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Anticoagulation in pregnancy MAHMOUD MOHAMED B.PHARM. RPH. MSC (MOLECULAR BIOLOGY) “A grand adventure is about to begin” Winnie the Pooh Case vignette 1 41 year old lady, G3P1 known case of prosthetic mitral valve on warfarin 8 mg and expressed a desire to become pregnant. Case vignette 2 36 years old female, recently diagnosed with DVT (1/12) on Warfarin 6 mg, came to ER with 5 weeks amenorrhea. A urine pregnancy test was positive at home and ß-hCG was 1500 IU/ml. What is next? Case concerns Warfarin versus UFH/LMWH (safety and efficacy) Management during labor and delivery Breast feeding Presentation Objectives Disease epidemiology Physiological changes during pregnancy Virchow’s triad during pregnancy Pharmacokinetic changes during pregnancy Safety and efficacy of antithrombotic Cases management Background Background annual mortality rate per 100,000 (2010) The Italy 3.9 UK 8.2 UAE 8.6 Qatar 14.3 USA 16.7 Hogan MC Foreman KJ Naghavi M Ahn SY Wang M Makela SM Lopez AD Lozano R Murray CJ Lancet. Background VTE accounts for 10 – 13% of maternal deaths VTE considered the third leading cause for maternal death VTE Risk increases during pregnancy 5 folds during antepartum 20 folds during the peurperium period Marshall AL Postgrad Med. Saucedo M Deneux-Tharaux C Bouvier-Colle MH French National Experts Committee on Maternal Mortality Obstet Gynecol. Background Cases between 2010 - 2014 Total Pregnancy complicated by deep vein thrombosis 42 Pregnancy complicated by pulmonary embolism Pregnancy complicated by presence of prosthetic heart valve 10 Pregnancy complicated by valvular heart disease 175 12 Risk factors Risk factors Physiological changes Hypercoagulability Drug pharmacokinetic Risk factors Pharmacokinetic during pregnancy Absorption Decrease gastric emptying and intestine motility this leads to increase Tmax and reduce Cmax Increase gastric pH due to decreased H excretion this would reduce weak acids SC absorption is enhanced due to enhanced tissue perfusion. Distribution Increase intravascular and extravascular volumes which lead to increased volume of distribution Decrease albumin concentration and heamodilution leads to decrease albumin bound drugs medication Competetive binding to protein by Estrogen and progesterone leads to increase free drugs concentration Metabolism CYP 450 enzymes are induced by Estrogen and progestron while others are competitively inhibited Elimination Increase renal flow and hence GFR rise by 50% and almost 80% later in pregnancy which leads to enhanced drug elimination, Feto-placenta unit Both placenta and fetal liver metabolize drugs Pharmacokinetic in pregnancy The net result of physiological changes in pregnancy lead to unpredictable drug therapeutic level. A signififcant dose alteration through out pregnancy was found, therefore frequent monitoring and dose changes is expected (Nancy L. Shapiro 2011). Heparin found to have lower peak plasma concentration compared to non-pregnant subjects, while time to peak plasma concentration is shorter in pregnant women. While aPTT is less in pregnanct ladies (Brancazio LR 1995). Treatment during pregnancy Antithrombotic Direct factor Xa inhibitors Direct thrombin inhibitors Maternal/fetal risk DURING PREGNANCY UFH Maternal risk • Thrombocytopenia or HIT (2 -3%) • Vertebral fractures (3 -15%) and osteoporosis (30%) • Skin reaction due to type 4 hypersensitivity reaction Fetal risk • UFH does not cross the placenta • Safe LMWH Maternal risk • Lower risk of bleeding compared to UFH (overall 1.98% including APH, PPH and wound hematoma) • Lower risk of HIT compared to UFH • Lower risk of osteoporosis and fractures • Similar adverse skin reactions Fetal risk • LMWH does not cross the placenta • Safe Warfarin Maternal risk • Pregnancy loss • Bleeding Fetal risk • Embryopathy i.e. Midfacial hypoplasia and stippled epiphyses (exposure 6 – 12 weeks) • CNS damage e.g. dorsal midline dysplasia and ventral midline dysplasia (anytrimester) • Minor neurodevelopmental problems (2nd – 3rd trimester) • Fetal haemorrhagic complications, e.g. intracranial haemorrhage Case management Case vignette 1 41 year old lady, G3P1 known case of prosthetic mitral valve on warfarin 8 mg and expressed a desire to become pregnant. Warfarin versus UFH/LMWH (safety and efficacy) Labor and delivery Breast feeding Case vignette 1 Maternal mortality is high (> 5%), and 24% thromboembolic events, and valve thrombosis without anticoagulation Anticoagulants carries a fetus risk of fetal abnormality, increase risk of miscarriage, hemorrhagic complications e.g. retro-placental bleeding, leading PTB and fetal death. Therefore, anticoagulation is recommended over no anticoagulation, and due to physiological changes, monitoring through out pregnancy is recommended. Case vignette 1 UFH has the highest risk of thromboembolic events followd by UFH in the 1st trimester and warfarin after when compared to warfarin through out pregnancy (33%, 9.2% versus 4%) and massive thrombosis of prosthetic valves in pregnancy and maternal risk of osteoporosis and thrombocytopenia LMWH has lower risk compared to UFH but valve thrombosis are also reported Warfarin is recommended in the second and third trimester with little teratogenic effect. Aspirin is recommended in the 2nd and 3rd trimester. Case vignette 1 warfarin dose < 5 mg 1st trimester IV UFH q12h warfarin dose > 5 mg, or < 5 mg but the patient refuses warfarin Pregnant with mechanical valve 2nd & 3rd trimester Continue warfarin Warfarin + aspirin 75 mg aPTT > 2X control LMWH q12h anti-Xa 0.8 – 1.2 U/ml (4 – 6 hours), Case vignette 1 Planned delivery Switch warfarin to LMWH or UFH Switch to UFH 36 hrs prior to delivery D/C UFH 4-6 hrs prior to delivery Switch to UFH 36 hrs prior to delivery If the patient on LMWH Consider protamine in emergent delivery Urgent delivery Vitamin K to target INR of 2 If the patient on Warfarin FFP in cases of emergent delivery D/C UFH 4-6 hrs prior to delivery Case vignette 1 Warfarin crosses the placenta and result in fetus and mother anticoagulation Higher risk of intracranial hemorrhage of mother is fully anticoagulated Therefore planned vaginal delivery with D/C of warfarin and starting UFH with aPTT > 2 times ULN is recommended, OR, Planned C/S with short stop of warfarin Case vignette 1 Resume UFH gradually at rate 500 U/hr and increase to therapeutic level over 24 – 72 hours Warfarin can be started: Same day of uncomplicated vaginal delivery 24 – 48 hours after C section Case vignette 2 36 years old female, recently diagnosed with DVT (1/12) on Warfarin 6 mg, came to ER with 5 weeks amenorrhea. A urine pregnancy test was positive at home and BHCG was 1500 IU/ml. What is next? Acute VTE ACCP 2012 Adjusted dose LMWH is preferred over UFH and Warfarin Therapy to be continued for 6 weeks postpartum and minimum of 3 months Discontinue LMWH 24 hours before induction of labor or LSCS or starting of neuraxial anesthesia Switch to IV UFH for patient with high risk of recurrent DVT of PE and discontinue 4 – 6 hours prior to delivery or epidural insertion History of VTE ACCP 2012 Antepartum clinical vigilance for patient with low risk of recurrent VTE Antepartum prophylaxis with prophylactic or intermediate dose LMWH Postpartum prophylaxis with prophylactic or intermediate dose of LMWH, OR Postpartum prophylaxis with Vitamin K antagonist with targeted INR 2 - 3 Adjusted dose or 75% of therapeutic dose for patient on long term Vitamin K antagonist. Case vignette 2 Drug Route Dose Target Monitoring Enoxaparin SubQ 1 mg/Kg q12h Increased by 10-25% Anti-Xa 0.6 to 1.0 IU/mL Starting: 4 hrs after 3rd or 4th dose Adjustment: 4 hrs after 3rd dose Maint.: Every 1-3 months UFH IV 80 units/kg then, 18 units/kg per hour aPTT correspond to Starting: every 6 hrs anti-Xa 0.3 – 0.7 U. Maint.: 1-2 times/day SubQ 17500 units q12h Increased by 10-30% aPTT correspond to Starting: 6 hrs after 2nd dose anti-Xa 0.3 – 0.7 U. Maint.: 6 hrs after 2nd dose. Then, 3-4 days, then every few weeks Frequent monitoring is recommended > 30/52 Case vignette 2 Labor and delivery Low risk High risk Very high risk D/C 24 hours prior to delivery Switched to IV UFH, D/C 4 to 6 hours prior to delivery No neuraxial anaesthesia Insert an inferior Vena cava catheter. OR proceed with full anticoagulation Unexpected delivery Preterm delivery expected No neuraxial anaesthesia switch to IV UFH at 36 weeks Proceed with full anticoagulation Case vignette 2 - Post delivery Restart LMWH, IV UFH, or SC UFH: 12 hours after a cesarean delivery or 6 hours after a vaginal birth Warfarin therapy Warfarin and heparin administered for at least five days. D/C The heparin if INR within therapeutic range (usually 2 to 3) for two consecutive days Breastfeeding Continue use of the following during breastfeeding UFH LMWH Warfarin Danaparoid and R-hirudin Use alternative anticoagulant during breastfeeding for the following: Fondaparinux Oral direct thrombin Oral Factor Xa inhibitors “ A baby is something you carry inside you for nine months, in your arms for three years, and in your heart until the day you die MARY MASON Thank you ”
