Biomarkers for Prediction of Pregnancy Outcome in Fertility Patients. Scott Nelson Muirhead Chair in Obstetrics & Gynaecology

Transcription

1 Biomarkers for Prediction of Pregnancy Outcome in Fertility Patients Scott Nelson Muirhead Chair in Obstetrics & Gynaecology

2 Why do we need to know ovarian response? Anna Sarah Just do IVF and see response Kelsey and Wallace PLOS One 2010.

3 Mild stimulation: one size fits all or does it? Lower live birth rates Mild stimulation OHSS risk still exists Fewer embryos FSH Level Programming of the cycle Follicle size (mm) Individualised FSH-dosing algorithms not available Mild ovarian response Macklon, et al. Endocrine Reviews Fauser, et al. Hum Reprod

4 So what options do we have? Paracrine Control Environmental Factors Small Antral 2-5 mm Endocrine Control FSH and LH Dependent Dominant 10 mm Ovulatory 20 mm Atresia Atresia Atresia Atresia Atresia Recruitment Growth Menstrual cycle >120 days 85 days 14 days True ovarian reserve Functional reserve

5 Can we get a handle on number of small antral follicles? Normal AFC Low AFC Courtesy of N Raine Fenning

6 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Jayaprakasan, et al. HR 2008, UOG 2009.

7 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software 2D 3D 3D automated Jayaprakasan, et al. HR 2008, UOG 2009.

8 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software Good association with oocyte yield r = 0.66 with 2D Jayaprakasan, et al. HR 2008, UOG 2009.

9 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software Good association with oocyte yield r = 0.78 with 3D inversion Jayaprakasan, et al. HR 2008, UOG 2009.

10 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software Good association with oocyte yield Good prediction of poor response Jayaprakasan, et al. HR 2008, UOG 2009.

11 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software Good association with oocyte yield Good prediction of poor response Good prediction of excessive response Broer, et al. HRU 2011.

12 Can we get a handle on number of small antral follicles? AFC can be measured anywhere in the cycle Improved accuracy with 3D and automated software Good association with oocyte yield Good prediction of poor response Good prediction of excessive response FSH dose nomogram Broer, et al. HRU 2011.

13 Primary alternative are endocrine markers AMH in pre-antral and early antral follicles Image courtesy of Hamish Fraser, MRC.

14 The new AMH Gen II assay DSL antibody Immunotech standards Values ~40% higher Wallace, Faye, Fleming and Nelson Annals of Clin Biochem 2011 (in press).

15 AMH is stable within and across menstrual cycles Tsepelidis. Hum Reprod van Disseldorp, et al. Hum Reprod

16 AMH menstrual cycle stability is dependent on age pmol/l pmol/l pmol/l pmol/l Sowers, et al. Fertil Steril

17 Validated AMH age nomogram for DSL N>25,000 Nelson, et al. Fertil Steril. 2010, submitted 2011.

18 Does AMH relate to ovarian response? Large prospective cohort of 340 women undergoing their first IVF cycle with a standard agonist approach: Prostap and 225IU AMH strongly correlates with oocyte yield AMH distinguishes treatment categories FSH does not Nelson, et al. Hum Reprod

19 AMH correlates with oocyte yield and is better than other predictors Author n R with oocytes AMH better than Ov. Vol d3 FSH d3 E 2 d3 inhb age Seifer (2002) Van Rooij (2002) Fanchin (2003) Muttukrishna (2004) Hazout (2004) Muttukrishna (2005) Elder Geva (2005) Ficicioglu (2006) La Marca (2007) Kwee (2007) Elgindy (2007) Nelson (2007) Wunder (2008) X Gnoth (2008) 132 Nardo (2008) La Marca, et al. Hum Reprod. Update 2010.

20 AMH for poor response: CUT-OFF values Author n Study design CUT-OFF value (ng/ml) Sens (%) Spec (%) Van Rooij (2002) 119 Prosp Muttukrishna (2004) 69 Prosp Muttukrishna (2005) 108 Retro Tremellen (2005) 75 Prosp Panarrubia (2005) 80 Prosp Ebner (2006) 141 Prosp Ficicioglu (2006) 50 Prosp La Marca (2007) 48 Prosp Smeenk (2007) 80 Prosp McIlveen (2007) 84 Prosp Kwee (2007) 110 Prosp Nelson (2007) 340 Prosp (correctly classified) Gnoth (2008) 132 Prosp AMH <1.0pmol/L only a few pregnancies to term La Marca, et al. Hum Reprod. Update 2010.

21 AMH - prediction of over-response Author n Study design CUT-OFF value (ng/ml) Sens (%) Spec (%) Prediction of hyper-response Kwee (2007) 110 Prosp Nelson (2007) 340 Prosp Prediction of OHSS Lee (2008) 262 Prosp Strengths: High number of patients Optimal classification of OHSS Only moderate to severe OHSS considered Limitations: Limited to Chinese population Not clear definition of PCOS women included TH Lee, et al. Hum Reprod

22 So can we use AMH to inform IVF? AMH: Stable molecule Relatively stable across cycle Stable between cycles One assay on the market Age related nomogram quadratic Strongly related to oocyte yield Can predict poor response Can predict excessive response Independent of age How can we utilise this information?

23 Prospective Evaluation of AMH based strategies Centre 1 (370) Control FSH Dose AMH Centre 2 (168) Control FSH Dose Agonist 150 High Response Risk of OHSS Antagonist Agonist 225 Normal Response Agonist Agonist 300 Reduced Response Antagonist 300 Antagonist Negligible Response Modified Natural Cycle Nelson, et al. Hum Reprod 2009.

24 Egg Yields % Cycles Lower oocyte yields in high responders Centre1 Centre 2 Excessive response P < P < Antagonist Agonist Antagonist Antagonist Reduced AMH Pmol/L Normal 5 15 Pmol/L High AMH >15 Pmol/L HighAMH >15 Pmol/L Reduced OHSS Nelson, et al. Hum Reprod

25 Individualisation significantly improves clinical pregnancy rates Centre1 Centre 2 P < Antagonist % Cycles 40 Agonist Agonist 20 Agonist Antagonist 0 Reduced AMH Pmol/L Normal AMH 5 15 Pmol/L High AMH >15 Pmol/L Adjusted for age and AMH antagonist protocol had substantially higher clinical pregnancy rates per cycle started [OR 4.40 (95% CI ), p<0.001] Nelson, et al. Hum Reprod

26 AMH dictated strategic approach AMH High Responders (150IU daily) Normal Responders Reduced Responders Negligible response Control FSH Dose Agonist Strategy Antagonist nwt Strategy / Obese Lower FSH dose normalised egg yields has Antagonist: negligible FSH + LH Negligible excess 150 / 225 responses impact on excess Low cryopreservation responses. High / maintained fresh CPR High cryopreservation Similar Agonist: outcomes HMG in or both rfsh centres: using GnRH 225 / 300 Agonist Negligible failure of OPU & over-stimulation rates High Dose FSH: Antagonist Strategy Long Minimal stimulation Short stimulation 225 / 300 High treatment cancellation Moderate cancellation No benefit burden from e.g. flare Reduced treatment higher FSH dose burden.

27 Composite measures incorporating AMH AMH and age are independent predictors of oocyte yield IMPORT consortium submitted.

28 Composite measures incorporating AMH AMH and age are independent predictors of oocyte yield AUROC 95% CI Age , 0.64 AMH , 0.83 Age & FSH , 0.77 Age & AFC , 0.80 Age & AMH , 0.84 Age & AMH & AFC , 0.86 Age & AMH & AFC &FSH , 0.86 IMPORT consortium submitted.

29 Composite measures incorporating AMH AMH and age are independent predictors of oocyte yield Maximal value is from AMH Never mind their age just measure AMH AUROC 95% CI Age , 0.64 AMH , 0.83 Age & FSH , 0.77 Age & AFC , 0.80 Age & AMH , 0.84 Age & AMH & AFC , 0.86 Age & AMH & AFC &FSH , 0.86 IMPORT consortium submitted.

30 So utilising biomarkers? Individualise expectations of oocyte yield Individualise treatment strategies Improve safety of IVF Prospectively evaluate novel therapies A role independent of the classical biomarker date of birth?

31 What are our chances of having a baby?

32 Can biomarkers predict spontaneous pregnancy? Increasing FSH reduced fecundity 40% decrease if FSH 15 U/litre Independent of age and cycle length Van der Steeg et al 2007 JCEM.

33 Can AMH predict spontaneous pregnancy? Low AMH associated with reduced chance of spontaneous pregnancy Steiner et al Obstetrics & Gynecol 2011

34 Can you predict fertility post chemo? Use menses as surrogate for fertility Pre treatment AMH higher in those with menses 5 years post chemo Amenorrhea Anderson et al 2011 JCEM.

35 Can you predict fertility post chemo? Use menses as surrogate for fertility Pre treatment AMH higher in those with menses 5 years post chemo AMH better predictor of amenorrhoea than age Anderson et al 2011 JCEM.

36 Can you predict fertility post chemo? Use menses as surrogate for fertility Pre treatment AMH higher in those with menses 5 years post chemo Anna AMH better predictor of amenorrhoea than age Sarah AMH may predict those who will benefit from cryopreservation Anderson et al 2011 JCEM.

37 Can you predict fertility post chemo? Use menses as surrogate for fertility Pre treatment AMH higher in those with menses 5 years post chemo Anna AMH better predictor of amenorrhoea than age Sarah AMH may predict those who will benefit from cryopreservation Anderson et al 2011 JCEM.

38 Can biomarkers predict IVF live birth? No everything including age awful Limitation of ROC analysis IMPORT consortium submitted.

39 Can biomarkers predict IVF live birth? Yes if you think of predict in conventional terms of low medium, or high risk Age (years) AMH (ng/ml) < > (0.01 to 0.16) 0.18 (0.12 to 0.26) 0.29 (0.17 to 0.44) (0.02 to 0.24) 0.27 (0.21 to 0.35) 0.40 (0.28 to 0.54) < (0.04 to 0.36) 0.38 (0.26 to 0.51) 0.52 (0.38 to 0.67) *Values in parenthesis are 95% confidence intervals La Marca and Nelson 2010 RBMO.

40 Will biomarkers add to established risk estimates? 144,000 fresh IVF cycles Baseline characteristics Freely available Nelson and Lawlor Plos Medicine IVFpredict.com

41 Live birth rate Accurate calibration is the key Observed Predicted Deciles of risk Nelson and Lawlor Plos Medicine IVFpredict.com

42 Live birth rate Accurate calibration is the key Observed Predicted Deciles of risk Nelson and Lawlor Plos Medicine IVFpredict.com

43 Summary Just do IVF is no longer an option Accurate prediction of live birth is feasible AMH is easy and relatively stable AFC accuracy is essential AFC and AMH relate strongly to oocyte yield Biomarkers can predict spontaneous live birth Biomarkers can direct fertility preservation Biomarkers can individualise expectations and treatment Biomarkers can improve outcomes and safety of IVF

44 Summary And your biomarker - AMH

45 GCRM Labs your AMH provider GCRMlabs.com

46 GCRM Labs your AMH provider GCRMlabs.com