Thrombophilia Made Simple for Obstetricians Dr Tan Lay Kok MBBS FRCOG MMED(O&G) FAMS Department of OBGYN, Singapore General Hospital

Scope Review of thrombophilia Relationship between thrombophilia & adverse pregnancy outcomes – the evidence Role of screening

Thrombophilia Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin gene mutation MTHFR and hyperhomocysteinaemia

Thrombophilia Acquired Anti-Phospholipid Syndrome (APS) APCR Elevated factor VIII Pregnancy Nephrotic syndrome

Thrombophilia made simple

Thrombophilia made simple

Thrombophilia made simple Physiological anticoagulants

Thrombophilia made simple Prothrombin gene mutation

Thrombophilia made simple Antithrombin deficiency Prothrombin gene mutation Factor V Leiden APC Resistance

Protein C deficiency Protein S deficiency Antithrombin deficiency Prothrombin gene mutation Factor V Leiden APC Resistance

Thrombophilia made simple Towards ANTICOAGULATION Antithrombin III Protein C Protein S Towards CLOT formation Factor V Thrombin Fibrinogen

Thrombophilia testing History of recurrent, atypical (axillary vein, CVT) thromboembolism Unprovoked thromboembolism Provoking factors eg COCP, pregnancy, surgery, trauma Family history of thromboembolism

Thrombophilia testing Has increased tremendously in last few decades in O&G Belief that thrombophilia underlies and causes bad pregnancy outcomes that screening for and treatment for thrombophilia improves outcomes

Seminars in Reproductive Medicine 2006 Feb; 24 (1) : 54-66.

WHAT NOT TO ORDER!

Thrombophilia but no thrombosis FVL / PT / APS PC / PS / homozygous FVL AT Combination Increasing risk

Thrombophilia but no thrombosis FVL / PT / APS PC / PS / homozygous FVL AT Combination Increasing risk Stratify risk & consider other risk factors Personal history Family history

2 Questions Do inherited thrombophilias, inherited or acquired, cause pregnancy complications? Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

Conclusions Thrombophilias likely a weak cause of early and “later” pregnancy loss; likely don’t contribute to pre-eclampsia and SGA; unknown if associated with abruption No proven preventative measures in thrombophilic pregnancies- LMWH is not candy!

Thrombophilias predispose to development of thrombosis in slow flow circulation of the placenta

Thrombophilia and Placenta- Mediated Pregnancy Complications

Thrombophilia and Placenta- Mediated Pregnancy Complications Pregnancy loss – recurrent miscarriage, late pregnancy loss IUGR Pre-eclampsia Abruptio

Current Opinion in Obstetrics & Gynecology 2012 Aug; 24 (4) : 229-34.

Association between Thrombophilia & Pregnancy complications

Factor V Leiden and Pregnancy Loss- Weak association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 04 FVL Outcome: 01 Pregnancy Loss Study FVL Positive FVL Negative RR (random) Weight or sub-category n/N 95% CI % Clark 2008 1/142 71/3802 6.14 0.38 [0.05, 2.69] Dizon-Townson 2005 8/134 264/4751 20.36 1.07 [0.54, 2.13] Lindqvist 2006 13/270 73/2210 22.39 1.46 [0.82, 2.59] Rodger 2008 3/133 28/2811 12.51 2.26 [0.70, 7.35] Karakantza 2008 4/13 47/379 17.19 2.48 [1.05, 5.85] Murphy 2000 3/16 24/572 13.61 4.47 [1.50, 13.33] Said 2006 2/93 4/1633 7.79 8.78 [1.63, 47.32] Total (95% CI) 801 16158 100.00 1.96 [1.13,3.38] Total events: 34 (FVL Positive), 511 (FVL Negative) Test for heterogeneity: Chi² = 12.77, df = 6 (P = 0.05), I² = 53.0% Test for overall effect: Z = 2.40 (P = 0.02) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 4.7% FVL Outcome Event Rates: FVL: 4.2% Loss No FVL: 3.2% Loss

Factor V Leiden and Pre-Eclampsia - No Association Review: Thrombophilic women and placenta mediated pregnancy complications (all studies) Comparison: 01 Factor V Leiden Outcome: 01 Pre-eclampsia Study FVL Positive FVL Negative RR (fixed) Weight or sub-category n/N 95% CI % Salomon 2004 1/38 28/605 5.20 0.57 [0.08, 4.07] Said 2006 5/93 98/1633 16.58 0.90 [0.37, 2.15] Rodger 2008 4/128 76/2783 10.49 1.14 [0.43, 3.08] Lindqvist 2006 5/257 34/2137 11.46 1.22 [0.48, 3.10] Dizon-Townson 2005 5/134 141/4751 12.15 1.26 [0.52, 3.02] Clark 2008 3/141 63/3731 7.20 1.26 [0.40, 3.96] Dudding 2008 17/243 204/4206 34.99 1.44 [0.89, 2.33] Murphy 2000 0/13 12/548 0.98 1.57 [0.10, 25.20] Karakantza 2008 0/13 8/379 0.95 1.60 [0.10, 26.30] Total (95% CI) 1060 20773 100.00 1.22 [0.89,1.66] Total events: 40 (FVL Positice), 664 (FVL Negative) Test for heterogeneity: Chi² = 1.62, df = 8 (P = 0.99), I² = 0% Test for overall effect: Z = 1.24 (P = 0.21) 0.1 0.2 0.5 1 2 5 10 Increases Risk Decreases Risk Exposure: 4.9% FVL Outcome Event Rates: FVL: 3.8% Pre-Eclampsia No FVL: 3.2% Pre-Eclampsia

Prothrombin GM and Pre-Eclampsia - No Association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 01 PGM Outcome: 02 Pre-eclampsia Study PGV Positive PGV Negative RR (fixed) Weight or sub-category n/N 95% CI % Dudding 2008 5/239 85/4176 44.16 1.03 [0.42, 2.51] Said 2006 3/41 100/1685 22.80 1.23 [0.41, 3.73] Rodger 2008 2/60 75/2851 14.83 1.27 [0.32, 5.04] Karakantza 2008 0/12 8/380 2.69 1.72 [0.11, 28.30] Salomon 2004 3/40 26/603 15.52 1.74 [0.55, 5.50] Total (95% CI) 392 9695 100.00 1.24 [0.72,2.12] Total events: 13 (PGV Positive), 294 (PGV Negative) Test for heterogeneity: Chi² = 0.56, df = 4 (P = 0.97), I² = 0% Test for overall effect: Z = 0.78 (P = 0.43) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 3.9% PGM Outcome Event Rates: PGM: 3.3% Pre-Eclampsia No PGM: 3.0% Pre-Eclampsia

Factor V Leiden and SGA<10th Percentile - No Association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 02 FVL Outcome: 01 IUGR (Birthweight <10th Percentile) Study FVL Positive FVL Negative RR (fixed) Weight or sub-category n/N 95% CI % Lindqvist 2006 23/257 221/2137 28.25 0.87 [0.57, 1.30] Dizon-Townson 2005 10/124 403/4428 13.07 0.89 [0.49, 1.62] Said 2006 10/93 179/1633 11.49 0.98 [0.54, 1.79] Rodger 2008 9/128 188/2783 9.84 1.04 [0.55, 1.98] Dudding 2008 33/587 368/7282 32.69 1.11 [0.79, 1.57] Salomon 2004 5/38 62/603 4.38 1.28 [0.55, 2.99] Murphy 2000 0/13 9/548 0.28 2.06 [0.13, 33.73] Total (95% CI) 1240 19414 100.00 1.00 [0.82,1.23] Total events: 90 (FVL Positive), 1430 (FVL Negative) Test for heterogeneity: Chi² = 1.60, df = 6 (P = 0.95), I² = 0% Test for overall effect: Z = 0.01 (P = 0.99) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 6.0% FVL Outcome Event Rates: FVL: 7.2% SGA(10th%ile) No FVL: 7.3% SGA(10th%ile)

Prothrombin GM and SGA<10th Percentile- No Association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 02 Intaruterine Growth Restriction Outcome: 02 PGM and IUGR (Birthweight < 10th percentile) Study PGV Positive PGV Negative RR (fixed) Weight or sub-category n/N 95% CI % Said 2006 5/41 184/1685 18.01 1.12 [0.49, 2.57] Dudding 2008 16/591 162/7251 50.31 1.21 [0.73, 2.01] Salomon 2004 5/39 62/602 15.54 1.24 [0.53, 2.92] Rodger 2008 5/60 190/2851 16.14 1.25 [0.53, 2.93] Total (95% CI) 731 12389 100.00 1.21 [0.85,1.71] Total events: 31 (Treatment), 598 (Control) Test for heterogeneity: Chi² = 0.05, df = 3 (P = 1.00), I² = 0% Test for overall effect: Z = 1.04 (P = 0.30) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 5.6% PGM Outcome Event Rates: PGM: 4.2% SGA(10th%ile) No PGM: 4.8% SGA(10th%ile)

Factor V Leiden and SGA 5th Percentile - No Association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 02 FVL Outcome: 04 IUGR (birth weight < 5th percentile) Study FVL positive FVL negative RR (fixed) Weight or sub-category n/N 95% CI % Said 2006 3/93 90/1633 29.62 0.59 [0.19, 1.81] Karakantza 2008 0/13 19/379 4.23 0.70 [0.04, 10.95] Clark 2008 6/141 168/3731 37.37 0.95 [0.43, 2.10] Dizon-Townson 2005 6/124 173/4428 28.78 1.24 [0.56, 2.74] Total (95% CI) 371 10171 100.00 0.91 [0.56,1.50] Total events: 15 (FVL positive), 450 (FVL negative) Test for heterogeneity: Chi² = 1.21, df = 3 (P = 0.75), I² = 0% Test for overall effect: Z = 0.36 (P = 0.72) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 3.7% FVL Outcome Event Rates: FVL: 4.0% SGA (5th%ile) No FVL: 4.4% SGA (5th%ile)

Factor V Leiden and Abruption - No Association Review: Thrombophilic women and placenta mediated pregnancy complications Comparison: 03 FVL Outcome: 01 Placenta Abruption (all studies) Study FVL Positive FVL Negative RR (random) Weight or sub-category n/N 95% CI % Dizon-Townson 2005 0/134 31/4751 9.01 0.56 [0.03, 9.08] Said 2006 0/93 6/1726 8.58 1.41 [0.08, 24.90] Lindqvist 2006 2/257 11/2137 22.44 1.51 [0.34, 6.78] Rodger 2008 3/128 39/2783 29.70 1.67 [0.52, 5.34] Karakantza 2008 3/13 12/379 30.27 7.29 [2.34, 22.74] Total (95% CI) 625 11776 100.00 2.28 [0.92, 5.67] Total events: 8 (FVL Positive), 99 (FVL Negative) Test for heterogeneity: Chi² = 6.30, df = 4 (P = 0.18), I² = 36.5% Test for overall effect: Z = 1.77 (P = 0.08) 0.1 0.2 0.5 1 2 5 10 Decreases Risk Increases Risk Exposure: 5.1% FVL Outcome Event Rates: FVL: 1.3% Abruption No FVL: 0.8% Abruption

2 Questions Do inherited thrombophilias cause placenta-mediated pregnancy complications? No - SGA, Pre-eclampsia Weakly - Pregnancy loss Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

2011 says not justified

British Journal of Haematology 2008 Nov; 143 (3) : 321-35 No difference from earlier statement in 2008

2008 Need for RCT

Does knowledge about thrombophilia status alter management? Except: Asymptomatic fertile women + family history of VTE + thrombophilic defect APS with venous /arterial thrombosis and well defined pregnancy complications

2 Questions Do inherited thrombophilias cause placenta-mediated pregnancy complications? No - SGA, Pre-eclampsia Weakly - Pregnancy loss Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

List of completed RCTs of interventions vs control to prevent pre-eclampsia in thrombophilic women – up to 2010

List of completed RCTs of interventions vs control to prevent small for gestational age babies in thrombophilic women – up to 2010

List of completed RCTs of interventions vs control to prevent placental abruption in thrombophilic women – up to 2010

List of completed RCTS of interventions vs control to prevent pregnancy loss in thrombophilic women – up to 2010 Gris, Blood, 2004 Laskin, J Rheumatology, 2009 Rey, J Thromb Haemost, 2009

In conclusion, antepartum prophylactic dose dalteparin in women with thrombophilia at increased risk of pregnancy loss, placenta-mediated pregnancy complications, or venous thrombosis does not reduce the occurrence of these complications. Further research is needed to establish whether low-molecular-weight heparin reduces the risk of recurrent severe pre-eclampsia, severely small-for-gestational-age infants (birthweight <5th percentile), or placental abruption.

Universal screening of women with previous poor obstetric history for inherited thrombophilia is inappropriate Use of LMWH in women with inherited thrombophilia with recurrent pregnancy loss is not indicated

We mustnt forget cost

difference translates into a number needed to treat of six— This 16% absolute difference translates into a number needed to treat of six— ie, six women would need to inject up to 400 needles per pregnancy at a drug cost of more than US$8000 per pregnancy to prevent one outcome. TIPPS Study 2014

Conclusion Association is not causation Evidence supporting thrombophilia screening is weak Not cost effective Unnecessary indiscriminate testing can be harmful Antiphospholipid syndrome is the only thrombophilia justified for screening in defined situations