CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 6, November/December 2022 AFRICA 323 Cardiology/American Heart Association (ACC/AHA) places more emphasis on patient preference than on age.11 In women desiring fertility and needing valve surgery, the benefits and risks of mechanical versus bio-prosthetic valves should be discussed.9,12 MHVs have the benefit of being more durable, with less chance of re-operation but with the need for lifelong anticoagulation with warfarin and international normalised ratio (INR) monitoring.8,13 In low- to middle-income countries (LMIC) such as South Africa, BPVs may not be a sustainable or accessible option due to socio-economic factors.14 BPVs, although significantly less thrombogenic, are prone to degeneration, especially in the young and during pregnancy, therefore needing re-operation.13,14 This unknown proportion of women are therefore generally offered MHV replacement and placed on lifelong anticoagulation with warfarin.3 This drug has been shown to be a highly effective option in the prevention of complications associated with MHV. Although this confers significant maternal benefit, it has been shown to be associated with deleterious consequences and complications to the developing embryo, with additional risk translated to the growing foetus.15 Pregnancy physiology Pregnancy is a hypercoagulable state induced by the physiological changes to the coagulation and fibrinolytic systems.1,2 This adaptive mechanism is to prevent post-partum haemorrhage. There is an increase in fibrinogen levels and coagulation factors with a decrease in protein C and a relative protein S resistance, important natural anticoagulants.15 However, the natural anticoagulant antithrombin III (ATIII) remains normal. Changes in the fibrinolytic system lead to impaired fibrinolysis. Pregnant women with prosthetic valves are therefore more at risk for thrombosis, stuck valves and TEC than the general population. The use of anticoagulation, patient compliance to regimens, strict mean targets set for therapy, as well as increased monitoring in pregnancy are warranted. What drugs are available for anticoagulation in pregnant women with MHVs? The most commonly used drugs for anticoagulation in pregnancy are the VKA and heparins, administered intravenously as unfractionated heparin (IV UFH) or subcutaneously as low-molecular-weight heparin (LMWH).16 Subcutaneous unfractionated heparin is rarely used. Direct oral anticoagulants (DOAC) are considered a preferred treatment option in patients with non-valvular atrial fibrillation, deep-vein thrombosis and pulmonary embolus in the general population.17 A 2021 updated systematic review and metaanalysis by Bitar et al. showed a significant reduction in systemic embolism and risk of intracranial haemorrhage in patients with non-valvular AF and valvular heart disease when compared to warfarin.18 This analysis was not applicable in more severe mitral stenosis and in MHVs. Furthermore, pre-clinical and in vitro studies evaluating its use in patients with MHVs were not found to be promising.19 The ACC/AHA and European Society of Cardiology (ESC) advocate the use of warfarin in MHVs until more evidence becomes available. Evidence on its safety and efficacy in pregnancy and breastfeeding has not been demonstrated.20 The 2020 International Society on Thrombosis and Hemostasis congress concluded that based on their available data, the risk of embryopathy with DOAC was lower than with warfarin.21 Therefore, elective termination of pregnancy for fear of embryo toxicity should not be offered. Instead, closer pregnancy monitoring, pharmacovigilance and reporting of adverse pregnancy outcomes were suggested as management options. They further elucidated that the data are deficient and hence the use of DOAC should be avoided in pregnancy. Historically, the use of LMWH had limited use in the anticoagulation of pregnant women with prosthetic valves. In early 2000, a controversy followed after Aventis Pharmaceuticals Inc and the Federal Drug Administration issued black-box warnings implicating LMWH in catastrophic TEC and maternal death.4 This recommendation was based on very small studies and small post-marketing reports. The systematic review by Chan et al. in 2000 recognised only three regimens at the time, namely VKA, sequential therapy and UFH.16 However, contemporary practice and recent consensus statements support the use of dose-adjusted LMWH, with vigilant anti-Xa monitoring to achieve peak levels four hours post drug administration, of between 0.8 and 1.2 U/ml. There is emerging evidence that trough levels should be maintained at 0.6 U/ml.9,22 LMWH has been shown to offer superior benefit to the foetus since it does not cross the placenta. However, the maternal risk for TEC is greater when compared to warfarin. In the first trimester there is generally an increase in renal plasma flow with a resultant increase in renal clearance.9 The increased renal clearance may necessitate much higher starting doses than the typical 1 mg/kg. Beresheim et al. conducted a small study that showed that the overall mean dose required to achieve therapeutic peak levels is 1.3 mg/kg.23 Generally, the first trimester may be associated with transitions from warfarin to heparin to lower the risk of embryopathy. Moreover, this practice is supported from data from the Registry of Pregnancy and Cardiac Disease (ROPAC), which showed higher rates of maternal adverse events during the first trimester compared to the rest of pregnancy.3,4 Therefore, these factors may place women at increased risk of TEC in the first trimester. Pharmacology: mode of action UFH binds to the enzyme inhibitor antithrombin III, the activated ATIII then inactivates thrombin and anti-factor Xa (Fig. 1).24 LMWH has a shorter glycosaminoglycan pentasaccharide structure compared to UFH and therefore only inhibits factor Xa. The therapeutic effects of UFH are monitored with activated partial thromboplastin time (aPTT) versus LMWH in which anti-Xa levels are used for monitoring. UFH has a half-life of one to two hours in comparison to LMWH, which has a half-life four times longer. This short half-life makes it the drug of choice prior to planned delivery. Furthermore, protamine sulphate can be used to reverse the effects of UFH. Protamine sulphate only partially reverses the effects of LMWH by about 70%.25 The main adverse events associated with UFH are heparininduced thrombocytopenia (HIT) and osteoporosis.24 These
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