Anticoagulation in Pregnancy and Puerperium : With a Focus on the Bene fi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis A

Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis A Nebojša M. Antonijević1,2, Ljubica M. Jovanović2, Branka M. Terzić2, Mirjana K. Kovač1,3, Tatjana Ž. Ilić Mostić4, Ivana D. Živković2, Dragan M. Matić2, Ratko M. Lasica1,2, Ivan V. Ranković5, Nebojša L. Radovanović1,2, Milika R. Ašanin1,2, Vladimir I. Kanjuh6


INTRODUCTION
Th e current number of women in the reproductive phase (from 15 to 45 years) in Europe is estimated at about 105 million, with about 5 million children annually born in average.About 1% of pregnancies among women in Europe are complicated by heart disease, the risk of cardiovascular disease in pregnant women being further increased by the fact that ever older women are giving birth [1].
Pregnancy is a condition of increased risk of thrombosis due to synergy of all the three components of the Virchow's triad [2].Due to altered physiology in pregnant women and hormonal status procoagulant factors and the procoagulant state dominates.Levels of fibrinolysis inhibitor (PAI-1 or PAI-2) produced by the placenta are elevated, causing a decrease in fi brinolytic activity during pregnancy.On the other hand, additional thrombogenic effect is associated with changes in the levels of natural anticoagulants, namely, a reduction in protein S levels is recorded as early as the fi rst trimester; the concentration of antithrombin (AT) decreases in case of a caesarean delivery.A series of homeostatic changes induced in pregnancy is associated with activated protein C resistance registered in a number of pregnant women [3][4][5].Also, there is an increase in platelet-endothelial adhesion molecules as well as endothelial cell activation associated with a proinfl ammatory state, especially during labour or caesarean section when damage to blood vessels is incurred [2,6,7].
In addition, the gravid uterus compresses major blood vessels of the abdomen and pelvis, this resulting in venous dilatation and slowed venous fl ow, which poses a risk of deep venous thrombosis of the pelvis and legs.Consequently, in certain conditions during pregnancy there is a need for administering adequate anticoagulant therapy.Some diseases and conditions require the use of vitamin K antagonists (VKA), whose teratogenic potential presents a signifi cant safety issue [2].Th ough VKA administration represents the most eff ective anticoagulant therapy for the prevention of thrombosis in pregnant women with mechanical heart valves, at the same time it may lead to serious birth defects, embryopathy, even stillbirth [8].Th erapy with heparin drugs, especially with low molecular weight heparins (LMWH) has reduced adverse fetal outcomes, but, on the other hand was accompanied by a higher incidence of prosthetic valve thrombosis in patients with prosthetic heart valves.Th e risk of thrombosis in practice may be reduced by using higher doses of LMWH, more frequent testing and adjusting not only peak anti-Xa activity levels analyzed from a blood sample 4 h aft er subcutaneous injection of LMWH, but also trough anti-Xa activity levels, analyzed in the blood sample immediately prior to the administration of subcutaneous injections of LMWH.When administering LMWH in order to prevent thrombosis prosthetic valves, it is advised to maintain anti Xa activity values at a high therapeutic level [2].

ORAL ANTICOAGULANTS DURING PREGNANCY
Anticoagulant therapy is indicated in pregnancy in women with mechanical prosthetic valves, with previous or current venous thrombosis and thromboembolism as well as in presence of a thrombus in the cardiac chambers, atrial fi brillation with a high thromboembolic risk, in pulmonary hypertension due to severe thrombophilia or if there is a history of recurrent miscarriage.Besides thrombophilia with recurrent miscarriage, anticoagulant therapy is also considered in cases of stillbirth, preeclampsia, post-thrombotic syndrome, ovarian hyperstimulation syndrome in the fi rst trimester, known to be likely associated with a hypercoagulable state [2,9].
Oral anticoagulation with vitamin K antagonists provides better maternal protection against thrombosis than heparin preparations, though its administration may be associated with a potential risk of embryopathy, fetal malformation as well as loss, especially in the period of 6-12 weeks of gestation and prior to delivery [8,10].It being considered by authors such as Dr. Celine Montovan that VKA administration, particularly between 6-12 weeks of pregnancy, may lead to embryotoxicity, this is a period when VKA replacement with heparin preparations is strongly suggested [9].It is of special importance when VKAs are administered at higher doses or when the dose of warfarin is higher than 5 mg per day [9].Warfarin in higher doses of 5 mg and more cause a higher percentage of fetal abnormalities, miscarriage and stillbirth [2].
Vitamin K antagonists (VKA) cross the placenta and may cause embriopathy in specifi c phases of the fi rst trimester [10,11].Also, VKA increase the risk of miscarriage, hemorrhaging and teratogenicity [10].Administering VKA in absolute and relative sensitive period of fetal development (from 28 to 112 days) may cause fetal abnormalities, disturbances in fetal osteogenesis and chondrogenesis.In addition, there occur abnormalities of the CNS, such as microcephaly [12].Th e most common fetal abnormalities associated with warfarin are: midfacial hypoplasia, stippled pineal gland (chondromalatia punctata), hypoplasia with nose, limb and fi nger deformities [9,10,13].
Rare anomalies such as the formation of the dorsal middle line dysplasia have 330 Volume 3 • Number 1 • January 2016 • HOPH been described as well as agenesis of the corpus callosum, Dandy-Walker malformation, mid line cerebellar atrophy, ventral middle line dysplasia which may lead to atrophy of the nervus opticus.Blindness, epilepsy, deafness, respiratory distress, kidney agenesis or hypofunction, anal dysplasia, cleft lip and soft palate may likewise occur [10,13].Th e risk of developing embryopathy is estimated at 5-7%, this percentage being higher when broadened to include the less pronounced CNS disorders induced by warfarin [9].
Due to the transfer of VKA through the placenta, the fetus is at signifi cantly increased risk of hemorrhage.Th e immaturity of the fetal liver is a major cause of slow warfarin metabolism and low clotting factor levels in the fetus itself, the anticoagulant eff ect thus being markedly greater than in the mother.Furthermore, there is a high risk of hemorrhage in newborns during childbirth, sometimes with a possible fatal outcome.Th erefore, interruption of VKA therapy at 34-36 weeks of gestation is recommended or a cesarean section suggested reducing the possibility of hemorrhage in the child due to birth trauma [9].Some authors specifi cally point out the development of retroplacental hematoma as a common cause of fetal loss [14].Th e European guidelines state that VKA administration in the third trimester of pregnancy can cause fetal and neonatal hemorrhage and placental abruption as well as lead in any trimester to abnormalities in the central nervous system, such as optic atrophy, microcephaly, mental retardation, hypotonia and spasticity [9,10,11,15].
Along with hemorrhagic complications and damage to the central nervous system, VKA administration in the second and third trimester causes a number of minor malformations and other neural-developmental problems.Larger cohort studies do not enlist the occurrence of major neurological anomalies when VKAs are administered in the second and third trimesters.Children whose mothers received VKAs during pregnancy do not diff er from other children related to the mean intelligence quotient scores while diff erences in reading and solving arithmetic problems are described.Contrary to the above assertion made in recommendations by the ACCP, Dr. Judit Wesseling has registered twice higher risk of minor neurological disorders and a higher incidence of reduced intelligence quotient (less than 80%) in children exposed to VKA during the second and third trimester of pregnancy (OR 2. 1, CI 1. 2-3.8) [16][17][18].
Teratogenic eff ect of VKA is dose-dependent, being lower at acenocoumarol doses of less than 2 mg or warfarin doses of less than 5 mg than at doses above 5 mg (8 vs. 2.6%).However, in certain populations even this dose proved to be too large, for example in Japanese examinees [12,19].W.C. Chan states the embryopathy incidence of 6.4%/ in mothers receiving warfarin doses less than 5 mg [9,20].Some studies report 81% of fetal complications in pregnant women with warfarin administered in a dose higher than 5 mg [13].
With a warfarin dose exceeding 5 mg/ day embryopathy is registered in 9% and fetal complications in 88% of the cases.At doses of warfarin less than 5 mg embryopathies are not registered while the risk of fetal complications is 15% [21,22].Th e North American recommendations (ACCP) state that the use of vitamin K antagonists during the fi rst 6 weeks carries no risk of embryopathy, as well as that warfarin should be replaced with heparin preparations in the period of 6-12 weeks [10].In the study by Chan and associates none of the 125 women using warfarin only during the fi rst 6 weeks of gestation gave birth to a child with birth defects [10,20].
Middeldorp S. reports that teratogenic eff ect only occurs when VKAs are administered in the 6-12 weeks of gestation period [16].
Schaeafer further states that none of the 235 newborn infants whose mothers received VKA only during the fi rst 8 weeks of gestation had abnormalities [10].
Frequent pregnancy tests are advised www.hophonline.orgto women already taking oral vitamin K antagonists trying to conceive.At the time of conception, substitution of vitamin K antagonists by heparin preparations is suggested not VKA replacement with LMWH while planning conception [10].
According to the North American recommendations, the use of VKA is not recommended three weeks before childbirth [10].
It should be specifi cally underlined that VKA should not be used from 6-12 weeks of pregnancy and 3 weeks before delivery and that during this period parenteral heparin preparation administration along with adequate monitoring of achieved anticoagulant eff ect is strongly advised in the course of this period.

PARENTERAL ANTICOAGULANTS IN PREGNANCY
Unfractionated heparin and low molecular weight heparins do not cross the placenta and therefore do not aff ect the formation and development of the fetus, but carry an increased risk of thrombotic complications in mothers with prosthetic heart valves, even with a properly adjusted dose and careful monitoring [14,21].
Heparin administration during pregnancy virtually eliminates the risk of embryopathy, has no adverse eff ect on development of the fetus, but does not provide protection from thrombotic complications equivalent to that of ensured by VKA administration [14,23].
Chan W.C. states that the use of heparin products in the period between 6 and 12 weeks does not lead to teratogenicity, but such a therapeutic approach entails a much higher risk of thromboembolic complications of 9.2% [9,20].
A combined approach of treatment with VKA and heparin drugs throughout the period of absolute risk for embriopathy, signifi cantly, almost completely eliminates the risk of embryopathy but increases the risk of thromboembolism and thrombosis of prosthetic valves [14].
Tanaka H. and his colleagues indicate the complexity of the problem of VKA administration in pregnant women.Being much safer for the fetus, unfractionated heparin administered in appropriate doses is recommended for the prevention of thrombosis valve (2-3 times prolonged aPTT compared to controls) but does not prevent completely valve thrombosis formation [8].On the other hand intracranial hemorrhage is recorded in patients treated with UFH along with considerable aPTT variation over 50% during the night [8].Recent studies fi nd warfarin the best suited anticoagulant medication for preventing valve thrombosis, noting that the valve thrombosis also register at VKA therapy, as confi rmed by Chan who determined an overall incidence of valve thrombosis of 4% [8,20].During administration of VKA individual cases of intracranial hemorrhage in the mother have also been recorded [8].Th e risk of hemorrhage in mothers receiving anticoagulant therapy is estimated at around 2.5%, pointing out that about 80% hemorrhage is peripartal [21].
It should be emphasized that in pregnancy there is an increase in the glomerular fi ltration rate as well as in plasma volume, consequently resulting in decreased plasma drug concentrations.In addition, placental heparinase activity is elevated, necessitating higher doses of LMWH.Th is also requires weekly checks of plasma anti-Xa levels in order to attain a target level of 1.0-1.2U/mL [21,24].
Quinn fi nds that a mean increase in the dose of LMWH of 54.4% is necessary during pregnancy to achieve the optimum anticoagulant eff ect [24].More recent research suggests that along with peak anti-Xa activity there should also be monitored trough (lowest) levels of anti-Xa activity [24].It is known that pregnant women receiving enoxaparin every 12h with peak anti-Xa levels of 0.7-1.2U/ mL are associated with sub-therapeutic trough levels, with a pre-dose level of less than 0.6 IU/ mL in over 50% of cases [24][25][26][27].
We would like to lay particular stress on the fact that low molecular weight heparins (according to the summary of product characteristics) are not indicated for the prophylaxis of thrombosis in patients with prosthetic heart valves [21,[28][29][30].
In his study, Salazar E. accentuated 2 cases of female patients who between 6-12 weeks of pregnancy developed fatal valve thrombosis upon replacement of acenocoumarol with heparin despite adequate anti-coagulation with aPTT ratio maintained between 55-95 seconds (control time of 30-35 seconds) concluding that subcutaneous heparin with a target aPTT 1, 5-2, 5 times the control heparin is not eff ective in preventing prosthetic valve thrombosis [21,31].
Th rombogenicity valve, clinical and laboratory parameters of patients should be kept in mind when choosing the most appropriate therapeutic regimen for pregnant women with mechanical valves.Factors known to increase the risk of prosthetic valve thrombosis are: older types of valves (ball-cage valves, Starr-Edwards, Bjork-Shiley valve standard, Omniscience) compared with newer types (St Jude Medical, Medtronic Hall), then the mitral valve position more than the aortic position, heart failure, an ejection fraction of less than 35%, atrial fi brillation, previous history of thromboembolism [2,10,21,32].A VKA is the most reliable anticoagulant in pregnancy.
Th e decision on whether to administer a VKA depends on the risk of valve thrombosis.It should never be neglected that prosthetic www.hophonline.orgheart valve thrombosis is a potentially fatal condition in all patients, particularly pregnant women [20,27].

PROSTHETIC VELVE THROMBOSIS PREVENTION IN PREGNANT WOMEN
American ACC/AHA (American College of Cardiology and the American Heart Association) guidelines, the ESC guidelines (European Society of Cardiology) and ACCP (American College of Chest Physicians) vary considerably among themselves in approaches to mechanical prosthetic heart valve thrombosis prevention [24].Th e ACC/AHA guidelines permit the continuation of vitamin K antagonists therapy during the fi rst trimester if the warfarin dose is lower than 5 mg or where low molecular weight heparins are administered in 2 doses to achieve high therapeutic peak levels of anti-Xa activity of 0.8-1.2U/mL in a sample taken 4-6 hours aft er subcutaneous injection [24,33].In case that the daily dose of warfarin is higher than 5 mg during the fi rst trimester the same guidelines alternatively propose the use of intravenous infusion of heparin with the target aPTT twice longer than the control [24,33].Administration of low-dose aspirin (75-100 mg daily) may be advised as an additional medication during the second and third trimester [24].If warfarin is the drug of choice during pregnancy, its dosing aims to achieve a target INR of 3.0 (2.5-3.5).
Th e ACCP (American College of Chest Physicians) guidelines published in 2012 guidelines recommend continuation of warfarin therapy in high-risk patients with prosthetic valve thrombosis risk factors de-fi ned above [10,24].In female patients with low risk for valve thrombosis subcutaneous administration of UFH is advised in order to achieve "mid-interval" aPTT at least 2 times higher than the control or anti-Xa level of 0.3-0.7 U/mL or alternatively low molecular weight heparin (LMWH) subcutaneously 6-12 weeks of gestation or throughout the entire pregnancy administered with 12h dosage regimen, it being recommended that target anti Xa levels planned for LMWH at the given dose regimen be achieved, monitored on a weekly basis [10,24].In addition to low molecular weight heparin in high-risk female patients there may also be considered administering a once daily regimen of 75 or 100 mg low-dose aspirin [10,24].In women with bileafl et aortic valve prosthesis with a lower risk of thrombosis achievement of slightly lower INR of 2.5 (2-3) using VKA therapy is advised instead of the target INR for patients with a high risk of 3.0 (2.5-3.5)[10].
Th e ESC guidelines 2011, in case of female patients with prosthetic mechanical valves when less than 5 mg of warfarin is needed to achieve an adequate INR also recommend continuation of warfarin up to 36 weeks of pregnancy with the risk of embryopathy less than 3%; and, if doses of warfarin greater than 5 mg between 6-12 weeks are necessary, switching to treatment with intravenous UFH infusions or LMWH (with monitoring to achieve an aPTT in the therapeutic range 2-2.5 higher than the control -A/N Author's Note) or LMWH with a one-week control of peak anti-Xa levels to attain a target value of 0.8-1.2U/ml in the blood sample taken 4-6 hours after injection [23,34].Trough levels of anti-Xa activity, so-called pre-dose levels are not yet suffi ciently harmonized, especially with regard to the relationship between thromboembolism and hemorrhage, for any fi rm conclusions to be reached, but for the time being it is considered that they should be higher than 0,6 U/mL [1].

Volume 3 • Number 1 • January 2016 • HOPH
Heparin treatment is initiated with an intravenous bolus (starting dose) of 80 IU/ kg (body weight bolus) followed by18 IU/kg/h infusion [35].To achieve a therapeutic aPTT measured every 6h during the initial phase of treatment, it is recommended that UFH be administered by intravenous route at doses adjusted based on the Raschke's nomogram [35].Th e standard dosage of subcutaneous heparin regimens in pregnancy is: 17,500 to 20000 IU every12 hours, or more precisely starting with the initial dose of 333 IU/ kg followed by the subsequent 2 x 250 IU/kg dose, it being advised that the mid-interval aPTT (measured 6h aft er the s.c. dose) be maintained to a ratio 2-3 times the control value [34][35][36][37].
When warfarin doses higher than 5 Aspirin in addition to anticoagulation is not recommended Table 5. Comparative review of current recommendations for anticoagulant therapy in patients with mechanical valves [45] mg are required to maintain the target INR, in the fi rst trimester it is advised to switch from warfarin to LMWH therapy with precisely tailored dosing regimens along with monitoring of anti-Xa activity [24].All of the above guidelines agree that it is harmful to administer LMWH without regularly monitoring the patient's anti-factor Xa levels [2,10,15,24,33,34].

PERIPARTUM USE OF ANTICOAGULANTS
According to the North American ACCP guidelines 2012, VKA administration is not recommended three weeks before anticipated delivery [10].Th e ACC/AHA 2014 guidelines advise discontinuation of VKA in 36 th week and initiation of therapy IV UFH (in recommended doses suffi cient to achieve target therapeutic aPTT levels that should exceed approximately 2-2.5 times the control value -A/N) it being advised that UFH be stopped about 4 to 8 hours prior to expected delivery and restarted 4 to 6 hours aft er delivery in the absence of signifi cant bleeding.Th en, VKA therapy resuming is recommended 24 h aft er delivery [23,33].
Th e ESC guidelines advise stopping VKAs at 36 weeks of gestation and their replacement with IV UFH or LMWH until 36 hours before delivery, when LMWH is switched to IV UFH [24,34].Th e ACCP guidelines advise that patients with very high risk of thromboembolism (older generation valves in www.hophonline.orgthe mitral position and previous thromboembolism) should continue with warfarin administration until close to delivery, generally 48 hours before the anticipated time of delivery, when VKA therapy is replaced with UFH or LMWH [10,24].
In the event of unexpected labour, prior to the scheduled date in the patient on oral anticoagulant therapy, a caesarean section is advised because of the risk of fetal intracranial hemorrhage in case of vaginal delivery or for other obstetric reasons [24].Panduranga advises discontinuation of IV UFH infusion 4-6 hours before delivery and restarting it 4-6 h aft er delivery [24].Montavon considers that UFH or LMWH should be introduced 12 hours following cesarean section or 6h aft er vaginal delivery in conjunction with a VKA on the following day to be overlapped with heparin preparations until therapeutic INR values are achieved [9].
Th erapy with heparin preparations, especially low molecular weight heparins, has proven eff ective in reducing adverse eff ects on the fetus, but is associated with a high rate of valve thrombosis in female patients with prosthetic heart valves.

Administration of anticoagulant therapy in nursing mothers
Anticoagulant therapy may be continued soon aft er birth, depending on the type of delivery and whether adequate hemostasis is achieved, usually aft er 6-12h, that is, 12-24h aft er epidural catheter removal.Treatment is initiated with  * acetylsalicylic acid unfractionated heparin or LMWH administered parenterally, overlapped with VKA on the following day, continued for two consecutive days until a therapeutic INR is achieved, when UFH or LMWH therapy is ceased [10].Th ough VKA administration to lactating women is considered safe for the newborn, it is thought that the transfer of coumarin into maternal milk may, however, leave exclusively breastfed babies at risk for vitamin K defi ciency [9,15].Th ere is no evidence that vitamin K supplementation longer than the one commonly recommended in newborns can compensate for this defect, but it was determined that INR monitoring in the infant may detect those who developed vitamin K defi ciency [9] Recommendations, on the other hand, advise that warfarin, acenocoumarol and heparin are safe to use during lactation [10].It is also advisable for nursing mothers to continue therapy with LMWH, or hirudin, but not with fondaparinux [10].According to the North American recommendations, low doses of aspirin, if indicated, can likewise be safely administered to nursing mothers, although some authors advise caution pointing to potential problems, such as rare occurrences of Reye's syndrome in neonates and infants [1,10,12].

Concise practical recommendations
Based on the foretasted, the following recommendations can be set apart: For women already on oral vitamin K antagonists (VKA) trying to conceive, according to the current ACCP guidelines frequent pregnancy tests are recommended as well as substitution of VKA with preparations of heparin when pregnant rather than an option of replacing VKA with low molecular weight heparins during the pre-conceptual period [2,10,15,33,34,46,47].
VKA administration, especially between 6-12 weeks of pregnancy, may lead to embryotoxicity, it therefore being a period when VKA replacement with heparin preparations is specifi cally advised, which is of crucial importance when VKA is given in higher doses, that is when the warfarin dose is greater than 5 mg daily and that of acenocoumarol higher than 2 mg as higher doses of VKA are associated with a higher rate of fetal abnormalities, stillbirth and miscarriage, while in some studies with VKA used at lower doses no embryopathy was recorded and the risk of fetal complications was several fold lower 336 Volume 3 • Number 1 • January 2016 • HOPH [2,8,20,21].
It is considered that the use of vitamin K antagonists during the fi rst 6 weeks does not carry the risk of embryopathy as well as that from 6-12 weeks gestation warfarin should be replaced with heparin preparations [10].Th e administration of heparin products between 6 and 12 weeks of pregnancy does not lead to teratogenicity, but such a therapeutic approach entails a much higher risk of thromboembolic complications of 9.2%, noting that the use of UFH in adequate doses recommended for valve thrombosis prophylaxis does not absolutely prevent valve thrombosis occurring as well as the fact that there is also a risk of considerable variation of aPTT levels along with a chance of bleeding, even intracranial hemorrhage [7,8,19].
Th e increasing use of LMWH (recommended by current guidelines but not yet offi cially indicated for the prevention of thrombosis of mechanical valves in the summaries of the drug characteristics) requires treatment with therapeutic doses, determined based on periodic monitoring of the anti-Xa activity (measurements of peak anti-Xa levels mandatory, it also being possible in specifi c cases to measure through anti Xa activity levels) [23][24][25][26][27][28][29].
Th erefore, the guidelines allow for the possibility of considering VKA administration during the fi rst trimester in case that the daily warfarin dose of less than 5 mg and the acenocoumarol one of less than 2 mg is suffi cient to achieve therapeutic anticoagulation, especially in patients with valves of high thrombogenicity, reduced ejection fraction, atrial fi brillation, a previous episode of thromboembolism and other risk factors for thromboembolic complications [1,23].A target INR of 2.5 is recommended in patients with newer generations of mechanical aortic valves (bileafl et or current generation tilting single disc), having no additional factors for thromboembolism, while a target INR of 3 is advised for patients with the foretasted aortic valves and risks for thromboembolism (atrial fi brillation, systolic heart failure, previous thromboembolism), older generation of aortic valves (ball in cage valves) or mitral valves [33].Replacement of peroral VKA therapy between 6-12 weeks with therapeutic doses of UFH or LMWH is advisable in case that higher doses of VKA are required to achieve the target INR for a specifi c valve (warfarin over 5 mg daily, acenocoumarol over 2 mg daily) [1].Th erapeutic doses of heparin are determined based on aPTT values and the initial therapeutic dose of LMWH in a subcutaneous regime applied twice daily, in the further course to be optimized to the target based on the levels of anti Xa [1].Th e ACCP guidelines also suggest the possibility of administering UFH via the subcutaneous route, it being advised that the dose should be adjusted to maintain the mean interval of aPTT value (at least 2, that is, more precisely 2-2.5 times higher than the control -A/N) or anti X target values from 0.35 to 0.75 U / mL [10].
Due to the VKA transfer to the fetus and immaturity of the fetal liver, the fetus is at greatly increased risk of hemorrhage, there is a possibility of retro placental hematoma, placenta abruption and fetal loss.Th erefore, interruption of VKA therapy at 34-36 weeks of gestation is generally recommended or a cesarean section suggested reducing the possibility of hemorrhage in the child due to birth trauma, though in some cases entailing very high risk of valve thrombosis VKAs may be administered even 48 hours before birth [8,13].VKA administration in the third trimester of pregnancy can cause fetal and neonatal hemorrhage as well as placental abruption while in any trimester it can lead to certain central nervous system anomalies [8][9][10]15].
It is advised that VKA be ceased in 36 th week, and then followed by IV UFH or LMWH until 36 hours prior to delivery, when LMWH are replaced with IV UFH [23,34].UFH is discontinued 4-6 hours before the expected time of delivery and restarted 4-6 h aft er delivery in the absence of signifi cant bleeding (there are positions that UFH or LMWH are to be introduced 12 hours aft er cesarean section), with/while VKA therapy continuation may be recommended 24 hours aft er delivery [8,23,33].Vitamin K antagonists, unfractionated heparin and LMWH may be safely used during lactation [10].

CONCLUSION
Th e appropriate use of anticoagulant therapy during pregnancy requires an assessment of potential benefi ts of the administered drug in the corresponding indication versus alternative medicines also taking into account possible complications caused by the specifi c drug administered that may aff ect the fetus (teratogenicity, fetotoxicity or fetal death).In addition, there is a need to assess the risk for thrombosis in the mother, with special attention paid to potential hemorrhagic complications.Personalization of therapy requires an assessment of risk factors for thrombosis, the risk for bleeding, consideration of comorbidities in the mother, especially renal function, particularly having regard to the stage of pregnancy.Th ere is no absolutely safe anticoagulant treatment in pregnancy, but selecting the safest option in relation to the stated risks for the mother and the child is always an overriding concern.

Antonijević
NM et al: Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis

1 .
Continuation of VKA therapy during the fi rst trimester if the dose of warfarin is lower than 5 mg with a target INR of 3.0 (2.5-3.5) or 2. LMWH in 2 doses achieving high therapeutic peak levels of anti-Xa activity of 0.8-1.2U / mL (taken 4-6 h after drug administration); 3.If the daily dose of warfarin is higher than 5mg during the fi rst trimester, administration of iv infusion of UFH with target aPTT 2 x longer than the control * Consider adding aspirin in low doses of 75-100mg ESC guidelines 2011.

Antonijević
NM et al: Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis

Antonijević NM et al:
Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis th dayNo eff ects at this stage, malformations do not occur, there is no implantation or abortion occurs

Table 1 .
[12]ral review of pregnancy stages, fetal toxicity and fetal teratogenicity in use of VKA[12]

Table 3 .
The

Table 4 .
The