Vera Regitz-Zagrosek1, 2 , Christa Gohlke-Baerwolf3, Bernard Iung4, 5 and Petronella G. Pieper6
Charité, University Medicine Berlin, Institute of Gender in Medicine (GiM), Charité Campus Mitte, Hessische Str. 3-4, Berlin, 10115, Germany
University Medicine Berlin, Center for Cardiovascular Research (CCR), Berlin, Germany
Department of Cardiology, Heart Center Bad Krozingen, Bad Krozingen, Germany
Cardiology Department, AP-HP, Bichat Hospital, Paris, France
University Paris Diderot, Sorbonne Paris Cité, Paris, France
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
In pregnant women, anticoagulation is needed for women with mechanical valves, for women who are at increased risk of venous thrombembolism, those who have cardiomyopathies and severely impaired ejection fraction (EF), for high-risk patients with atrial fibrillation, those who have acute coronary syndromes and for some patients with congenital heart disease. The most frequently used drugs are Vitamin K antagonists, heparins, clopidogrel, and acetyl salicylic acid. They differ in the level of protection and risk they bear for the mother and her fetus and their precise use varies according to the specific indication. Both the indications and drugs have been discussed in the guidelines of the European Society of Cardiology on the management of cardiovascular diseases in pregnancy and were recently reviewed in European Heart Journal ((Regitz-Zagrosek et al. 2011) and Current Problems in Cardiology, in press). The present chapter is based on these publications.
International normalized ratio
Low molecular weight heparin
In pregnant women, anticoagulation is needed for women with mechanical valves, for women who are at increased risk of venous thrombembolism, those who have cardiomyopathies and severely impaired ejection fraction (EF), for high-risk patients with atrial fibrillation, those who have acute coronary syndromes and for some patients with congenital heart disease. The most frequently used drugs are Vitamin K antagonists, heparins, clopidogrel, and acetyl salicylic acid. They differ in the level of protection and risk they bear for the mother and her fetus and their precise use varies according to the specific indication. Both the indications and drugs have been discussed in the guidelines of the European Society of Cardiology on the management of cardiovascular diseases in pregnancy and were recently reviewed in European Heart Journal ((Regitz-Zagrosek et al. 2011) and Current Problems in Cardiology). The present chapter is based on these publications.
The most frequently used anticoagulants in pregnancy are heparins, vitamin K antagonists and acetylsalicylic acid used as an anti-aggregant drug. With few exceptions, they have rarely been studied in prospective trials (McLintock et al. 2009; Barbour et al. 2004; Schaefer et al. 2006). Knowledge is mainly based on observational studies and retrospective analysis of registries (Sillesen et al. 2011). Experiences with unplanned and planned exposure to drugs in pregnancy are collected in two large databases: www.embryotox.de and www.safefetus.com. Accordingly drugs have been classified by FDA into categories A-X in relation to pregnancy (Table 1). The European Society of Cardiology guidelines on Management of cardiovascular diseases in Pregnancy list drugs with their FDA classification, their reported adverse effects for mother, fetus and the newborn. They also specify each drug’s placenta permeability and transfer into breast milk.
FDA categories for classification of drugs in pregnancy
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).
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.
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.
Classes of recommendation
Classes of recommendations
Suggested wording to use
Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.
Is recommended/is indicated
Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.
Weight of evidence/opinion is in favour of usefulness/efficacy.
Should be considered
Usefulness/efficacy is less well established by evidence/opinion.
May be considered
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).
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.
D-Dimer levels increase physiologically with each trimester. In one study the mean preconception D-dimer concentration was 0.43 (SD 0.49) mg/L, and rose in the first, second, and third trimester to 0.58 mg/L (SD 0.36), 0.83 (SD 0.46) mg/L, and 1.16 (SD 0.57) mg/L, respectively, indicating a 39 % relative increase in D-dimer concentration for each trimester compared with the previous one (Kline et al. 2005).
Thus a positive D-dimer test based on the conventional cut-off level is not necessarily indicative of DVT and new cut-off levels are needed. However, the degree of the pregnancy related increase in D-dimer levels rarely reaches levels which usually are associated with DVT. Therefore the ESC guidelines recommend that the diagnosis is made by determination of D-Dimer levels, respecting the physiologically increased levels and compression ultrasound leg vein imaging. Compression ultrasound leg vein imaging has a high sensitivity and specificity for proximal deep vein thrombosis. Serial compression ultrasonography with Doppler imaging of the iliac vein performed over a 7-day period excludes deep-vein thrombosis in symptomatic pregnant women (Chan et al. 2013).
Treatment in acute deep vein thrombosis is based on the use of therapeutic doses of LMWH. LMWH should be administered in a weight adjusted, twice daily regimen (see treatment of pulmonary embolism).
Symptoms and signs of pulmonary embolism during pregnancy are the same as in the non-pregnant state (new onset dyspnoea, chest pain, tachycardia, haemoptysis and collapse). Clinical assessment of pulmonary embolism is however more difficult, because dyspnoea and tachycardia are not uncommon in normal pregnancy. A high index of suspicion is important for the timely diagnosis of venous thromboembolism. All pregnant women with signs and symptoms suggestive of venous thromboembolism, particularly dyspnoea of acute onset or worsening dyspnoea should have objective testing performed as expeditiously as it is the case in non-pregnant patients. According to the consensus of the European Society of Cardiology task force (Regitz-Zagrosek et al. 2011) D-dimer concentration should be measured in patients with suspected pulmonary embolism, followed by bilateral compression ultrasonography. If this is normal in the presence of negative D-dimer levels then pulmonary embolism is unlikely and anticoagulation with LMWH is not warranted.
In patients with suspected pulmonary embolism, positive D-dimer levels and positive compression ultrasonography, anticoagulation treatment is indicated. If D-dimer levels are elevated and compression ultrasonography is negative in patients with suspected pulmonary embolism, further testing is required. Computed tomography pulmonary angiography should be performed, when the diagnosis cannot be confirmed or excluded with the above discussed tools. In these patients it is preferred over ventilation–perfusion lung scanning for the diagnosis of pulmonary embolism (Torbicki et al. 2008). Both techniques are associated with fetal radiation exposure, with ventilation–perfusion lung scanning delivering a higher fetal dose of radiation than computed tomography pulmonary angiography. However, radiation doses are below the limit that is regarded as dangerous for the fetus (Torbicki et al. 2008; Winer-Muram et al. 2002).
LMWH has also become the drug of choice for the treatment of venous thromboembolism in pregnancy and puerperium. The efficacy and safety of several LMWH preparations was shown in a review of 2,777 pregnant women, treated for deep vein thrombosis or pulmonary embolism. The risk of recurrent venous thromboembolism with treatment doses of LMWH was 1.15 %. The observed rate of major bleeding was 1.98 %. Heparin – induced thrombocytopenia is markedly lower with LMWH than with UFH and so is heparin – induced osteoporosis (0.04 %) (Greer and Nelson-Piercy 2005). In clinically suspected deep vein thrombosis or pulmonary embolism treatment with LMWH should be given until the diagnosis is excluded by objective testing. The recommended therapeutic dose is calculated on bodyweight (e.g. Enoxaparin 1 mg/kg bodyweight twice daily, Dalteparin 100 IU/kg bodyweight twice daily) aiming for peak anti-Xa values (4–6 h post-dose) of 0.6–1.2 IU/ml (Bates et al. 2008). The necessity to monitor anti-Xa values regularly in patients with venous thromboembolism is still controversial. Whereas it is considered necessary in patients with mechanical valves in whom LMWH is used this is not so clear in patients with venous thromboembolism. Given the need for dose-increase as pregnancy progresses to maintain a certain therapeutic anti-Xa –level (Barbour et al. 2004; Friedrich and Hameed 2010) it seems reasonable to also determine anti-Xa levels during pregnancy in patients with venous thromboembolism. This appears particularly justified in view of the fact, that pulmonary embolism occurred in women receiving preventive doses of LMWH (Knight 2008). This topic also requires further studies. A simple guide is to adjust the dose according to increasing weight during pregnancy.
UFH also does not cross the placenta, but is associated with more thrombocytopenia, osteoporosis and more frequent dosing when given subcutaneously compared to LMWH. It is favoured in patients with renal failure and when urgent reversal of anticoagulation by protamine may be needed as well as in the acute treatment of massive pulmonary emboli. In patients with acute pulmonary embolism with haemodynamic compromise intravenous administration of UFH is recommended (loading dose of 80 units/kg, followed by a continuous intravenous infusion of 18 units/kg/h).
The activated partial thromboplastin time has to be determined 4–6 h after the loading dose, 6 h after any dose change and then at least daily when in the therapeutic range. The therapeutic target activated partial thromboplastin time ratio is usually 1.5–2.5 times the average laboratory control value. The dose is then titrated to achieve a therapeutic activated partial thromboplastin time, defined as the activated partial thromboplastin time that corresponds to an anti-Xa level of 0.3–0.7 IU/mL. After improvement in haemodynamics and stabilisation of the patient UFH can be switched to LMWH in therapeutic doses and maintained during pregnancy. LMWH should be switched to intravenous UFH at least 36 h before the induction of labour or caesarean delivery. UFH should be discontinued 4–6 h before anticipated delivery, and restarted 6 h after delivery if there are no bleeding complications. Neither UFH nor LWMH are found in breast milk in any significant amount and they do not represent a contraindication to breastfeeding.
Thrombolytics are considered to be relatively contraindicated during pregnancy and peripartum and should only be used in high risk patients with severe hypotension or shock (Torbicki et al. 2008). The risk of haemorrhage, mostly from the genital tract, is about 8 % (Turrentine et al. 1995). In about 200 reported patients, mostly streptokinase was used and more recently recombinant tissue plasminogen activator. Both thrombolytics do not cross the placenta in significant amounts. Fetal loss of 6 and 6 % preterm delivery were reported (Ahearn et al. 2002). Urokinase does cross the placenta and is therefore not primarily advised. There are very few studies on fondaparinux in pregnancy, one has shown minor transplacental passage of fondaparinux (Dempfle 2004). Because of the scarce data it should not be used in pregnancy.
In patients with recent pulmonary embolism, heparin treatment should be restarted 6 h after a vaginal birth and 12 h after a caesarean delivery, if no significant bleeding has occurred. Dose adjustments may be necessary because of decreases in blood volume and renal clearance. Vitamin K antagonists may be started on the second day after delivery and continued for at least 3–6 months (6 months if pulmonary embolism occurred late in pregnancy). The INR should be between 2 and 3 and needs regular monitoring, ideally once every 1–2 weeks. Vitamin K antagonists do not enter the breast milk in active forms and are safe for nursing mothers.
Cardiomyopathies and Heart Failure
The aetiology of cardiomyopathies occurring in association with pregnancy is diverse with acquired (peripartum cardiomyopathy, toxic cardiomyopathy) and inherited (hypertrophy cardiomyopathy, dilated cardiomyopathy, storage disease, etc.) forms of cardiomyopathy. Their incidence differs according to regions and the precise incidence in Europe is not known. However, mothers with cardiomyopathies have a high mortality during and after pregnancy (Sliwa et al. 2010). A thrombus in the left ventricle and associated embolic events are rare but dangerous complications of heart failure due to cardiomyopathies. The European Society of Cardiology guidelines on treatment of chronic heart failure recommend anticaoagulation with vitamin K antagonists for patients with very low ejection fraction; ventricular thrombi or atrial fibrillation (McMurray et al. 2012). Accordingly, pregnant women who have a dilated or peripartum cardiomyopathy together with atrial arrhythmias or ventricular thrombi should be anticoagulated using LMWH or Vitamin K antagonists according to stage of pregnancy, as discussed above. The newer anticoagulant agents (dabigatran, apixaban, fondaparinux) are not recommended because of lack of experience.
Care should be taken with anti-coagulation therapy in the immediate phase after delivery, but once the risk of obstetric haemorrhage has passed, it should be considered in patients with very low EF. Peripheral embolism including cerebral embolism and ventricular thrombi are especially frequent in peripartum cardiomyopathy patients (Sliwa et al. 2010). This is in part due to increased procoagulant activity in the peripartum phase (Brenner 2004).
In hypertrophic cardiomyopathy therapeutic anticoagulation with LMWH or Vitamin K antagonists is recommended for those with paroxysmal or persistent atrial fibrillation.
Patients with valvular atrial fibrillation with either native or prosthetic valves require anticoagulation during pregnancy. For management of patients with prosthetic valves see above chapter on mechanical valves. Also in patients with native valves atrial fibrillation is associated with a high thromboembolic risk, particularly in patients with severe mitral stenosis. The occurrence of atrial fibrillation requires immediate anticoagulation with intravenous UFH, followed by LMWH in the first and last trimester and oral anticoagulants or LMWH for the second trimester. LMWH should be given in weight- adjusted therapeutic doses (twice daily) until 36 h prior to delivery. If oral anticoagulants are used, the INR can be kept between 2.0 and 2.5, thus minimizing the risk for the fetus.
The thromboembolic risk in non-valvular atrial fibrillation depends upon the presence of risk factors. Patients without structural heart disease or risk factors (“lone atrial fibrillation”) have the lowest risk of thromboembolic events and do not require anticoagulation or antiplatelet therapy outside or during pregnancy; however, studies during pregnancy are not available. An increase in thromboembolic risk in non-valvular atrial fibrillation is assessed with the CHADS2 criteria (Fuster et al. 2006) and the CHA2DS2VASC score (Camm et al. 2010) in non-pregnant patients. In these, oral anticoagulation is only beneficial when the thromboembolic risk is ≥4.0 events per 100 patient years (correlates to ≥2 risk points with the CHADS2 score or 2 risk points with the CHA2DS2VASCscore). The same considerations therefore apply to pregnant patients; thromboprophylaxis is recommended in patients with increased CHA2DS2VASC scores. The choice of the anticoagulant is made according to the stage of pregnancy. Vitamin K antagonists are recommended in most cases from the second trimester until 1 month before expected delivery (Camm et al. 2010). Subcutaneous administration of weight adjusted therapeutic doses of LMWH is recommended during the first trimester and during the last month of pregnancy. Not enough safety data are available for the newer anticoagulant agents in pregnancy (Dabigatran, Apixaban, Fondaparinux or Rivaroxaban). Either single or dual antiplatelet therapy (clopidogrel and acetylsalicylic acid) were not as effective as warfarin in high risk patients with atrial fibrillation (Healey et al. 2008; Camm et al. 2010).
Studies in non-pregnant older patients show that LMWH is effective and can be used if appropriate monitoring is available. Subcutaneous administration of weight adjusted therapeutic doses is recommended during the first trimester and during the last month of pregnancy.
For patients with atrial fibrillation duration <48 h and no thromboembolic risk factors, intravenous heparin or weight adjusted therapeutic dose LMWH may be considered peri-cardioversion, without the need for post-cardioversion oral anticoagulation. The indications for prophylactic antiarrhythmic drugs and anticoagulation relates to the presence of symptoms and the presence of risk factors for thromboembolism, respectively (Camm et al. 2012). In patients with risk factors for stroke or atrial fibrillation recurrence, anti-thrombotic treatment should be continued following cardioversion (Camm et al. 2012).
Acute Coronary Syndromes
Acute coronary syndromes in pregnancy may be an indication for use of antithrombotic agents in the context of percutaneous coronary intervention and stent implantation. Primary percutaneous coronary intervention is the preferred modality of reperfusion during pregnancy since it avoids potential hazards of thrombolysis and it is the only means to diagnose and treat spontaneous coronary dissection. Spontaneous coronary artery dissections are more prevalent among pregnant than non-pregnant women, occurring mainly around delivery or in the early postpartum period (Roth and Elkayam 2008). Stenting should favor the use of bare-metal stents with 3–4 weeks of dual antiplatelet therapy (Regitz-Zagrosek et al. 2011). UFH or LMWH is used during percutaneous coronary intervention and stopped after 24–48 h. Because of the relatively higher frequency of spontaneous coronary dissection in pregnancy, intravenous thrombolysis should be used only in women with ST-segment elevation ACS who cannot be treated with primary percutaneous coronary intervention. Recombinant tissue plasminogen activator does not cross the placenta but carries a bleeding risk, in particular retroplacental bleeding.
The use of antiplatelet agents is rarely indicated in pregnancy. It should be limited to the shortest duration possible, for example after stent implantation. In this case, Clopidogrel and aspirin should be used. The use of more recent antiplatelet drugs (prasugrel, ticagrelor), bivalirudin and glycoprotein IIb/IIIa inhibitors is not recommended during pregnancy (Regitz-Zagrosek et al. 2011).
Congenital Heart Disease
Anticoagulation therapy is an issue in pregnant women with congenital heart disease when they have mechanical valves, (paroxysmal) atrial fibrillation or flutter, or severely reduced ejection fraction. Women with pulmonary hypertension who have an indication for anticoagulation outside pregnancy should continue anticoagulation therapy during pregnancy (Regitz-Zagrosek et al. 2011). In women with pulmonary hypertension associated with intracardiac shunts, both the risk of thromboembolism and of bleeding are elevated. These women are prone to haemoptysis and thrombocytopenia. Therefore, the indication for anticoagulation should be carefully considered on an individual basis.
In women with the Fontan circulation, the risk of thromboembolism is considered high, especially in patients with an atriopulmonary connection. Therefore therapeutic anticoagulation should be considered.
In patients with congenital heart disease anticoagulation therapy is chosen dependant on the stage of pregnancy, with LMWH in the first trimester and the last month of pregnancy, while vitamin K antagonists can be used in the second and third trimester.
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