Management of APS in pregnancy Prof. Munther A Khamashta MD FRCP PhD Director: Graham Hughes Lupus Research Laboratory The Rayne Institute, St Thomas Hospital ( Dubai Hospital Rheumatology Department ) Challenges in Obstetrics & Gynaecology, Kuwait, February 2017

Antiphospholipid syndrome Major clinical features Recurrent arterial / venous thrombosis Recurrent pregnancy loss Thrombocytopenia Livedo reticularis is a prominent marker Hughes GRV. BMJ 1983, 287: 1088

Antiphospholipid syndrome Associated clinical features Leg ulcers Transverse myelitis Headache Chorea, epilepsy Cognitive disorders Heart valve lesions Haemolytic anaemia Pulmonary hypertension

Classification criteria for definite APS Clinical Vascular thrombosis: venous, arterial or small vessel Pregnancy morbidity: - 3 consecutive miscarriages (<10 weeks) - 1 fetal death (10 weeks) - 1 premature birth (34 weeks due to severe pre-eclampsia / placental insufficiency) Laboratory Lupus anticoagulant IgG/IgM aCL (medium/high titre) IgG/IgM anti-b2GPI 2 occasions, 12 weeks apart Miyakis et al. J Thromb Haemost 2006

With treatment >85% success rate aPL and pregnancy loss 3 consecutive miscarriages 15% 2nd or 3rd trimester loss 30% IUGR + late loss 40% With treatment >85% success rate

Antiphospholipid Syndrome in pregnancy Uteroplacental insufficiency Miscarriages aPL Fetal death IUGR Uteroplacental insufficiency Pre-eclampsia Abruption Premature delivery Thrombosis

aPL and pregnancy Proposed mechanisms Block placental prostaglandin & thromboxane Carreras et al. Lancet 1981 Compete / displace annexin V Rand et al. New Engl J Med 1981 Inhibit trophoblast proliferation Chamley et al. Lancet 1998 Di Simone et al. Arthritis Rheum 2001 Complement activation Holers et al. J Exp Med 2002 Girardi et al. J Clin Invest 2003

Placental pathology Placental infarction Microvascular thrombosis Increased syncytial knotting “Premature aging” of villi Fibrinoid necrosis Atherosis, thrombosis and hyalinization of decidual vessels Pathological changes are not always present Poor correlation with clinical outcome Stone S et al. Placenta 2006; 27: 457-67

Management of pregnancy in aPL-positive women Recommendations No thrombosis / miscarriage No treatment - Careful monitoring Low-dose aspirin (no evidence) Previous thrombosis Heparin + Low-dose aspirin Recurrent early miscarriage Low-dose aspirin Late fetal loss / severe pre-eclampsia / IUGR Khamashta et al . Best pract res clin Rheumatol 2016.

What to do if aspirin/heparin fails? APS pregnancy What to do if aspirin/heparin fails? Try again with aspirin/heparin Add: ? low dose steroids ? IVIG ? hydroxychloroquine ? Azathioprine ? Statins Bramham K,et al Blood. 2011 ;117:6948-51 Lefkou J Clin Invest. 2016 Aug 1;126(8):2933-40

ANTITHROMBOTICS & EPIDURAL Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the Second ASRA Consensus Conference on Neuraxial Anesthesia and anticoagulation) Reg Anesth Pain Med 2003; 28: 172-97 LMWHeparin low dose: STOP 12 hours in advance LMWHeparin full dose: STOP 24 hours in advance

1000 patients with APS Deep vein thrombosis / PE 48% Pregnancy loss 35% Thrombocytopenia 30% Livedo reticularis 24% Stroke / TIA 20% Superficial thrombophlebitis 9% Hemolytic anemia 7% Primary APS: 53%, associated with SLE: 36% Cervera et al. Arthritis Rheum 2002

Antiphospholipid syndrome Thrombotic events n = 1000 over 10 years Baseline 10 years DVT 39% 4% Stroke/TIAs 31% 9% Pulmonary emboli 14% 4% Myocardial infarction 6% 2% Cervera R et al Ann Rheum Dis 2015;74:1011

Antiphospholipid syndrome Obstetric manifestations n = 1000 over 10 years Baseline 10 years Pre-eclampsia 5% 6% Early pregnancy loss < 10 wks 35% 17% Late pregnancy loss ≥ 10 wks 17% 5% Live birth with prematurity 11% 48% Live birth with IUGR 2% 26% Cervera R et al Ann Rheum Dis 2015;74:1011

aPL and infertility No other topic in reproductive medicine better illustrates the concept of controversy than the role of aPL in infertility Stovall & Van Voorhis. Clin Obstet Gynecol. 1999

Infertility and aPL Current practice infertile women undergoing IVF-ET “panel” assay of 5-8 aPL controversial therapeutic implications treatment with heparin / aspirin / IVIG recommended by some Where is the evidence?

aPL and relative likelihood of clinical pregnancy with IVF Birdsall et al, 1996 Denis et al, 1997 El-Roeiy et al, 1987 Gleicher et al, 1994 Kowalik et al, 1997 Kutteh et al, 1997 Sher et al, 1994 Average Hornstein. Fertil Steril 2000

aPL and relative likelihood of live birth with IVF Birdsall et al, 1996 Denis et al, 1997 El-Roeiy et al, 1987 Gleicher et al, 1994 Kowalik et al, 1997 Average Hornstein. Fertil Steril 2000

Routine testing for aPL is not indicated in IVF Based on existing data therapy not justified

Thromboprophylaxis is essential… Doctor, please don’t forget my mummy! Thromboprophylaxis is essential…

Background Thromboembolic risk Normal population 0.1-0.3% APS pregnancy 4-5% Martinez-Zamora MA et al Ann Rheum Dis. 2012; 71:61-6 Pengo V et al. Blood. 2011; 118: 4714-8

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study VTE-free survival. Shown are the VTE-free survival rates in initially nonthrombotic women with pregnancy loss (3 unexplained consecutive spontaneous abortions before the 10th week or 1 unexplained fetal death at or beyond the 10th week) with positive aPLAbs, with a positive F5 6025 or F2 rs1799963 polymorphism (constitutional thrombophilia), or with a negative thrombophilia screening (negative). Gris J et al. Blood 2012;119:2624-2632 ©2012 by American Society of Hematology