ACOG/CDC Maternal Mortality Meeting Taking Maternal Mortality Review Into Action Deep Venous Thrombosis

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1 ACOG/CDC Maternal Mortality Meeting Taking Maternal Mortality Review Into Action Deep Venous Thrombosis Michael J. Paidas, M.D. Professor Co-Director, Yale Women and Children s Center for Blood Disorders Co-Director, National Hemophilia Foundation-Baxter Clinical Fellowship at Yale Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine Aqua Room, Hilton Bayfront Hotel, May 6, 2012

2 Rate of VTE in pregnancy 1. The incidence of VTE increases exponentially with age, from 5/100,000/year among children to 6/1000/year among 80 year olds. 2. Among reproductive age women (< 40 years) the risk of VTE is 1/10, A retrospective cohort study of 268,525 patients over a 19 year period reported a prevalence of VTE of 1 per 1627 births. 4. Thus the risk of VTE is increased 6-fold during pregnancy. Cushman. Semin Hematol. 2007; 44:62-9. Gherman et al. Obstet Gynecol. 1999; 94:730-4.

3 DVT, PE & Trimester 1. DVT is more common in antepartum compared with postpartum period (74% vs. 26%; P<.001) (mean gest. age at Dx of 16.8 ± 2.4 wks). But puerperal period is only 6 wks, thus it is associated with the greatest risk per time. 2. Among patients with antepartum DVT, 50% are detected by 15 wks, 38% between 16 & 30 wks and only 17% after 30 wks. 3. In contrast, most PE s are diagnosed in the postpartum period (60%) and are strongly associated with cesarean delivery [Relative Risk (RR) of 30; p < 0.001]. Gherman et al. Obstet Gynecol. 1999; 94:730-4.

4 Pregnancy as the stress test of life Susceptibility / vulnerability Genetics Metabolic syndrome Life style factors Socioeconomic status Pregnancy complications Hypertensive disorders Low fetal growth Preterm delivery Placental abruption Stillbirth Gestational diabetes Mortality / morbidity Cardiovascular disease Type 2 diabetes Autoimmune diseases? Cancer? Sattar N, Greer IA., BMJ 42002

5 Population Follow up:median 14.6y (interquartile range ) Accruing 11,600,945 person-years Singleton deliveries during (1,795,806 deliveries of 965,475 women) First delivery (n=797,021) Women aged 15 to 50 years (n=796,915) Lykke JA, et. al Hypertension Jun;53(6): No prior cardiovascular diseases or diabetes mellitus, or deceased or emigrated within 3 months. (n=782,287)

6 Subsequent thromboembolism Combination Rate HR CI p No complications (reference) Preeclampsia ( ) <0.001 Preeclampsia + PTD ( ) Preeclampsia + SGA ( ) <0.001 Preeclampsia + PTD + SGA ( ) <0.001 Lykke JA, Langhoff-Roos, Sibai BM, Funai E, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension Jun;53(6):

7 VTE per 100K woman yrs VTE per 1000 deliveries % of VTE events VTE by Week Postpartum Pomp et al 2008 Jacobsen et al Heit et al 2005 Modified from Table 5. Jackson E et al Obstet Gynecol 2011;117:

8 FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone This update is in follow-up to the FDA Drug Safety Communication posted on 9/26/11: 1 Safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone. [ ] 8

9 Update to CDC US MEC for Contraceptive Use 2010 Days Postpartum Breast feeding < with risk for VTE without risk for VTE with risk for VTE without risk for VTE 2 2 > Non breastfeeding Category of Guidance 1) No restriction 2) Benefits generally > risk 3) Risks usually > benefits 4) Risks unacceptable MEC= Medical Eligibility Criteria MMWR Morbidity and mortality weekly report 2011;60:

10 Update to CDC US MEC for Contraceptive Use 2010 Risk Factors for VTE 1) Age 35y or older 2) Previous VTE 3) Thrombophilia 4) Immobility 5) Transfusion at delivery 6) BMI 30 or greater 7) Postpartum hemorrhage 8) Post Cesarean delivery 9) Preeclampsia 10)Smoking

11 Clinicaltrials.gov Search Rank Status Study 1 Not yet recruiting Need for Antepartum Thromboprophylaxis in Pregnant Women With One Prior Episode of Venous Thromboembolism (VTE) Conditions:Venous Thromboembolism; Deep Vein Thrombosis; Pulmonary EmbolismInterve ntion: 2 Recruiting Evaluation of the LMWH Thromboprophylaxis in Pregnancy Condition:PregnancyIntervention: 3 Completed The STOP CLOT Pilot Study: Study of Low Molecular Weight Heparin in High Risk Cesarean Section Condition:Deep Vein Thrombosis 4 Recruiting Venous Thromboembolism Prophylaxis Post Cesarean Section Conditions:Bleeding; Venous Thromboembolism 5 Not yet recruiting Comparison of 2 Low Molecular Heparin as a Thromboprophylaxis Postpartum 11

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13 ACOG Practice Bulliten Thromboembolism in Pregnancy Number 123, September 2011 Pneumatic compression devices recommended prior to Cesarean delivery for all women not already receiving thromboprophylaxis Studies of routine thromboprophylaxis for Cesarean delivery too small & underpowered. For patients with undergoing Cesarean delivery with additional risk factors for thromboembolism, individual risk assessment may require thromboprophylaxis with both pneumatic compression devices and UFH or LMWH. 13

14 Risk Factors for VTE Antepartum & Postpartum VTE Odds ratio (95% CI) Postpartum VTE Odds ratio (95% CI) Thrombophilia 51.8 ( ) Previous VTE 24.8 ( ) Family history of VTE 3.9 Superficial venous thrombosis 10.0 ( ) BMI >25 kg/m ( ) Antepartum immobilization 7.7 ( ) BMI > 25 kg/m 2 & antepartum immobilization 62.3 ( ) Infection (vaginal) 20.2 ( ) Infection (Cesarean) 6.2 ( ) Pre-eclampsia &IUGR 5.8 ( ) Emergency Cesarean 2.7 ( ) Hemorrhage (w/o surg.) 4.1 ( ) Hemorrhage (w/ surgery) 12.1 ( ) Antepartum VTE Odds ratio (95% CI) Assisted Reproduction 4.3 ( ) Modifed from Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M.Lancet Feb 6;375(9713):

15 SUGGESTED POSTPARTUM THROMBOPHYLAXIS POSTPARTUM Previous VTE or thrombophilia or BMI >25 kg/m² and antepartum Immobilisation Multiple postpartum VTE risk factors (see table 1) One other risk factor for postpartum VTE or no risk factors for postpartum VTE Prophylactic LMWH, or UFH 5000 IU three times daily if LMWH unavailable Consider prophylactic LMWH, or UFH 5000 IU twice daily if LMWH unavailable No pharmaco prophylaxis, compression stockings, and early mobilisation Bourjeily, G., Paidas, M., Khalil, H., Rosene-Montella, K., Rodger, M. Pulmonary embolism in pregnancy. Lancet, (9713): p

16 SUGGESTED ANTEPARTUM THROMBOPHYLAXIS Antepartum Previous VTE provoked by factors other than hormonal factors and no thrombophilia VTE unprovoked and/or thrombophilia and/or hormonally provoked* Strong antenatal risk factors for VTE Other No Pharmaco prophylaxis Prophylactic LMWH, or UFH (I trim 5000 IU; II trim 7500 IU; III trim IU) twice daily if LMWH unavailable Prophylactic LMWH, or UFH (I trim 5000 IU; II trim 7500 IU; III trim IU) twice daily if LMWH unavailable No Pharmaco prophylaxis Bourjeily, G., Paidas, M., Khalil, H., Rosene-Montella, K., Rodger, M. Pulmonary embolism in pregnancy. Lancet, (9713): p

17 Yale YNHH Thromboprophylaxis for Obese Patient Weight BMI (kg/m 2 ) >30 Consider prophylaxis if 1 other current or persisting risk TEP risk factor is present, vaginal or Cesarean >40 Administer prophylaxis irrespective of concurrent risk factors are present, vaginal or Cesarean RECO Dose Regimen enoxaparin 40mg daily enoxaparin 30mg every 12 hrs, Start 12 hrs post delivery. Continue while in hospital Start 12 hrs post delivery. Continue while in hospital

18 Am J Respir Crit Care Med Nov 15;184(10):

19 Diagnostic Algorithm for Imaging of Suspected PE in Pregnancy Leung AN et al. Radiology Feb;262(2):

20 Risk of VTE is correlated with age Annual incidence of all venous thromboembolism, deep vein thrombosis (DVT) alone, and pulmonary embolism (PE) with or without deep vein thrombosis (PE ± DVT) by age.

21 Risk of Venous thromboembolism duing the postpartum period: A systematic review. Jackson E, Curtis K, Gaffleild ME. Obstet Gynecol 2011; 117:

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23 Pettker CM et al. Am J Obset Gynecol 2009;200: 492. e.1-.8.

24 Pettker CM et al. Am J Obset Gynecol 2009;200: 492. e.1-.8.

25 Risk Factors for VTE Antepartum & Postpartum VTE Odds ratio (95% CI) Postpartum VTE, continued Odds ratio (95% CI) Thrombophilia 51.8 ( ) Previous VTE 24.8 ( ) Family history of VTE 3.9 Superficial venous thrombosis 10.0 ( ) BMI >25 kg/m ( ) Antepartum immobilization 7.7 ( ) BMI > 25 kg/m 2 & antepartum immobilization Antepartum VTE 62.3 ( ) Assisted Reproduction 4.3 ( ) Smoking 2.1 ( ) Postpartum VTE Hemorrhage (w/osurg.) 4.1 ( ) Hemorrhage (w/ surgery) 12.1 ( ) Infection (vaginal) 20.2 ( ) Infection (Cesarean) 6.2 ( ) IUGR 3.8 ( ) Pre-eclampsia 3.1 ( ) Pre-eclampsia &IUGR 5.8 ( ) Emergency Cesarean 2.7 ( ) Other possible risk factors Cesarean 2.1 ( ) Cesarean 1.3 ( ) Age 2.1 ( ) Age 0.8 ( ) Parity 1.1 ( ) Parity 1.7 ( ) Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M.Lancet Feb 6;375(9713):

26 PRESERVE-1 A Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1) M. J. Paidas, MD 1 ; B. M. Sibai, MD 2 ; and S. Lowry, MD 3 ; for the PRESERVE-1 Study Group 1 Yale School of Medicine, New Haven, CT; 2 University of Cincinnati, Cincinnati, OH; 3 GTC Biotherapeutics, Framingham, MA

27 Pleiotropic Effects of Antithrombin

28 PRESERVE-1 Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia RANDOMIZE 60 pregnant women with PPE presenting between weeks of gestation IV rhat 500 mg BID (n=20) IV rhat 1500 mg 24-h CI (n=20) IV placebo (n=20)* Maternal, fetal, and neonatal assessments and complications Primary Objectives Assess safety of recombinant antithrombin (rhat) in both mother and fetus/neonate Assess the pharmacokinetics of rhat in preterm preeclampsia (PPE) in the mother and neonate at delivery Assess the efficacy of rhat for the treatment of PPE in addition to expectant management to prolong gestational age at delivery Secondary Objectives Assess the impact of maternal rhat treatment on perinatal and neonatal clinical outcomes