328 © The Serbian Medical Society 2014 Education article Hospital Pharmacology. 2016;3(1):328-340 A Topic: this subjectmatter. professional databasesandaccessiblemedicaljournalstextbooksdealingwith Methods: further increasedbythefactthateverolderwomenaregivingbirth. plicated byheartdisease,theriskofcardiovasculardiseaseinpregnantwomenbeing annually borninaverage. About 1%ofpregnanciesamongwomeninEuropearecom- 45 years)inEuropeisestimatedatabout105million,with5millionchildren Introduction: SUMMARY Serbia 6 5 4 3 2 1 Nebojša M.Antonijević Puerperium: Anticoagulation inPregnancyand derivativeshavenoembryotoxicandfetotoxic characteristice weight heparin(LowMolecularWeight Heparin-LMWH)whenplanningapregnancy. when pregnantarerecommendedratherthanVKA replacement withlowmolecular ing toconceivefrequentpregnancytests,andsubstitution ofVKA withheparindrugs Chest Physicians - ACCP) forwomenalreadyonoralvitaminKantagonistsactively try- . InaccordancewiththeNorth-Americanguidelines(AmericanCollegeof and inthemother. The choiceofappropriateanticoagulantdepends onthestageof known dose-relatedriskofembryotoxicity, genotoxicity, andhemorrhage inthefetus during pregnancy, vitaminKantagonists(VKA)ontheotherhandalsoentailawell- risk forthrombosis,especiallyinpatientswithmechanicalprostheticheartvalves but theyarelesse MECHANICAL HeartValves Antagonists onthePreventionof and Risksofthe Applications ofVitamin K Nebojša L.Radovanović Dragan M.Matić Mirjana K.Kovač Department of Cardiovascular Pathology, Serbian Academy and of Belgrade, Art, Science Clinicof Gastroenterology and Hepatology, Clinicof and Gynecology Obstetrics, Clinical Transfusion Institute of Serbia Belgrade, Serbia, Clinicof Cardiology, ClinicalCentre of Serbia Belgrade, Serbia, Medical Faculty, University Serbia of Belgrade, Belgrade, E-mail: Clinic ofCardiology, ClinicalCentreofSerbia,11000Belgrade,Serbia Specialist inInternalMedicine,Subspecialist inCardiology Assistant Professor NebojšaM. Antonijevi Corresponding author: Beingcertainlydrugswiththebestanticoagulante Preparing this paperisbasedonasystematicPubMedsearchofexisting [email protected] The currentnumberofwomeninthereproductivephase(from 15to 2 1,3 ff , Ratko M.Lasica ective atpreventingvalvethrombosis, due towhichtheyhave , Tatjana Ž.IlićMostić 1,2 With aFocusontheBene 1,2 , Ljubica M.Jovanović , Milika R. Ašanin, Milika R. ć , MD,PhD, Clinical Centre of Serbia Belgrade, Serbia, 1,2 Centre of Serbia Belgrade, Serbia, , Ivan V. Ranković 4 , Ivana D. Živković 1,2 , Vladimir I.Kanjuh 2 , Branka M.Terzić ff doi:10.5937/hpimj1601328A ect insituationsofhigh ISSN 2334-9492(Online) 5 , UDC: 615.273-055.26 2 , fi 6 ff ts 2 ects ofVKA , 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 Valves Thrombosis recently been superseded by improved techniques for monitoring eff ects of heparin, with a mentioned made that low molecular weight heparin used in high therapeutic doses requires obligatory (on a weekly basis) monitoring of anti-factor Xa coagulation activities. Conclusion: Adequate therapy during pregnancy requires an analysis of risk factors for thrombosis, hemorrhage risk, consideration of comorbidities in preg- nant women, especially renal function, especially taking into account the . Though it must be admitted that there is no absolutely safe anticoagulant ther- apy during pregnancy, a choice of the safest option regarding the stated risks for the mother and the child is of paramount importance. Keywords: pregnancy, anticoagulant therapy, mechanical prosthetic valves A

INTRODUCTION and legs. Consequently, in certain conditions during pregnancy there is a need for admin- Th e current number of women in the repro- istering adequate anticoagulant therapy. Some ductive phase (from 15 to 45 years) in Europe diseases and conditions require the use of vita- is estimated at about 105 million, with about min K antagonists (VKA), whose teratogenic 5 million children annually born in average. potential presents a signifi cant safety issue [2]. About 1% of among women in Th ough VKA administration represents the Europe are complicated by heart disease, the most eff ective anticoagulant therapy for the risk of cardiovascular disease in pregnant prevention of thrombosis in pregnant women women being further increased by the fact that with mechanical heart valves, at the same time ever older women are giving birth [1]. it may lead to serious birth defects, embryopa- Pregnancy is a condition of increased thy, even stillbirth [8]. Th erapy with heparin risk of thrombosis due to synergy of all the drugs, especially with low molecular weight three components of the Virchow’s triad [2]. (LMWH) has reduced adverse fe- Due to altered physiology in pregnant women tal outcomes, but, on the other hand was ac- and hormonal status procoagulant factors and companied by a higher incidence of prosthetic the procoagulant state dominates. Levels of fi - valve thrombosis in patients with prosthetic brinolysis inhibitor (PAI-1 or PAI-2) produced heart valves. Th e risk of thrombosis in prac- by the are elevated, causing a decrease tice may be reduced by using higher doses of in fi brinolytic activity during pregnancy. On LMWH, more frequent testing and adjusting the other hand, additional thrombogenic ef- not only peak anti-Xa activity levels analyzed fect is associated with changes in the levels of from a blood sample 4 h aft er subcutaneous natural , namely, a reduction in injection of LMWH, but also trough anti-Xa protein S levels is recorded as early as the fi rst activity levels, analyzed in the blood sample trimester; the concentration of antithrombin immediately prior to the administration of (AT) decreases in case of a caesarean delivery. subcutaneous injections of LMWH. When A series of homeostatic changes induced in administering LMWH in order to prevent pregnancy is associated with activated protein thrombosis prosthetic valves, it is advised to C resistance registered in a number of preg- maintain anti Xa activity values at a high ther- nant women [3-5]. Also, there is an increase apeutic level [2]. in platelet-endothelial adhesion molecules as well as endothelial cell activation associated METHODS with a proinfl ammatory state, especially dur- ing labour or caesarean section when damage Preparing this paper is based on a systematic to blood vessels is incurred [2,6,7]. PubMed search of existing professional data- In addition, the gravid uterus com- bases and accessible medical journals and text- presses major blood vessels of the abdomen books dealing with this subject matter. and pelvis, this resulting in venous dilata- tion and slowed venous fl ow, which poses a risk of deep of the pelvis www.hophonline.org 329 Hospital Pharmacology. 2016; 3(1):328-340

ORAL ANTICOAGULANTS DURING been described as well as agenesis of the cor- PREGNANCY pus callosum, Dandy-Walker malformation, mid line cerebellar atrophy, ventral middle Anticoagulant therapy is indicated in preg- line dysplasia which may lead to atrophy of nancy in women with mechanical prosthetic the nervus opticus. Blindness, epilepsy, deaf- valves, with previous or current venous throm- ness, respiratory distress, kidney agenesis or bosis and thromboembolism as well as in pres- hypofunction, anal dysplasia, cleft lip and soft ence of a thrombus in the cardiac chambers, palate may likewise occur [10,13]. Th e risk of atrial fi brillation with a high thromboembolic developing embryopathy is estimated at 5-7%, risk, in pulmonary due to severe this percentage being higher when broadened thrombophilia or if there is a history of recur- to include the less pronounced CNS disorders rent miscarriage. Besides thrombophilia with induced by [9]. recurrent miscarriage, anticoagulant therapy Due to the transfer of VKA through is also considered in cases of stillbirth, pre- the placenta, the fetus is at signifi cantly in- eclampsia, post-thrombotic syndrome, ovar- creased risk of hemorrhage. Th e immaturity of ian hyperstimulation syndrome in the fi rst the fetal liver is a major cause of slow warfarin trimester, known to be likely associated with a metabolism and low clotting factor levels in hypercoagulable state [2,9]. the fetus itself, the anticoagulant eff ect thus be- Oral anticoagulation with vitamin K ing markedly greater than in the mother. Fur- antagonists provides better maternal protec- thermore, there is a high risk of hemorrhage in tion against thrombosis than heparin prepa- newborns during childbirth, sometimes with a rations, though its administration may be as- possible fatal outcome. Th erefore, interruption sociated with a potential risk of embryopathy, of VKA therapy at 34-36 weeks of gestation is fetal malformation as well as loss, especially in recommended or a cesarean section suggested the period of 6-12 weeks of gestation and prior reducing the possibility of hemorrhage in the to delivery [8,10]. It being considered by au- child due to birth trauma [9]. Some authors thors such as Dr. Celine Montovan that VKA specifi cally point out the development of ret- administration, particularly between 6-12 roplacental hematoma as a common cause of weeks of pregnancy, may lead to embryotox- fetal loss [14]. Th e European guidelines state icity, this is a period when VKA replacement that VKA administration in the third trimes- with heparin preparations is strongly suggest- ter of pregnancy can cause fetal and neonatal ed [9]. It is of special importance when VKAs hemorrhage and as well as are administered at higher doses or when the lead in any trimester to abnormalities in the dose of warfarin is higher than 5 mg per day central nervous system, such as optic atrophy, [9]. Warfarin in higher doses of 5 mg and more microcephaly, mental retardation, hypotonia cause a higher percentage of fetal abnormali- and spasticity [9,10,11,15]. ties, miscarriage and stillbirth [2]. Along with hemorrhagic complica- Vitamin K antagonists (VKA) cross tions and damage to the central nervous sys- the placenta and may cause embriopathy in tem, VKA administration in the second and specifi c phases of the fi rst trimester [10,11]. third trimester causes a number of minor mal- Also, VKA increase the risk of miscarriage, formations and other neural-developmental hemorrhaging and teratogenicity [10]. Admin- problems. Larger cohort studies do not enlist istering VKA in absolute and relative sensitive the occurrence of major neurological anoma- period of fetal development (from 28 to 112 lies when VKAs are administered in the sec- days) may cause fetal abnormalities, distur- ond and third trimesters. Children whose bances in fetal osteogenesis and chondrogen- mothers received VKAs during pregnancy esis. In addition, there occur abnormalities of do not diff er from other children related to the CNS, such as microcephaly [12]. Th e most the mean intelligence quotient scores while common fetal abnormalities associated with diff erences in reading and solving arithmetic warfarin are: midfacial hypoplasia, stippled problems are described. Contrary to the above pineal gland (chondromalatia punctata), hyp- assertion made in recommendations by the oplasia with nose, limb and fi nger deformities ACCP, Dr. Judit Wesseling has registered twice [9,10,13]. higher risk of minor neurological disorders Rare anomalies such as the forma- and a higher incidence of reduced intelligence tion of the dorsal middle line dysplasia have quotient (less than 80%) in children exposed to VKA during the second and third trimester

330 Volume 3 • Number 1 • January 2016 • HOPH 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

Table 1. General review of of pregnancy (OR 2. 1, CI 1. 2-3.8) [16-18]. STAGE OF TERATOGENICITY AND pregnancy stages, fetal toxicity Teratogenic eff ect of VKA is dose-de- PREGNANCY FETAL TOXICITY and fetal teratogenicity pendent, being lower at acenocoumarol doses No eff ects at this stage, in use of VKA [12] of less than 2 mg or warfarin doses of less than From fertilization malformations do not oc- 5 mg than at doses above 5 mg (8 vs. 2.6%). till the 27th day cur, there is no implanta- However, in certain populations even this dose tion or abortion occurs proved to be too large, for example in Japanese Absolutely sensitive stage, important for the forma- From 28th to 50th examinees [12,19]. W.C. Chan states the em- tion of fetal organs, there day bryopathy incidence of 6.4%/ in mothers re- is a high risk of teratoge- ceiving warfarin doses less than 5 mg [9,20]. nicity Some studies report 81% of fetal complications Relatively sensitive pe- riod, the formation of the in pregnant women with warfarin adminis- From 51th to 112th genital area, soft palate is tered in a dose higher than 5 mg [13]. day not yet completed, terato- With a warfarin dose exceeding 5 mg/ genicity like palate cleft day embryopathy is registered in 9% and fetal Potentially sensitive stage, complications in 88% of the cases. At doses of the risk of teratogenic- From 113th to warfarin less than 5 mg embryopathies are not ity is small, attention delivery registered while the risk of fetal complications should be paid to the fetal is 15% [21,22]. Th e North American recom- toxicity mendations (ACCP) state that the use of vi- tamin K antagonists during the fi rst 6 weeks carries no risk of embryopathy, as well as that to women already taking oral vitamin K antag- warfarin should be replaced with heparin onists trying to conceive. At the time of con- preparations in the period of 6-12 weeks [10]. ception, substitution of vitamin K antagonists In the study by Chan and associates none of by heparin preparations is suggested not VKA the 125 women using warfarin only during the replacement with LMWH while planning con- fi rst 6 weeks of gestation gave birth to a child ception [10]. with birth defects [10,20]. According to the North American Middeldorp S. reports that teratogen- recommendations, the use of VKA is not ic eff ect only occurs when VKAs are admin- recommended three weeks before childbirth istered in the 6-12 weeks of gestation period [10]. [16]. It should be specifi cally underlined Schaeafer further states that none of that VKA should not be used from 6-12 weeks the 235 newborn infants whose mothers re- of pregnancy and 3 weeks before delivery and ceived VKA only during the fi rst 8 weeks of that during this period parenteral heparin gestation had abnormalities [10]. preparation administration along with ad- Frequent pregnancy tests are advised equate monitoring of achieved anticoagulant

Table 2. The eff ects of anti- Medicine FDA Adverse eff ects Teratogenicity Use during Remark thrombotic drugs in lactation and puerperium [1,12] Allowed; Small amounts Vitamin K of metabolites antagonists Teratogenicity, fetal bleed- X Yes pass into breast - (warfarin, ing complications milk, but with- aceno-coumarol) out the side eff ects Bone demineralization dur- ing extended use, osteopo- Heparin rosis, fractures in mother, (UFH) C No Allowed - risk of HIT, higher incidence of thrombosis than with warfarin Low molecular Lower risk of HIT and osteo- weight heparins B No Allowed porosis than with UFH (LMWH) Danaparoid B - No Allowed - www.hophonline.org 331 Hospital Pharmacology. 2016; 3(1):328-340

eff ect is strongly advised in the course of this receiving anticoagulant therapy is estimated period. at around 2.5%, pointing out that about 80% hemorrhage is peripartal [21]. PARENTERAL ANTICOAGULANTS It should be emphasized that in preg- IN PREGNANCY nancy there is an increase in the glomerular fi ltration rate as well as in plasma volume, con- Unfractionated heparin and low molecular sequently resulting in decreased plasma drug weight heparins do not cross the placenta and concentrations. In addition, placental hepari- therefore do not aff ect the formation and de- nase activity is elevated, necessitating higher velopment of the fetus, but carry an increased doses of LMWH. Th is also requires weekly risk of thrombotic complications in moth- checks of plasma anti-Xa levels in order to at- ers with prosthetic heart valves, even with a tain a target level of 1.0-1.2 U/mL [21,24]. properly adjusted dose and careful monitoring Quinn fi nds that a mean increase [14,21]. in the dose of LMWH of 54.4% is necessary Heparin administration during preg- during pregnancy to achieve the optimum an- nancy virtually eliminates the risk of embry- ticoagulant eff ect [24]. More recent research opathy, has no adverse eff ect on development suggests that along with peak anti-Xa activity of the fetus, but does not provide protection there should also be monitored trough (low- from thrombotic complications equivalent est) levels of anti-Xa activity [24]. It is known to that of ensured by VKA administration that pregnant women receiving enoxaparin ev- [14,23]. ery 12h with peak anti-Xa levels of 0.7-1.2 U/ Chan W.C. states that the use of hepa- mL are associated with sub-therapeutic trough rin products in the period between 6 and 12 levels, with a pre-dose level of less than 0.6 IU/ weeks does not lead to teratogenicity, but such mL in over 50% of cases [24-27]. a therapeutic approach entails a much higher We would like to lay particular stress risk of thromboembolic complications of 9.2% on the fact that low molecular weight heparins [9,20]. (according to the summary of product charac- A combined approach of treatment teristics) are not indicated for the prophylaxis with VKA and heparin drugs throughout the of thrombosis in patients with prosthetic heart period of absolute risk for embriopathy, sig- valves [21,28-30]. nifi cantly, almost completely eliminates the In his study, Salazar E. accentuated risk of embryopathy but increases the risk of 2 cases of female patients who between 6-12 thromboembolism and thrombosis of pros- weeks of pregnancy developed fatal valve thetic valves [14]. thrombosis upon replacement of acenocou- Tanaka H. and his colleagues indicate marol with heparin despite adequate anti-co- the complexity of the problem of VKA admin- agulation with aPTT ratio maintained between istration in pregnant women. Being much safer 55-95 seconds (control time of 30-35 seconds) for the fetus, unfractionated heparin adminis- concluding that subcutaneous heparin with a tered in appropriate doses is recommended for target aPTT 1, 5-2, 5 times the control heparin the prevention of thrombosis valve (2-3 times is not eff ective in preventing prosthetic valve prolonged aPTT compared to controls) but thrombosis [21,31]. does not prevent completely valve thrombosis Th rombogenicity valve, clinical and formation [8]. On the other hand intracranial laboratory parameters of patients should be hemorrhage is recorded in patients treated kept in mind when choosing the most appro- with UFH along with considerable aPTT vari- priate therapeutic regimen for pregnant wom- ation over 50% during the night [8]. Recent en with mechanical valves. Factors known to studies fi nd warfarin the best suited anticoag- increase the risk of prosthetic valve thrombo- ulant medication for preventing valve throm- sis are: older types of valves (ball-cage valves, bosis, noting that the valve thrombosis also Starr-Edwards, Bjork-Shiley valve standard, register at VKA therapy, as confi rmed by Chan Omniscience) compared with newer types (St who determined an overall incidence of valve Jude Medical, Medtronic Hall), then the mi- thrombosis of 4% [8,20]. During administra- tral valve position more than the aortic posi- tion of VKA individual cases of intracranial tion, heart failure, an ejection fraction of less hemorrhage in the mother have also been re- than 35%, atrial fi brillation, previous history corded [8]. Th e risk of hemorrhage in mothers of thromboembolism [2,10,21,32]. A VKA is the most reliable anticoagulant in pregnancy.

332 Volume 3 • Number 1 • January 2016 • HOPH 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 e decision on whether to administer a VKA heart valve thrombosis is a potentially fatal depends on the risk of valve thrombosis. It condition in all patients, particularly pregnant should never be neglected that prosthetic women [20,27].

Table 3. The recommendations RECOMMENDATIONS ANTICOAGULANT REGIME and the various modalities of 1. Continuation of VKA therapy during the fi rst trimester if the dose of war- administering parenteral anti- farin is lower than 5 mg with a target INR of 3.0 (2.5-3.5) or coagulants and vitamin K an- 2. LMWH in 2 doses achieving high therapeutic peak levels of anti-Xa activity tagonists during pregnancy in of 0.8-1.2 U / mL (taken 4-6 h after drug administration); ACC/AHA guidelines 2014. patients with mechanical heart 3. If the daily dose of warfarin is higher than 5mg during the fi rst trimes- valves compared with the war- ter, administration of iv infusion of UFH with target aPTT 2 x longer than farin dose needed to achieve a the control therapeutic INR [1,7,33] * Consider adding in low doses of 75-100mg 1. In patients with prosthetic mechanical valves in cases when less than 5 mg of warfarin is required to achieve adequate INR /for achieving adequate INR is required less than 5 mg of warfarin continue with the application of ESC guidelines 2011. warfarin till the 36 weeks of pregnancy; 2. If the required warfarin dose is greater than 5 mg, then switch between 6-12 weeks from VKA to treatment with iv infusions UFH or LMWH s.c. with a one-week control of anti-Xa levels (a target value of 0.8-1.2 U/ml in the blood sample taken 4-6 hours after injection)

PROSTHETIC VELVE fi ned above [10,24]. In female patients with THROMBOSIS PREVENTION IN low risk for valve thrombosis subcutaneous PREGNANT WOMEN 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 American ACC/AHA (American College of 0.3-0.7 U/mL or alternatively low molecular Cardiology and the American Heart Associa- weight heparin (LMWH) subcutaneously 6-12 tion) guidelines, the ESC guidelines (European weeks of gestation or throughout the entire Society of Cardiology) and ACCP (American pregnancy administered with 12h dosage regi- College of Chest Physicians) vary considerably men, it being recommended that target anti among themselves in approaches to mechani- Xa levels planned for LMWH at the given dose cal prosthetic heart valve thrombosis preven- regimen be achieved, monitored on a weekly tion [24]. Th e ACC/AHA guidelines permit basis [10,24]. In addition to low molecular the continuation of vitamin K antagonists weight heparin in high-risk female patients therapy during the fi rst trimester if the warfa- there may also be considered administering a rin dose is lower than 5 mg or where low mo- once daily regimen of 75 or 100 mg low-dose lecular weight heparins are administered in 2 aspirin [10,24]. In women with bileafl et aortic doses to achieve high therapeutic peak levels valve prosthesis with a lower risk of thrombo- of anti-Xa activity of 0.8-1.2 U/mL in a sample sis achievement of slightly lower INR of 2.5 taken 4–6 hours aft er subcutaneous injection (2-3) using VKA therapy is advised instead of [24,33]. In case that the daily dose of warfarin the target INR for patients with a high risk of is higher than 5 mg during the fi rst trimester 3.0 (2.5-3.5) [10]. the same guidelines alternatively propose the Th e ESC guidelines 2011, in case use of intravenous infusion of heparin with of female patients with prosthetic mechani- the target aPTT twice longer than the control cal valves when less than 5 mg of warfarin is [24,33]. Administration of low-dose aspirin needed to achieve an adequate INR also rec- (75-100 mg daily) may be advised as an addi- ommend continuation of warfarin up to 36 tional medication during the second and third weeks of pregnancy with the risk of embry- trimester [24]. If warfarin is the drug of choice opathy less than 3%; and, if doses of warfarin during pregnancy, its dosing aims to achieve a greater than 5 mg between 6-12 weeks are nec- target INR of 3.0 (2.5-3.5). essary, switching to treatment with intravenous Th e ACCP (American College of UFH infusions or LMWH (with monitoring to Chest Physicians) guidelines published in achieve an aPTT in the therapeutic range 2-2.5 2012 guidelines recommend continuation of higher than the control – A/N Author’s Note) warfarin therapy in high-risk patients with or LMWH with a one-week control of peak prosthetic valve thrombosis risk factors de- anti-Xa levels to attain a target value of 0.8-1.2 www.hophonline.org 333 Hospital Pharmacology. 2016; 3(1):328-340

U/ml in the blood sample taken 4-6 hours af- Heparin treatment is initiated with ter injection [23,34]. Trough levels of anti-Xa an intravenous bolus (starting dose) of 80 IU/ activity, so-called pre-dose levels are not yet kg (body weight bolus) followed by18 IU/kg/h suffi ciently harmonized, especially with regard infusion [35]. To achieve a therapeutic aPTT to the relationship between thromboembolism measured every 6h during the initial phase of and hemorrhage, for any fi rm conclusions to treatment, it is recommended that UFH be ad- be reached, but for the time being it is consid- ministered by intravenous route at doses ad- ered that they should be higher than 0,6 U/mL justed based on the Raschke’s nomogram [35]. [1]. Th e standard dosage of subcutaneous hepa-

Table 4. The dosage of UNFRACTIONATED UNFRACTIONATED ENOXAPARIN NADROPARIN DALTEPARIN VITAMIN K anticoagulant drugs [34,38-45] HEPARIN (UFH) HEPARIN (UFH) ANTAGONISTS INTRAVENOUS SUBCUTANEOUS (VKA) Dosing according to body weight: an initial bolus iv 5000-10000 IU or 80 IU/kg, then continue with 18 The initial dose 2 x 100 IU/ Dosing accord- IU/kg/h iv of kg 2x86 IU/kg ing to the INR; Dose of heparin 333 IU/kg s.c., 1mg/kg/12h (max to s.c. target INR 2-3 modify according then continue s.c. 18000 IU per (3,5) to the aPTT, target 2 x 250 IU/kg s.c. day) aPTT 1.5-2 times higher than the control value (Rasche nomo- gram)

rin regimens in pregnancy is: 17,500 to 20000 advised that the mid-interval aPTT (measured IU every12 hours, or more precisely starting 6h aft er the s. c. dose) be maintained to a ratio with the initial dose of 333 IU/ kg followed by 2-3 times the control value [34-37]. the subsequent 2 x 250 IU/kg dose, it being When warfarin doses higher than 5

Recommendation ACC / AHA ACCP ESC Can be used through- Can be used throughout If warfarin dose is ≤ 5mg out pregnancy, with pregnancy in high risk pa- daily, oral anticoagulants Table 5. Comparative review of substitution by dose tients, with substitution by Oral throughout pregnancy is current recommendations for adjusted UFH or LMWH dose adjusted LMWH or UFH anticoagulants the safest regimen (asso- anticoagulant therapy in pa- during weeks 6-12 of close to term (time frame ciated with <3% embry- tients with mechanical valves gestation if preferred not specifi ed but normally opathy) [45] by the patient 48h before delivery) INR 3 for all patients INR 2-3 for patients with Anticoagulation No INR target with mechanical pros- bileafl et aortic valves with- Target recommendation thetic heart valves out high risk features LMWH or UFH during Monitored UFH or Dose adjusted and monitored weeks 6-12 of gestation Heparin LMWH might be options LMWH or UFH throughout should be considered if Derivatives throughout gestation pregnancy or during weeks high dose warfarin is re- (UFH, LMWH) or during weeks 6-12 of 6-12 of gestation is accept- quired to maintain thera- gestation able peutic anticoagulation In low risk patients, LMWH LMWH dose should be LMWH dose should be should be given twice daily adjusted to give an adjusted to give an and the dose adjusted to LMWH anti-factor Xa activity anti-factor Xa activity of achieve the manufacturer’s 0.7-1.2U/ml 4-6h after 0.8-1.2 U/ml 4-6h after peak inhibition of anti -fac- administration administration tor Xa 4h after s.c. injection Low dose aspirin in ad- Low dose aspirin in addition Aspirin in addition to dition to anticoagula- Aspirin to anticoagulation in high anticoagulation is not tion during the second risk patients recommended and third trimesters

334 Volume 3 • Number 1 • January 2016 • HOPH 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

Table 6. Recommendation for HIGHER RISK LOWER RISK anticoagulant therapy for wom- Old generation MPHV in mitral position, MPHV in New generation MPHV in mitral position and MPHV an with MPHV during pregnancy tricuspid position atrial fi brillation, history of TE in aortic position in relation to thromboembolism on heparin risk [24,36] LMWH SQ Q 12h (through anti-Xa ≥ 0.6 IU/ml, peak anti-Xa < 1.5 IU/ml), then UFH iv (aPTT > * acetylsalicylic acid Warfarin (INR 2.5 - 3.5) for 35 to 36 weeks fol- 2.0) to parturition lowed by iv UFH (aPTT >2.5) to parturition or UFH s.c. (mid-interval aPTT 2.0-3.0) or LMWH LMWH through (pre-dose) anti-Xa ≥ 0.7 + ASA* (through anti-Xa ≥ 0.6 IU/ml, for 12 weeks. fol- 81 to 100mg /day lowed by warfarin (INR 2.5-3.0) up to 35 weeks, then s.c. UFH (mid-interval aPTT 2.0-3.0) or LMWH (through anti-Xa ≥ 0.6 IU/ml) OR OR

LMWH SQ Q 12h through anti-Xa ≥ 0.7 IU/ml, LMWH SQ Q 12h through anti-Xa ≥ 0.6 IU/ml, peak peak anti-Xa < 1.5 IU/ml or UFH SQ Q12h or anti-Xa < 1.5 IU/ml or UFH SQ Q12h or iv (mid in- iv (mid interval aPTT 2.5-3.5) for 12 weeks, terval aPTT 2.0-3.0) for 12 weeks, followed by followed by warfarin (INR 2.5 to 3.5) to 35 to warfarin (INR 2.5 to 3.0) to 35 to 36 weeks, then 36 weeks, then UFH iv (aPTT > 2.5) or LMWH UFH iv (aPTT > 2.0) to parturition through (pre-dose) anti-Xa ≥ 0.7 to parturition + UFH s.c. (mid interval aPTT 2.0-3.0) or LMWH ASA* 81 to 100mg /day (through anti-Xa ≥ 0.6 IU/ml) mg are required to maintain the target INR, in the mitral position and previous thromboem- the fi rst trimester it is advised to switch from bolism) should continue with warfarin admin- warfarin to LMWH therapy with precisely tai- istration until close to delivery, generally 48 lored dosing regimens along with monitoring hours before the anticipated time of delivery, of anti-Xa activity [24]. when VKA therapy is replaced with UFH or All of the above guidelines agree that LMWH [10,24]. it is harmful to administer LMWH without In the event of unexpected labour, regularly monitoring the patient’s anti-factor prior to the scheduled date in the patient on Xa levels [2,10,15,24,33,34]. oral anticoagulant therapy, a caesarean section is advised because of the risk of fetal intrac- PERIPARTUM USE OF ranial hemorrhage in case of vaginal delivery ANTICOAGULANTS or for other obstetric reasons [24]. Panduranga advises discontinuation of IV UFH infusion According to the North American ACCP 4-6 hours before delivery and restarting it guidelines 2012, VKA administration is not 4-6 h aft er delivery [24]. Montavon considers recommended three weeks before anticipated that UFH or LMWH should be introduced 12 delivery [10]. Th e ACC/AHA 2014 guidelines hours following cesarean section or 6h aft er advise discontinuation of VKA in 36th week vaginal delivery in conjunction with a VKA on and initiation of therapy IV UFH (in recom- the following day to be overlapped with hepa- mended doses suffi cient to achieve target rin preparations until therapeutic INR values therapeutic aPTT levels that should exceed are achieved [9]. approximately 2-2.5 times the control value Th erapy with heparin preparations, - A/N) it being advised that UFH be stopped especially low molecular weight heparins, has about 4 to 8 hours prior to expected delivery proven eff ective in reducing adverse eff ects on and restarted 4 to 6 hours aft er delivery in the the fetus, but is associated with a high rate of absence of signifi cant bleeding. Th en, VKA valve thrombosis in female patients with pros- therapy resuming is recommended 24 h aft er thetic heart valves. delivery [23,33]. Th e ESC guidelines advise stop- Administration of anticoagulant therapy in ping VKAs at 36 weeks of gestation and their nursing mothers replacement with IV UFH or LMWH un- til 36 hours before delivery, when LMWH is Anticoagulant therapy may be continued soon switched to IV UFH [24,34]. Th e ACCP guide- aft er birth, depending on the type of delivery lines advise that patients with very high risk of and whether adequate hemostasis is achieved, thromboembolism (older generation valves in usually aft er 6-12h, that is, 12-24h aft er epidur- al catheter removal. Treatment is initiated with www.hophonline.org 335 Hospital Pharmacology. 2016; 3(1):328-340

unfractionated heparin or LMWH adminis- [2,8,20,21]. tered parenterally, overlapped with VKA on It is considered that the use of vitamin the following day, continued for two consecu- K antagonists during the fi rst 6 weeks does not tive days until a therapeutic INR is achieved, carry the risk of embryopathy as well as that when UFH or LMWH therapy is ceased [10]. from 6-12 weeks gestation warfarin should be Th ough VKA administration to lactating replaced with heparin preparations [10]. Th e women is considered safe for the newborn, it administration of heparin products between is thought that the transfer of coumarin into 6 and 12 weeks of pregnancy does not lead to maternal milk may, however, leave exclusively teratogenicity, but such a therapeutic approach breastfed babies at risk for vitamin K defi ciency entails a much higher risk of thromboembo- [9,15].Th ere is no evidence that vitamin K sup- lic complications of 9.2%, noting that the use plementation longer than the one commonly of UFH in adequate doses recommended for recommended in newborns can compensate valve thrombosis prophylaxis does not abso- for this defect, but it was determined that INR lutely prevent valve thrombosis occurring as monitoring in the infant may detect those who well as the fact that there is also a risk of con- developed vitamin K defi ciency [9] Recom- siderable variation of aPTT levels along with a mendations, on the other hand, advise that chance of bleeding, even intracranial hemor- warfarin, acenocoumarol and heparin are safe rhage [7,8,19]. to use during lactation [10]. It is also advisable Th e increasing use of LMWH (rec- for nursing mothers to continue therapy with ommended by current guidelines but not LMWH, danaparoid or hirudin, but not with yet offi cially indicated for the prevention of fondaparinux [10]. According to the North thrombosis of mechanical valves in the sum- American recommendations, low doses of maries of the drug characteristics) requires aspirin, if indicated, can likewise be safely ad- treatment with therapeutic doses, determined ministered to nursing mothers, although some based on periodic monitoring of the anti-Xa authors advise caution pointing to potential activity (measurements of peak anti-Xa levels problems, such as rare occurrences of Reye’s mandatory, it also being possible in specifi c syndrome in neonates and infants [1,10,12]. cases to measure through anti Xa activity lev- els) [23-29]. Concise practical recommendations Th erefore, the guidelines allow for the possibility of considering VKA administration Based on the foretasted, the following recom- during the fi rst trimester in case that the daily mendations can be set apart: warfarin dose of less than 5 mg and the aceno- For women already on oral vitamin K coumarol one of less than 2 mg is suffi cient to antagonists (VKA) trying to conceive, accord- achieve therapeutic anticoagulation, especially ing to the current ACCP guidelines frequent in patients with valves of high thrombogenic- pregnancy tests are recommended as well ity, reduced ejection fraction, atrial fi brillation, as substitution of VKA with preparations of a previous episode of thromboembolism and heparin when pregnant rather than an option other risk factors for thromboembolic compli- of replacing VKA with low molecular weight cations [1,23]. A target INR of 2.5 is recom- heparins during the pre-conceptual period mended in patients with newer generations of [2,10,15,33,34,46,47]. mechanical aortic valves (bileafl et or current VKA administration, especially be- generation tilting single disc), having no ad- tween 6-12 weeks of pregnancy, may lead to ditional factors for thromboembolism, while a embryotoxicity, it therefore being a period target INR of 3 is advised for patients with the when VKA replacement with heparin prepa- foretasted aortic valves and risks for throm- rations is specifi cally advised, which is of cru- boembolism (atrial fi brillation, systolic heart cial importance when VKA is given in higher failure, previous thromboembolism), older doses, that is when the warfarin dose is greater generation of aortic valves (ball in cage valves) than 5 mg daily and that of acenocoumarol or mitral valves [33]. Replacement of peroral higher than 2 mg as higher doses of VKA are VKA therapy between 6-12 weeks with thera- associated with a higher rate of fetal abnor- peutic doses of UFH or LMWH is advisable malities, stillbirth and miscarriage, while in in case that higher doses of VKA are required some studies with VKA used at lower doses to achieve the target INR for a specifi c valve no embryopathy was recorded and the risk (warfarin over 5 mg daily, acenocoumarol over of fetal complications was several fold lower 2 mg daily) [1].

336 Volume 3 • Number 1 • January 2016 • HOPH 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 erapeutic doses of heparin are de- addition, there is a need to assess the risk for termined based on aPTT values and the initial thrombosis in the mother, with special atten- therapeutic dose of LMWH in a subcutane- tion paid to potential hemorrhagic complica- ous regime applied twice daily, in the further tions. Personalization of therapy requires an course to be optimized to the target based on assessment of risk factors for thrombosis, the the levels of anti Xa [1]. Th e ACCP guidelines risk for bleeding, consideration of comorbidi- also suggest the possibility of administering ties in the mother, especially renal function, UFH via the subcutaneous route, it being ad- particularly having regard to the stage of preg- vised that the dose should be adjusted to main- nancy. Th ere is no absolutely safe anticoagu- tain the mean interval of aPTT value (at least lant treatment in pregnancy, but selecting the 2, that is, more precisely 2-2.5 times higher safest option in relation to the stated risks for than the control – A/N) or anti X target values the mother and the child is always an overrid- from 0.35 to 0.75 U / mL [10]. ing concern. Due to the VKA transfer to the fetus and immaturity of the fetal liver, the fetus is ACKNOWLEDGEMENT at greatly increased risk of hemorrhage, there is a possibility of retro placental hematoma, Th is paper is an integral part of the project placenta abruption and fetal loss. Th erefore, Study of pathological morphological lesions: interruption of VKA therapy at 34-36 weeks of congenital and acquired heart defects (and gestation is generally recommended or a cesar- their pulmonary circulation), myocardium ean section suggested reducing the possibility and coronary vessels conducted by the Depart- of hemorrhage in the child due to birth trau- ment of Medical Sciences, Serbian Academy of ma, though in some cases entailing very high Sciences and Arts and project no. 173008 of risk of valve thrombosis VKAs may be ad- 2011 Complex diseases as a model system for ministered even 48 hours before birth [8,13]. studying modulation of phenotypic-structural VKA administration in the third trimester of analysis of molecular biomarkers under the pregnancy can cause fetal and neonatal hem- auspices of the Ministry of Science, Republic orrhage as well as placental abruption while of Serbia. in any trimester it can lead to certain central We thank Jelena M. Antonijevic, a nervous system anomalies [8-10,15]. specialist in interpreting, for language-editing It is advised that VKA be ceased in the text of our manuscript. 36th week, and then followed by IV UFH or LMWH until 36 hours prior to delivery, when REFERENCES LMWH are replaced with IV UFH [23,34]. UFH is discontinued 4-6 hours before the ex- 1. Nishimura RA, Otto CM, Bonow RO, Carabello pected time of delivery and restarted 4-6 h aft er BA, Erwin JP 3rd, Guyton RA et al. 2014 AHA/ACC delivery in the absence of signifi cant bleeding Guidelines for the management of patients with : A report of the American (there are positions that UFH or LMWH are College of Cardiology/American Heart Association to be introduced 12 hours aft er cesarean sec- Task Force on Practice Guidelines. Circulation 2014; tion), with/while VKA therapy continuation 129:2440-92 may be recommended 24 hours aft er delivery 2. McLintock C, Brighton T, Chunilal S, Dekker G, [8,23,33]. Vitamin K antagonists, unfraction- McDonnell N, McRae S. et al; Councils of the Society ated heparin and LMWH may be safely used of Obstetric Medicine of Australia and New Zealand; during lactation [10]. Australasian Society of Thrombosis and Haemosta- sis. Recommendations for the diagnosis and treat- ment of deep venous thrombosis and pulmonary CONCLUSION embolism in pregnancy and the postpartum period. Aust N Z J Obstet Gynaecol. 2012;52(1):14-22 Th e appropriate use of anticoagulant therapy 3. Bremme K. Haemostasis in normal pregnancy. In: during pregnancy requires an assessment of Brenner B, Marder V, Conard J, editors. Womens Is- potential benefi ts of the administered drug sues in Thrombosis and Haemostasis. Martin Dunitz in the corresponding indication versus al- Ltd, a member of the Taylor&Francis Group, 2002; ternative medicines also taking into account 151-65. possible complications caused by the specifi c 4. Kovač M. Trombofi lija i komplikacije u trudnoći. drug administered that may aff ect the fetus Zadužbina Andrejević, Beograd 2010;1-76. (teratogenicity, fetotoxicity or fetal death). In 5. Kovac M, Lalic-Cosic S, Dmitrovic J, Djordjevic www.hophonline.org 337 Hospital Pharmacology. 2016; 3(1):328-340

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Primena antikoagulantne terapije u trudnoći i puerperijumu: sa fokusom na korist i rizik od primene antagonista vitamina K na prevenciju tromboze mehaničkih srčanih zalistaka

Nebojša M. Antonijević1,2, Ljubica M. Jovanović2, Branka M. Terzić2, Mladen J. Kočica3, Vuk D. Andrijašević3, Mirjana K. Kovač1,4, Tatjana Ž. Ilić Mostić5, Ivana D. Živković2, Dragan M. Matić2, Ratko M. Lasica1,2, Ivan V. Ranković6, Nebojša L. Radovanović1,2, Milika R. Ašanin1,2, Vladimir I. Kanjuh7 A 1 Medicinski fakultet Univerziteta u Beogradu, Beograd, Srbija 2 Klinika za kardiologiju, Klinički centar Srbije, Beograd, Srbija 3 Klinika za kardiohirurgiju, Klinički centar Srbije, Beograd, Srbija 4 Institut za transfuziju krvi Srbije, Beograd, Srbija 5 Klinika za ginekologiju i akušerstvo, Klinički centar Srbije, Beograd, Srbija 6 Klinika za gastroenterologiju i hepatologiju, Klinički centar Srbije, Beograd, Srbija 7 Odbor za kardiovaskularnu patologiju, Srpska akademija nauka i umetnosti, Beograd, Srbija

KRATAK SADRŽAJ Uvod: U Evropi živi oko 105 miliona žena u reproduktivnoj fazi (od 15 do 45 godina), a tokom godine se prosečno rodi oko 5 miliona dece. Oko 1% trudnoća kod žena u Evropi je komplikovano srčanim bolestima, a činjenica da sve starije žene rađaju, povećava rizik od kardiovaskularnih bolesti trudnica. Metodologija: Priprema ovog rada bazirana je na sistematskom pretrazivanju PubMed: postojecih strucnih baza dostupnih medicinskih casopisa i udzbenika koji se bave ovom tematikom u periodu 1999. do 2015. Tema: U stanjima visokog rizika za nastanak tromboze, naročito u bolesnica sa mehaničkim veštačkim zaliscima u trudnoći antagonisti vitamina K (VKA) predstavl- jaju lekove sa najboljim antikoagulantnim efektom, ali na drugoj strani i dobro pozna- tim dozno zavisnim rizikom od embriotoksičnosti, fetotoksičnosti, hemoragijom kod fetusa i kod majke. Izbor odgovarajućeg antikoagulansa zavisi od stadijuma trudnoće. Po savetu severno-američkih preporuka (American College of Chest Physicians – ACCP) za žene koje već koriste peroralne antagoniste vitamina K (VKA) i pokušavaju da os- tanu trudne, savetuju se česti testovi trudnoće, supstitucija VKA preparatima hepa- rina kada zatrudne, pre nego zamena VKA sa niskomolekularnim heparinima (Low Molecular Weight Heparin – LMWH) u periodu planiranja trudnoćе. Heparinski derivati nemaju embriotoksično i fetotoksično dejstvo karakteristično za VKA, ali imaju slabiji efekat na sprečavanje tromboze valvule, što se u novije vreme pokušava nadomestiti savršenijim tehnikama praćenja dejstva heparina, uz napomenu da se niskomolekul- ski heparin koristi u visokim terapijskim dozama uz obavezno (sedmično) praćenje aktivnosti anti Xa faktora koagulacije. Zaključak: Pravilna antikoagulantna terapija u trudnoći zahteva analizu faktora rizika za nastanak tromboze, rizika za krvarenje, sagledavanje komorbiditeta kod trudnice, naročito renalne funkcije, posebno imajući na umu gestacionu starost trudnoće (ges- tation age). Apsolutno sigurna antikoagulantna terapije u trudnoći ne postoji, ali se u odnosu na navedene rizike za majku i dete mora odabrati najbezbednija opcija. Ključne reči: trudnoća, antikoagulantna terapija, mehaničke veštačke valvule

Received: July 27, 2015 Accepted: September 21, 2015

340 Volume 3 • Number 1 • January 2016 • HOPH