1. Anticoagulation in pregnancy MAHMOUD MOHAMED B.PHARM. RPH. MSC (MOLECULAR BIOLOGY)

2. “ A grand adventure is about to begin ” Winnie the Pooh

3. 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.

4. 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?

5. Case concerns  Warfarin versus UFH/LMWH (safety and efficacy)  Management during labor and delivery  Breast feeding

6. Presentation Objectives  Disease epidemiology  Physiological changes during pregnancy  Virchow’s triad during pregnancy  Pharmacokinetic changes during pregnancy  Safety and efficacy of antithrombotic  Cases management

7. Background

8. Hogan MC Hogan MC 1, Foreman KJ, Naghavi M, Ahn SY, Wang M, Makela SM, Lopez AD, Lozano R, Murray CJ. Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5. Lancet. 2010 May 8;375(9726):1609-23Foreman KJNaghavi MAhn SYWang MMakela SMLopez ADLozano RMurray CJ Lancet.  T he annual mortality rate per 100,000 (2010)  Italy 3.9  UK 8.2  UAE 8.6  Qatar 14.3  USA 16.7

9. 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 Marshall AL 1. Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgrad Med. 2014 Nov;126(7):25-34.Postgrad Med. Saucedo M Saucedo M 1, Deneux-Tharaux C, Bouvier-Colle MH; French National Experts Committee on Maternal Mortality. Ten years of confidential inquiries into maternal deaths in France, 1998-2007. Obstet Gynecol. 2013 Oct;122(4):752-60.Deneux-Tharaux CBouvier-Colle MHFrench National Experts Committee on Maternal Mortality Obstet Gynecol. http://www.who.int/mediacentre/factsheets/fs348/en/

10. Background Cases between 2010 - 2014Total Pregnancy complicated by deep vein thrombosis42 Pregnancy complicated by pulmonary embolism10 Pregnancy complicated by presence of prosthetic heart valve12 Pregnancy complicated by valvular heart disease175 Medical records, Women's Hospital, HMC

11. Risk factors

12. Physiological changes Hypercoagulability Drug pharmacokinetic

13. Risk factors Marshall AL. Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgrad Med. 2014 Nov;126(7):25-34. doi: 10.3810/pgm.2014.11.2830.

14. 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 Dawes M, Chowienczyk PJ. Pharmacokinetics in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2001 Dec;15(6):819-26.

15. 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). Dawes M, Chowienczyk PJ. Pharmacokinetics in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2001 Dec;15(6):819-26.

16. Treatment during pregnancy

17. Antithrombotic Direct factor Xa inhibitors Direct thrombin inhibitors

18. Maternal/fetal risk DURING PREGNANCY

19. 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 Marshall AL1. Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgrad Med. 2014 Nov;126(7):25-34 Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

20. 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 Marshall AL1. Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgrad Med. 2014 Nov;126(7):25-34 Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

21. 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 (2 nd – 3 rd trimester) Fetal haemorrhagic complications, e.g. intracranial haemorrhage Marshall AL1. Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgrad Med. 2014 Nov;126(7):25-34 Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

22. Case management

23. 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

24. 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.

25. Case vignette 1  UFH has the highest risk of thromboembolic events followd by UFH in the 1 st 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 2 nd and 3 rd trimester.

26. Case vignette 1 Pregnant with mechanical valve 1 st trimester warfarin dose < 5 mg Continue warfarin warfarin dose > 5 mg, or < 5 mg but the patient refuses warfarin IV UFH q12h aPTT > 2X control LMWH q12h anti-Xa 0.8 – 1.2 U/ml (4 – 6 hours), 2 nd & 3 rd trimester Warfarin + aspirin 75 mg

27. 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 Urgent delivery If the patient on LMWH Switch to UFH 36 hrs prior to delivery Consider protamine in emergent delivery D/C UFH 4-6 hrs prior to delivery If the patient on Warfarin Vitamin K to target INR of 2 FFP in cases of emergent delivery

28. 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

29. 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

30. 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?

31. 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 Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

32. 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. Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

33. Case vignette 2 DrugRouteDoseTargetMonitoring EnoxaparinSubQ1 mg/Kg q12h Increased by 10-25% Anti-Xa 0.6 to 1.0 IU/mL Starting: 4 hrs after 3 rd or 4 th dose Adjustment: 4 hrs after 3 rd dose Maint.: Every 1-3 months UFHIV80 units/kg then, 18 units/kg per hour aPTT correspond to anti-Xa 0.3 – 0.7 U. Starting: every 6 hrs Maint.: 1-2 times/day SubQ17500 units q12h Increased by 10-30% aPTT correspond to anti-Xa 0.3 – 0.7 U. Starting: 6 hrs after 2 nd dose Maint.: 6 hrs after 2 nd dose. Then, 3-4 days, then every few weeks Frequent monitoring is recommended > 30/52

34. Case vignette 2 Labor and delivery Low risk D/C 24 hours prior to delivery High risk Switched to IV UFH, D/C 4 to 6 hours prior to delivery Very high risk No neuraxial anaesthesia Insert an inferior Vena cava catheter. OR proceed with full anticoagulation Unexpected delivery No neuraxial anaesthesia Proceed with full anticoagulation Preterm delivery expected switch to IV UFH at 36 weeks

35. 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

36. 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 Bates SM1, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300.

37. “ ” 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 M ARY M ASON Thank you