Pregnancy Category A
Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
Pregnancy Category B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.
Pregnancy Category C
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Pregnancy Category D
There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Pregnancy Category X
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Pregnancy Category N
FDA has not classified this drug.
Heparin is a well-studied drug in pregnancy. The most common adverse effects observed include osteoporosis and thrombocytopenia in the mother, if the drug is used for longer periods (Regitz-Zagrosek et al. 2011). These adverse effects are significantly less frequent if low molecular weight heparin (LMWH) is used. Heparins do not cross the placenta and are not transferred to breast milk. They are classified by FDA as B.
Warfarin, acenocoumarol and phenprocoumon are known to induce coumarin-embryopathies, probably in a dose dependent manner. They will cross the placenta and are transferred to breast milk in low amounts (10 %, well tolerated as inactive metabolites). Warfarin and acenocoumarol are classified by FDA into category D.
The newer anticoagulant Danaparoid (with a heparin like action) is classified category B by FDA. No teratogenic effects were found in animal studies or in approximately 80 reported human cases (www.embryotox.de). It may be used as an alternative to heparins if these are contraindicated – for example in Heparin induced thrombocytopenia.
The newer anticoagulant drugs have not been evaluated in pregnancy and are therefore not recommended in pregnant patients. This applies to Dabigatran, a direct thrombin inhibitor, and the Factor Xa-inhibitors Rivaroxaban, Apixaban and Fondaparinux.
All these new drugs cross the placental barrier in varying degrees and are also therefore not recommended.
For acetyl salicylic acid large datasets are available that do not describe any teratogenic effects. It crosses the placenta and is transferred to the breast milk, but appears to be well tolerated. It is classified category B by FDA. For the platelet inhibitor Clopidogrel, no teratogenity was found in rat and mouse studies and in more than 30 documented human cases (www.embrytox.de). Transfer to breast milk is unknown. Clopidogrel has recently been upgraded from category C to B by the FDA classification. The use of more recent antiplatelet drugs (prasugrel, ticagrelor), bivalirudin and glycoprotein IIb/IIIa inhibitors is not recommended during pregnancy because of insufficient safety data (Regitz-Zagrosek et al. 2011).
Mechanical Valves
Pregnancy in patients with mechanical valves is associated with an increased risk of valve thrombosis, of haemorrhagic complications, and adverse perinatal outcome. The character and magnitude of the maternal and associated fetal risk depends largely on the anticoagulation regimen used during pregnancy and the quality of anticoagulation control.
The procoagulant mechanisms associated with pregnancy contribute to the markedly increased risk of valve thrombosis in pregnant women. In a large review this risk was 3.9 % with oral anticoagulants throughout pregnancy, 9.2 % when unfractionated heparin (UFH) was used in the first trimester and oral anticoagulants in the second and third trimester, and 33 % with UFH throughout pregnancy (Chan et al. 2000). Maternal death occurred in these groups in 2, 4, and 15 %, respectively, and was usually related to valve thrombosis (Chan et al. 2000). A review of recent literature confirmed the low risk of valve thrombosis with oral anticoagulants throughout pregnancy (2.4 %, 7/287 pregnancies) compared to UFH in the first trimester (10.3 %, 16/156 pregnancies) (Abildgaard et al. 2009). The risk is probably lower with adequate dosing and is also dependant on type and position of the mechanical valve as well as on additional patient-related risk factors.
UFH throughout pregnancy is additionally associated with thrombocytopenia and osteoporosis. LMWHs are also associated with the risk of valve thrombosis (Oran et al. 2004; Elkayam et al. 2004). The risk is lower, but still present, with dose adjusting according to anti-Xa levels (Oran et al. 2004; McLintock et al. 2009; Quinn et al. 2009; Yinon et al. 2009; Abildgaard et al. 2009). In 111 pregnancies in which LMWH with dose adjustment according to anti-Xa levels were used throughout pregnancy, valve thrombosis occurred in 9 % (Oran et al. 2004). Too lower target anti-Xa levels or poor compliance probably contributed to valve thrombosis in all but one pregnancy. A review reported lower frequency of valve thrombosis with LMWH in the first trimester only, but in a small patient group (3.6 %, 2/56 pregnancies) (Abildgaard et al. 2009).
The use of LMWH during pregnancy in women with mechanical prostheses is still controversial because evidence is scarce. Unresolved questions concern optimal anti-Xa levels, the importance of peak versus pre-dose levels and the best time intervals for anti-Xa monitoring. Studies are urgently needed.
There is a marked increase in dose requirement during pregnancy to keep the anti- Xa levels in the therapeutic range, (Barbour et al. 2004; Quinn et al. 2009) because of increased volume of distribution and increased renal clearance. Therefore regular monitoring of anti-Xa levels is necessary. It has been demonstrated that pre-dose anti-Xa levels are often subtherapeutic when peak levels are between 0.8 and 1.2 U/ml (Barbour et al. 2004; Friedrich and Hameed 2010). Even when predose anti-Xa level monitoring and more frequent dosing lead to higher pre-dose levels combined with lower peak levels, there are no data available to show that this approach achieves a stable, consistent therapeutic intensity of anticoagulation and will prevent valve thrombosis and bleeding (Yinon et al. 2009; Barbour et al. 2004; Friedrich and Hameed 2010).
Current evidence indicates that oral anticoagulants throughout pregnancy, under strict international normalized ratio control, are the safest regimen for the mother (Chan et al. 2000; Abildgaard et al. 2009; Sillesen et al. 2011). However adequate randomized studies that compare different regimens are not available. The superiority of either UFH or LMWH in the first trimester is unproven though a recent review suggests higher efficacy of LMWH (Abildgaard et al. 2009). However the only randomized study comparing weight adjusted doses of LMWH (enoxaparin) with warfarin and initial UFH in pregnant women was prematurely terminated after the occurrence of valve thrombosis in two of seven women on LMWH (HIP-CAT study) (Oran et al. 2004; Elkayam et al. 2004) No LMWH is officially approved (labelled) for pregnant women with mechanical valves in any country.
All anticoagulation regimens carry an increased risk of miscarriage and of haemorrhagic complications, including retroplacental bleeding leading to premature birth and fetal death (Elkayam and Bitar 2005; Chan et al. 2000; McLintock et al. 2009; Oran et al. 2004; Quinn et al. 2009; Yinon et al. 2009). Comparison between studies is however impaired by reporting differences. Oral anticoagulants cross the placenta and their use in the first trimester can result in embryopathy in 0.0–10 % of cases (Schaefer et al. 2006; Vitale et al. 1999; Chan et al. 2000). UFH and LMWH do not cross the placenta and embryopathy does not occur. Substitution of oral anticoagulants with UFH in weeks 6–12 nearly eliminates the risk of embryopathy. The incidence of embryopathy was low (2.6 %) in a small series when warfarin dose was <5 mg and 8 % when warfarin dose was >5 mg daily (Cotrufo et al. 2002; Vitale et al. 1999; Sillesen et al. 2011). The dose-dependency was confirmed in several recent studies (Cotrufo et al. 2002; Vitale et al. 1999; Sillesen et al. 2011) however not in all (McLintock 2013). Major central nervous system abnormalities occur in 1 % of children when oral anticoagulants are used in the first trimester (van Driel et al. 2002). A low risk of minor central nervous system abnormalities and intracranial bleeding exists with oral anticoagulants outside the first trimester only (van Driel et al. 2002) whereby the intensity of anticoagulation and its control plays a significant role. Vaginal delivery while the mother is on oral anticoagulants is contraindicated because of the risk of fetal intracranial bleeding.
Individualized Management
Pre-pregnancy evaluation should include assessment of symptoms and echocardiographic evaluation of ventricular function, as well as prosthetic and native valve function. Type and position of the prosthetic valve(s) as well as history of valve thrombosis should be taken into account. The advantages and disadvantages of different anticoagulation regimens should be discussed extensively. The mother and her partner must understand that according to current evidence oral anticoagulants are the most effective regimen to prevent valve thrombosis, and therefore the safest regimen for her; those risks that put the mothers life in jeopardy will also jeopardize the survival of the baby. On the other hand the risk of embryopathy and fetal hemorrhage also needs discussion. Compliance with prior anticoagulant therapy should be considered and the management of the regimen that is chosen should be planned in detail. The effectiveness of the anticoagulation regimen should be monitored weekly and clinical follow-up including echocardiography should be performed monthly.
Individual Drug Therapy
The main goal of anticoagulation therapy in pregnant women with mechanical valves is to prevent the occurrence of valve thrombosis and its lethal consequences for both mother and fetus. The following recommendations should be seen in this perspective. The class of recommendations based on the wording used is explained in Table 2.
Table 2
Classes of recommendation
Classes of recommendations | Definition | Suggested wording to use |
|---|---|---|
Class I | Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. | Is recommended/is indicated |
Class II | Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. | |
Class IIa | Weight of evidence/opinion is in favour of usefulness/efficacy. | Should be considered |
Class IIb | Usefulness/efficacy is less well established by evidence/opinion. | May be considered |
Class III | Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. | Is not recommended |
Oral anticoagulants should be continued until pregnancy is achieved.
UFH or LMWH throughout pregnancy is not recommended because of the high risk of valve thrombosis with these regimens in combination with low fetal risk with oral anticoagulants in the second and third trimester‑. Continuation of oral anticoagulants throughout pregnancy should be considered when warfarin dose is <5 mg daily (or phenprocoumon <3 mg or acenocoumarol <2 mg daily) because the risk of embryopathy is low, while oral anticoagulants are in large series the most effective regimen to prevent valve thrombosis (Chan et al. 2000; Sillesen et al. 2011). After full disclosure to the pregnant woman that oral anticoagulants throughout pregnancy are the safest regimen for her and that low dose coumarin therapy carries an embryopathy risk of less than 3 %, discontinuation of oral anticoagulants and a switch to UFH or LMWH between pregnancy weeks 6 and 12 (under strict dose control and supervision) may be considered. When a higher-dose oral anticoagulants are required, discontinuation of oral anticoagulants between weeks 6 and 12 and replacement by adjusted-dose UFH (activated partial thromboplastin time ≥2 times the control, in high risk patients applied as intravenous infusion) or LMWH (twice daily with dose adjustment according to weight and according to anti-Xa levels) should be considered. The anti-Xa level should be maintained between 0.8 and 1.2 U/ml, determined 4–6 h after dosing (Butchart et al. 2005; Regitz-Zagrosek et al. 2011). The European Society of Cardiology task force (Regitz-Zagrosek et al. 2011) advises weekly control of peak anti-Xa levels because of the need for increasing dosages of LMWH during pregnancy (Vahanian et al. 2012; Barbour et al. 2004; Bonow et al. 2006; Abildgaard et al. 2009; Quinn et al. 2009).
The importance of also monitoring the pre-dose level of anti-Xa, and the necessity to maintain this level above 0.6 IU/ml, has been insufficiently studied, particularly in relation to thromboembolic events and bleeding and no firm recommendations can be made. The starting dose for LMWH is 1 mg/kg bodyweight if enoxaparin is chosen and 100 IU/kg for dalteparin, given twice daily subcutaneously. The dose should be adjusted according to increasing weight during pregnancy (Lebaudy et al. 2008) and anti-Xa levels. The European Society of Cardiology task force does not recommend the addition of acetylsalicylic acid to this regimen because there are no data to prove its efficacy and safety in pregnant women. The use of LMWH in the first trimester is limited by several factors including the scarcity of data about its efficacy (Abildgaard et al. 2009) and safety, uncertainties concerning the optimal dosing to prevent both valve thrombosis and bleeding, and the variable availability of anti-Xa level testing.
Irrespective of the regimen used, the effect of the anticoagulants should be monitored very carefully, and in the case of oral anticoagulants the international normalized ratio (INR) should be determined at weekly intervals. The intensity of the INR should be chosen according to the type and location of the prosthetic valve, according to present guidelines (Vahanian et al. 2012). Intense education about anticoagulation and self-monitoring of anticoagulation in suitable patients is recommended. In cases where UFH is used, once a stable activated partial thromboplastin time has been achieved, the aPTT should be monitored weekly by 4–6 h after starting the first dose, aiming for prolongation of the aPTT by ≥2 times the control.
Diagnosis and Management of Valve Thrombosis
When a woman with a mechanical valve presents with dyspnoea and/or an embolic event, immediate transthoracic echocardiography is indicated to search for valve thrombosis, usually followed by transoesophageal echocardiography. Fluoroscopy can be performed with limited fetal risk. The management of valve thrombosis is similar to the management in non-pregnant patients. This includes optimizing anticoagulation using intravenous heparin and resumption of oral anticoagulation in non-critically ill patients with recent sub-therapeutic anticoagulation. Surgery is indicated when anticoagulation fails and for critically ill patients with obstructive thrombosis (Vahanian et al. 2012). Most fibrinolytic agents do not cross the placenta, but the risk of embolization (10 %) and of retroplacental bleeding leading to obstetric haemorrhage is a concern and experience in pregnancy is limited. 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 (Vahanian et al. 2012). The mother should be informed about the risks (see Table 2).
Venous Thromboembolism
Pregnancy and the puerperium are associated with a five times higher risk of venous thromboembolism than in the general female population of childbearing age. Venous thromboembolism complicates about 0.05–0.20 % of all pregnancies (Liu et al. 2009; Heit et al. 2005; O’Connor et al. 2010; Rutherford and Phelan 1991; Sullivan et al. 2004). Venous thromboembolism encompasses pulmonary embolism and deep vein thrombosis. Pulmonary embolism is the third most common cause of direct maternal death in the UK occurring in 0.70/100,000 maternities (Wilkinson and Trustees and Medical Advisers 2011). The case fatality rate is 3.5 % (Knight 2008).
The presence of risk factors contributes to an increased risk of venous thromboembolism during pregnancy and the puerperium. Seventy nine percent of women dying from an antenatal pulmonary embolism in the UK had identifiable risk factors (CEMACH 2008; Knight 2008). The most significant risk factors for venous thromboembolism in pregnancy are a prior history of unprovoked deep vein thrombosis or pulmonary embolism (Marik and Plante 2008) and thrombophilias.
In the recent CMACE- study (Wilkinson and Trustees and Medical Advisers 2011) 88 % of women dying of pulmonary embolism had risk factors, but being overweight or obese were the most important risk factors. The identification of risk factors influences the choice of preventive strategies. All women should undergo a documented assessment of risk factors for venous thromboembolism before pregnancy or in early pregnancy. Based on type and number of risk factors present in the individual patient three risk groups can be identified (high, intermediate and low-risk groups) and preventive measures applied accordingly.
Patients at high risk are those with previous recurrent venous thromboembolism and previous unprovoked or oestrogen related venous thromboembolism or a single previous venous thromboembolism associated with a thrombophilic condition or a family history of thromboembolic disease.
Patients with intermediate risk are those with three or more risk factors other than those listed as high-risk factors. These include: pregnancy with medical co-morbidities, maternal age >35 years, obesity (body mass index >30 kg/m2), hyperemesis and dehydration, smoking, gross varicose veins, and obstetric factors like pre-eclampsia, ovarian hyperstimulation syndrome, multiple pregnancy, caesarean section, prolonged labour (> 24 h) and peripartum hemorrhage (>1 l or transfusion). Transient risk factors are current systemic infection, immobility, any surgical procedure in pregnancy or <6 weeks post-partum.
Patients at low risk are those with less than three risk factors, except for overweight and obesity, which was shown to be an important risk factor of its own. However the influence of single risk factors other than those included in the high risk group is not known.
LMWH has become the drug of choice for the prevention of venous thromboembolism in pregnant women. It causes less bone loss than UFH and the osteoporotic fracture rate is lower (0.04 % of pregnant women treated with LMWH) (Greer and Nelson-Piercy 2005; Bates et al. 2008; Royal College of Obstetricians and Gynecologists 2009).
The dose of LMWH for thromboprophylaxis is based on bodyweight. However, previous recommended doses are mostly based on studies in non-pregnant patients, and there are no studies available on the optimal doses in women who are obese or puerperal (Bates et al. 2008). Although the incidence of venous thromboembolism decreased recently, particularly in obese patients a significant residual risk of venous thromboembolism remains (Wilkinson and Trustees and Medical Advisers 2011). It is therefore suggested, that women of high risk should receive a prophylactic dose of LMWH that is half of the therapeutic dose, weight adjusted, applied twice daily (e.g. Enoxaparin of 0.5 mg/kg body weight twice daily or Dalteparin 50 units/kg 12 hourly) (Regitz-Zagrosek et al. 2011) and studies should be conducted in these patients.
Acute Deep Vein Thrombosis
Deep vein thrombosis (DVT) is characterized by leg swelling, which is a frequent finding in pregnancy. Since deep vein thrombosis is left sided in over 85 % of cases, due to compression of the left iliac vein by the right iliac artery and the gravid uterus, swelling of the left leg is specifically suspicious. A clinical decision rule has been suggested based upon three variables: if the suspected DVT does not affect the left leg presentation, if the calf circumference difference is <2 cm and if the presentation was later than the first trimester combined with negative ultrasound examination of the legs, the negative predictive value is 100 % (95 % CI 95.8–100 %) (Chan et al. 2009). This clinical decision-rule needs validation in prospective studies.
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