changes in aPTT values. However, the physiologic changes of pregnancy alter the metabolism of LMWH, resulting in lower peak levels and a higher rate of clearance - so a pregnant woman may need higher doses or more frequent dosing (3).
In terms of monitoring, while no definitive recommendations exist, peak anti-Xa activity can be measured at 4 hours after LMWH administration, with a target value of 0.7-1.2 iu/ml (4,5).
American College of Chest Physicians (ACCP) recommendations only consider this dose cost-efficient for patients with prosthetic heart valves, in other patients they advise a weight-adjusted dose to be correct. Weekly monitoring is indicated by the ESC pregnancy guidelines, while monthly monitoring is advocated by others.
II - Warfarin and acenocoumarol
Warfarin and acenocoumarol are the most widely used oral anticoagulants. However their use is very limited in pregnancy, due to their known teratogenic effects especially when exposure occurs between week 6 and 12.
Indeed, warfarin embryopathy affects around 6.4% exposed pregnancies . It includes nasal hypoplasia and stippling of vertebrae or bony epiphyses. Fetal hemorrhage (including intracranial bleeding) can also complicate the course of these pregnancies. A patient needing long-term anticoagulation (e.g. patients with mechanical prosthetic valves) wanting to become pregnant should be tested for pregnancy often to allow for a swift substitution of warfarin with LMWH or UFH once the test is positive.
Newer anticoagulants on the other hand have not gained enough use in pregnant women, so limited data exist on their efficiency. The 2012 ACCP guidelines recommend avoiding the use of oral direct thrombin (e.g. dabigatran) and anti-Xa (e.g. rivaroxaban, apixaban) inhibitors, while the ESC guidelines recommends avoidance of fondaparinux in pregnancy.
Indeed, warfarin embryopathy affects around 6.4% exposed pregnancies . It includes nasal hypoplasia and stippling of vertebrae or bony epiphyses. Fetal hemorrhage (including intracranial bleeding) can also complicate the course of these pregnancies. A patient needing long-term anticoagulation (e.g. patients with mechanical prosthetic valves) wanting to become pregnant should be tested for pregnancy often to allow for a swift substitution of warfarin with LMWH or UFH once the test is positive.
Newer anticoagulants on the other hand have not gained enough use in pregnant women, so limited data exist on their efficiency. The 2012 ACCP guidelines recommend avoiding the use of oral direct thrombin (e.g. dabigatran) and anti-Xa (e.g. rivaroxaban, apixaban) inhibitors, while the ESC guidelines recommends avoidance of fondaparinux in pregnancy.
III - Thromboembolic disease
Deep venous thrombosis occurs about six times more often in pregnant women than in nonpregnant women (6) and in developed countries pulmonary embolism (PE) is the leading cause of death in these women. However, the overall incidence of thromboembolism is only about one event per 1,000 pregnancies. Thus, routine thromboprophylaxis in all pregnant women is not justified3.
Pregnant women at high-risk for DVT have one of the following factors: 1) previous recurrent venous thromboembolism VTE (>1 episode); 2) unprovoked or oestrogen-related VTE; 3) single previous VTE associated to thrombophilia or family history.
According to current ESC guidelines, these patients should receive antenatal prophylaxis with LMWH as well as post-partum for the duration of 6 weeks Dose regimens include subcutaneous enoxaparin 40 mg every 24 h or dalteparin 5000 units every 24 h. Higher doses (50-100% of therapeutic doses depending on the setting) are indicated in very high risk patients, with repeated VTE recurrences who were receiving OAC before pregnancy.
Acute VTE is conventionally treated with LMWH or unfractionated heparin. Recent ACCP guidelines indicate a preference for adjusted dose subcutaneous LMWH over adjusted dose UFH (grade 1B recommendation). The ESC guidelines have a different perspective, indicating that UFH is recommended in high-risk VTE patients (eg. massive pulmonary emboli) while LMWH in non-high risk patients. Also, bridging to warfarin is not recommended during pregnancy, continuation of LMWH being preferred in this situation. The duration of treatment of acute VTE in pregnancy is another matter of debate: current recommendations suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in comparison with shorter durations of treatment (ACCP grade 2C recommendation).
If PE occurs, the management decision should be made depending on the hemodynamic and risk status of the patient. The ACCP guidelines recommend that the use of thrombolysis to treat PE in the pregnant patient be reserved for life threatening situations.
Pregnant women at high-risk for DVT have one of the following factors: 1) previous recurrent venous thromboembolism VTE (>1 episode); 2) unprovoked or oestrogen-related VTE; 3) single previous VTE associated to thrombophilia or family history.
According to current ESC guidelines, these patients should receive antenatal prophylaxis with LMWH as well as post-partum for the duration of 6 weeks Dose regimens include subcutaneous enoxaparin 40 mg every 24 h or dalteparin 5000 units every 24 h. Higher doses (50-100% of therapeutic doses depending on the setting) are indicated in very high risk patients, with repeated VTE recurrences who were receiving OAC before pregnancy.
Acute VTE is conventionally treated with LMWH or unfractionated heparin. Recent ACCP guidelines indicate a preference for adjusted dose subcutaneous LMWH over adjusted dose UFH (grade 1B recommendation). The ESC guidelines have a different perspective, indicating that UFH is recommended in high-risk VTE patients (eg. massive pulmonary emboli) while LMWH in non-high risk patients. Also, bridging to warfarin is not recommended during pregnancy, continuation of LMWH being preferred in this situation. The duration of treatment of acute VTE in pregnancy is another matter of debate: current recommendations suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in comparison with shorter durations of treatment (ACCP grade 2C recommendation).
If PE occurs, the management decision should be made depending on the hemodynamic and risk status of the patient. The ACCP guidelines recommend that the use of thrombolysis to treat PE in the pregnant patient be reserved for life threatening situations.
IV - Mechanical valve prosthesis
Prosthetic heart valve thrombosis (PVT) is a rare complication, with an estimated incidence of around 3% per patient-year. However, during pregnancy, changes in the haemostatic system lead to a pro-coagulant state that increases the risk of PVT to up to 10% with a risk of maternal mortality from valve thrombosis estimated at 1-4% (7).
ACCP recommendations regarding anticoagulant regimens for pregnant women with mechanical heart valves are (all Grade 1A):
(a) Adjusted-dose bid LMWH throughout pregnancy. It is suggested that doses be adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous-injection (and ESC guidelines recommend that in this setting LMWH should be avoided, unless anti-Xa levels are monitored) or
(b) Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h 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 units/mL or
(c) UFH or LMWH (as above) until the 13th week, with substitution by vitamin K antagonists until close to delivery when UFH or LMWH is resumed.
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 (Grade 2C). Moreover, for pregnant women with prosthetic valves at high risk of thromboembolism, we suggest the addition of low-dose aspirin, 75 to 100 mg/d (Grade 2C).
However, continuation of oral anticoagulation throughout pregnancy should be considered when the warfarin dose is <5 mg daily (or acenocoumarol<2 mg daily) because the risk of embryopathy is low, while OACs are in large series the most effective regimen to prevent valve thrombosis. This is to be considered mainly in high risk patients, where bridging to heparin can have a higher thromboembolic risk.
If mechanical valve thrombosis occurs during pregnancy, the first line of therapy is efficient anticoagulation with heparins followed by warfarin. Fibrinolysis should be applied in critically ill patients when surgery is not immediately available. Because fetal loss is high with surgery, fibrinolysis may be considered instead of surgery in non-critically ill patients when anticoagulation fails. Fibrinolysis is the therapy of choice in right-sided prosthetic valve thrombosis.
ACCP recommendations regarding anticoagulant regimens for pregnant women with mechanical heart valves are (all Grade 1A):
(a) Adjusted-dose bid LMWH throughout pregnancy. It is suggested that doses be adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous-injection (and ESC guidelines recommend that in this setting LMWH should be avoided, unless anti-Xa levels are monitored) or
(b) Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h 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 units/mL or
(c) UFH or LMWH (as above) until the 13th week, with substitution by vitamin K antagonists until close to delivery when UFH or LMWH is resumed.
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 (Grade 2C). Moreover, for pregnant women with prosthetic valves at high risk of thromboembolism, we suggest the addition of low-dose aspirin, 75 to 100 mg/d (Grade 2C).
However, continuation of oral anticoagulation throughout pregnancy should be considered when the warfarin dose is <5 mg daily (or acenocoumarol<2 mg daily) because the risk of embryopathy is low, while OACs are in large series the most effective regimen to prevent valve thrombosis. This is to be considered mainly in high risk patients, where bridging to heparin can have a higher thromboembolic risk.
If mechanical valve thrombosis occurs during pregnancy, the first line of therapy is efficient anticoagulation with heparins followed by warfarin. Fibrinolysis should be applied in critically ill patients when surgery is not immediately available. Because fetal loss is high with surgery, fibrinolysis may be considered instead of surgery in non-critically ill patients when anticoagulation fails. Fibrinolysis is the therapy of choice in right-sided prosthetic valve thrombosis.
V - Peripartum
Risk of bleeding, either operative hemorrhage, or perianesthesic spinal/epidural hematoma, is one of the primary concerns, peripartum. Therefore, peripartum treatment adjustments should be made. The last LMWH dose should be administered at least 10-12 hours before epidural needle insertion in case of a prophylactic dose and ideally 24 hours before in the case of an intermediate/therapeutic dose. For UFH the pause interval should be at least 6 hours and obtain aPTT prior to needle insertion or subcutaneous administration .(3,4). LMWH could be replaced by intravenous UFH at least 36 hours before planned delivery in high-risk patients. UFH should be continued until 4-6 hours before planned delivery and restarted 4-6 hours after delivery if there are no bleeding complications. The same ‘rules’ apply for epidural needle and for caesarean section.
Another concern is linked to the fact that puerperium is the time of maximal daily risk of pregnancy-associated VTE, increasing if associated risk factors are present (Table 2).
Table 2. Major risk factors associated with postpartum VTE (modified after (4))
Anticoagulation should be resumed at least 12 hours after vaginal delivery and epidural anesthesia and removal of catheter or 24 hours after cesarean section. Thromboprophylactic doses can be resumed 6-8 hours after delivery or caesarean section, unless hemostasis ensues. Therapeutic doses of heparin should be preferably delayed until 48 hours after delivery or caesarean section. If necessary, oral anticoagulation can be restarted postpartum, warfarin being compatible with lactation.
Another concern is linked to the fact that puerperium is the time of maximal daily risk of pregnancy-associated VTE, increasing if associated risk factors are present (Table 2).
Table 2. Major risk factors associated with postpartum VTE (modified after (4))
- Immobility (strict bed rest for ≥1 week in the antepartum period)
- Postpartum hemorrhage (≥1,000 ml with surgery)
- Previous VTE
- Preeclampsia with fetal growth restriction
- Thrombophilia: antithrombin deficiency, factor V Leiden (homozygous or heterozygous), prothrombin G20210A (homozygous or heterozygous)
- Medical conditions: systemic lupus erythematosus; heart disease; sickle cell disease
- Blood transfusion
- Postpartum infection
Anticoagulation should be resumed at least 12 hours after vaginal delivery and epidural anesthesia and removal of catheter or 24 hours after cesarean section. Thromboprophylactic doses can be resumed 6-8 hours after delivery or caesarean section, unless hemostasis ensues. Therapeutic doses of heparin should be preferably delayed until 48 hours after delivery or caesarean section. If necessary, oral anticoagulation can be restarted postpartum, warfarin being compatible with lactation.
VI - Lactation
Based on current data on milk excretion of most used anticoagulants, in lactating women:warfarin, acenocoumarol, or LMWH or UFH can be continued during breastfeeding (Grade 1A ); fondaparinux might be replaced by alternative anticoagulants (Grade 2C); and oral direct thrombin (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban) should be replaced by alternative anticoagulants (Grade 1C).
Conclusion
Knowledge of the preferred anticoagulation regimens and indications is important in pregnancy and puerperium. Special dose-adjustments and trimester-related preferences of anticoagulant drugs should be considered by treating physicians. Careful risk stratification of thromboembolic disease is crucial to management.
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