Thrombosis during assisted reproduction. Scott Nelson Muirhead Chair in Obstetrics & Gynaecology

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1 Thrombosis during assisted reproduction Scott Nelson Muirhead Chair in Obstetrics & Gynaecology

2 ART can be as safe as natural pregnancy!! What used to be the risk of thrombosis in ART!! We can use AMH to personalise ovarian stimulation!! We can combine multiple novel strategies to abolish IVF related VTE

3 How we used to do IVF Van Voorhis et al N Engl J Med 2007

4 ART does not increase the risk of arterial thrombosis Arterial thrombosis per 10,000 treatments Hansen A et al. Hum Reprod 2012

5 ART increases the risk of VTE Venous Thromboembolism (%) Henriksson P et al. BMJ 2013

6 ART increases the risk of pulmonary embolism Pulmonary Embolism (%) Henriksson P et al. BMJ 2013

7 VTE in ART is primarily a first trimester phenomenon Odds Ratio First Second Third Postnatal Trimester Rova et al Fertil Steril 2012

8 Others suggest that VTE risk still higher after first trimester VTE cases per 10,000 pregnancies 36 VTE events among the 16,191 pregnancies 727 VTE events among the 805,464 pregnancies Hansen et al Hum Reprod 2014

9 VTE risk is higher after delivery in IVF pregnancies VTE cases per 10,000 pregnancies IRR 1.2 (95% CI ) for singleton IVF IRR 3.9 (95% CI ) for multiple IVF Reference Hansen et al Hum Reprod 2014

10 Increased risk of VTE persists beyond pregnancy VTE cases per 10,000 treatments Hansen et al Hum Reprod 2014

11 The VTE risk factors are potentially modifiable Odds Ratio Fresh IVF No OHSS Fresh IVF + OHSS FET >40y BMI >30kg/m 2 Multiple pregnancy Rova et al Fertil Steril 2012

12 Reducing the risk of VTE obesity Aggressive stimulation hcg Fresh transfer of multiple embryos OHSS Older women We can change these

13 How we can minimise VTE risk during ovarian stimulation

14 We can ensure optimal preconceptual health

15 The big challenge of assessing variability Sarah Oocyte number Melisa Age Wallace and Kelsey PLOS One 2010

16 AMH is produced by small but not larger follicles AMH in pre-antral and early antral follicles Courtesy of Hamish Fraser, MRC

17 Anderson RA Clin Endocrinol 2012 Nelson, Telfer & Anderson Hum Repro Update 2014 The growing follicle produces changing hormones AMH Inhibin B, estradiol

18 AMH can predict ovarian response at all ages AMH Age Nelson et al Hum Reprod 2007 Nelson et al Fertil Steril 2012

19 AMH can predict ovarian response at all ages Oocytes collected AMH Age Nelson et al Hum Reprod 2007 Nelson et al Fertil Steril 2012

20 Broer et al Fertil Steril 2008 Broer et al Hum Reprod Update 2011 AMH can predict the extremes of ovarian response Poor Excessive

21 AMH can optimise stimulation Population % Inadequate gonadotrophin exposure Iatrogenic Poor response Optimal 15 Excessive gonadotrophin exposure Iatrogenic OHSS Oocyte yield

22 We can use AMH to stratify care AMH (pmol/l) 40 Antagonist hcg/gnrha trigger Standard treatment Maximise oocyte yield Nelson et al Hum Reprod 2009 Nelson et al Fertil Steril 2013

23 Humaiden et al. Hum Repro Update 2011 Iliodromiti et al. Hum Reprod 2013 We can avoid using hcg to mature oocytes LH surge after GnRHa trigger

24 Ovarian stimulation adversely affects endometrium Normal High progesterone Labarta, et al. Hum Repro 2011

25 We can choose not to replace embryos in the fresh cycle Risk Ratio 95% CI! Antepartum haemorrhage 0.67 (0.5, 0.81)! Preterm labour 0.84 (0.48, 0.90)! Small for gestational age 0.45 (0.30, 0.66)! Low birth weight 0.69 (0.62, 0.76)! Perinatal Mortality 0.68 (0.48, 0.96) Maheshwari et al. Fertil Steril 2013

26 How we can reduce the risk of multiples

27 We can limit the number of embryos to transfer Lawlor and Nelson Lancet 2012

28 We can limit the number of embryos to transfer Lawlor and Nelson Lancet 2012

29 We can use culture selection Day 1 Day 2 Day 3 Day 4 Day 5 Day 5 / 6 Pronuclear stage Blastocyst

30 Many blastocysts will still be chromosomally abnormal Mean Euploid (%) Mean Aneuploid (%) CGH results of 1218 cleavage-stage embryos embryos from 203 women Ata et al. RBMOnline 2012

31 We can use time lapse to select the correct blastocyst Embryoscope at Glasgow Royal Infirmary

32 How we can combine these novel approaches to abolish IVF related VTE

33 The safest and best approach for our patients Use AMH to identify at greatest risk Use GnRH antagonist strategy GnRH agonist trigger Culture all embryos to blastocyst and freeze Replace single embryo in frozen cycle Completely removes OHSS and VTE risk Reduces VTE risk Nelson et al Hum Reprod 2012 Nelson Thrombosis Research 2013

34 The safest and best approach for our patients Use AMH to identify at greatest risk Use GnRH antagonist strategy GnRH agonist trigger Culture all embryos to blastocyst and freeze Replace single embryo in frozen cycle Completely removes OHSS and VTE risk Reduces VTE risk Nelson et al Hum Reprod 2012 Nelson Thrombosis Research 2013