PGD/PGS Is Not Indicated in All Cases of IVF Norbert Gleicher, MD

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1 PGD/PGS Is Not Indicated in All Cases of IVF Norbert Gleicher, MD Medical Director CHR-NY Visiting Professor, Department of Ob/Gyn, Yale University School of Medicine. New Haven, CT Editor-In-Chief, JARG

2 NEW MEDICAL INDICATIONS ADVANCED FEMALE AGE Platteau et al, Fertil. Steril REPEATED PREGNANCY LOSS REPEATED IVF FAILURE Platteau et al, Fertil. Steril Munne et al, RBMOnline. 2003

3 New Medical Indications cont. Some authors even advocate universal PGD (Aneuploidy) Baruch et al, RBMOnline. 2005

4 EUROPEAN TERMINOLOGY Low-Risk PGD (PGS) High-Risk PGD

5 High-Risk PGD SINGLE GENE DEFECTS Autosom. dominant Autosom. recessive X- linked disorders CHROMOSOMAL ABNORMALITIES Translocations Structural abnormalities

6 LOW-RISK PGD or PREIMPLANTATION GENETIC SCREENING (PGS) ALL PGD, PERFORMED TO BETTER IVF OUTCOMES

7 AN ESTABLISHED TECHNIQUE SINCE 2001 ASRM/SART 2001

8 AN ESTABLISHED TECHNIQUE? LACKS DATA PGD Working Group: Baruch et al, RBMOnline ANEUPLOIDY SCREENING INACCURATE Self correction Li et al, Fertil. Steril Munne et al, Fertil Steril How inaccurate? DAMAGE TO EMBRYOS? DAMAGE TO OFFSPRING?

9 RISK-BENEFIT

10 R/B EASY TO ESTABLISH FOR Single Gene Defects Specific Chromosomal Abnormalities Special Indications Elective Gender Selection

11 R/B IS MORE DIFFICULT TO ESTABLISH WHERE BENEFITS ARE NOT KNOWN FOR SURE: Advanced Female Age Pregnancy Loss Repeat IVF Failure

12 IN THESE CASES IT IS ALSO RELEVANT FOR R/B WHETHER EMBRYO BIOPSY INHERENTLY REDUCES AN EMBRYO S IMPLANTATION CHANCE

13 CHR-NY 2005* AGE GROUP NO PGD PGD 30 22% 50% % 37% % 28% 41 7% 8% Oocyte Donation 47% 50% *Clinical Pregnancy rate per ET

14 PGD CYCLES SHOW UNIVERSALLY POOR PREGNANCY RATES ESHRE PGD CONSORTIUM: 16% (SEXING) 12% (STRUCT. CHROM.) 21% (MONOGENIC) Sermon et al, Lancet Reanalysis: Even worse outcomes Sermon et al, Hum. Reprod. 2004

15 USA No PGD outcome data published Verlinski: 22.5% Tarkan, L. New York Times. 11/22/05

16 THE EFFECT OF PGD There is NO data in the literature to support the claim that PGD does NOT affect IVF pregnancy chances. Indeed, what data is available suggest the opposite. Has to be considered in R/B

17 DEFENSE Lower pregnancy rates should be expected due to the discarding of abnormal embryos Sermon et al, Lancet. 2004

18 CAN PGD FOR ANEUPLOIDY IMPROVE PREGNANCY CHANCES? EMBRYO SELECTION WORKS Verlinski et al, J Assist. Reprod. Genetics :165-9 Munne et al, Fertil. Steril. 2002; 78:254-6 Munne et al, RBMOnline 2003; 7:91-7 Munne et al, Fertil. Steril. 2006; 85: EMBRYO SELECTION DOES NOT WORK Staessen et al, Hum. Reprod. 2004; 19: Platteau et al, Fertil. Steril. 2005;

19 EMBRYO SELECTION Only makes sense with large embryo numbers Restricts benefit to good ovarian reserve Restricts benefit mostly to younger women Staessen et al, (2004) investigated older women

20 Staessen et al, Hum. Reprod. 2004; 19: Women Randomized to PGD vs. No PGD No improvement in implantation/embryo No improvement in pregnancy chance Significant decrease in embryos for ET Almost significant decrease in 1 st hcg (28% vs 19.5%; p=0.07) PGD may reduce pregnancy chances

21 DOES PGD REDUCE PREGNANCY CHANCES? Staessen et al, 2004 EMBRYO MANIPULATION REASONABLY AFFECTS EMBRYOS May be difficult to detect May be balanced out by beneficial effect OVERALL EFFECT OF PGD WILL, THEREFORE, DEPEND ON THE BALANCE OF POSITIVE AND NEGATIVE EFFECTS

22 DOES PGD REDUCE PREGNANCY LOSS? Empirically sound logical since most loss genetic As losses increase in numbers, nongenetic causes increase in parallel Differences in opinion

23 DOES PGD REDUCE PREGNANCY LOSS? con t DIFFERENCES IN OPINION PGD is effective in reducing loss Munne et al. Fertil. Steril. 2002; 78:234-6 Clementi et al. Hum. Reprod. 2005; 20: Munne et al. Fertil. Steril. 2006; PGD is not effective in reducing miscarriages Miscarriages Platteau et al. Fertil. Steril. 2005; 83:397-42

24 Munne et al. Fertil Steril 2006; 85: RETROSPECTIVE COMPARISON OF 2279 IVF CYCLES (1965 PATIENTS) WITH PGD TO ROUTINE IVF OUTCOMES FROM SAME CENTERS AVERAGE AGE 39.6 YEARS 393 CYCLES (17.2%) NO ET 26.7% PREGNANCY RATE CONCLUDED THAT PGD SIGNIFICANTLY REDUCES THE RISK OF MISCARRIAG IN INFERTILE PATIENTS UNDERGOING IVF.

25 Munne et al. continued Control group inappropriate Retrospective review biased Cycles vs Patients (314 repeat cycles) 1999 SART data Adverse effects of PGD Pregnancy rate 26.7% for PGD National IVF rate 2002: 34%, a 22% difference

26 Munne et al. conclusions PGD does not appear to reduce miscarriage risk overall PGD may haves some effect in older women PGD reduces pregnancy chances

27 Especially in older patients, who have fewer embryos, a lower pregnancy chance, percentage wise affects overall pregnancy chance to a greater extent.

28 DOES PGD TREAT IVF FAILURE? NO DATA! EMPIRICALLY ATTRACTIVE SELECTIVE APPLICATION

29 CONCLUSIONS PGD data unsatisfactory PGD should not be considered an established technique PGD should not be marketed for unproven indications PGD potentially affects pregnancy chances with IVF adversely

30 CONCLUSIONS cont. PGD appears indicated for Single gene disorders Translocation Fragile-X Sex-Linked disease Special Indications (HLA-matching) Elective use (Gender)

31 CONCLUSIONS con t PGD s INDICATION IS QUESTIONABLE FOR Decreasing pregnancy loss Treating IVF failure Improving IVF outcomes

32 CONCLUSIONS con t PGD should only be performed under study conditions Every PGD center should establish its own R/B for the performance of PGD in its various indications Indications for PGD can be expected to vary based on patient age and ovarian function

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