1. 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

2. 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

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

4. 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

5. 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

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

7. 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

8. 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:

9. 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.

10. 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 ;117:
Lefkou J Clin Invest Aug 1;126(8):

11. 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:
LMWHeparin low dose: STOP 12 hours in advance
LMWHeparin full dose: STOP 24 hours in advance

12. 1000 patients with APS Deep vein thrombosis / PE 48%
Pregnancy loss %
Thrombocytopenia %
Livedo reticularis %
Stroke / TIA %
Superficial thrombophlebitis %
Hemolytic anemia %
Primary APS: 53%, associated with SLE: 36%
Cervera et al. Arthritis Rheum 2002

13. Antiphospholipid syndrome
Thrombotic events n = 1000 over 10 years
Baseline years
DVT % %
Stroke/TIAs % % Pulmonary emboli % %
Myocardial infarction % %
Cervera R et al Ann Rheum Dis 2015;74:1011

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

15. 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

16. 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?

17. 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

18. 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

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

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

22. 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:

23. 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 F or F2 rs polymorphism (constitutional thrombophilia), or with a negative thrombophilia screening (negative).
Gris J et al. Blood 2012;119:
©2012 by American Society of Hematology