When peri-menopausal women want to conceive dreams and facts

Transcription

1 When peri-menopausal women want to conceive dreams and facts «The perimenopause» October 6, 2012 DELVIGNE ANNICK, MD, PHD ART CENTER LIÈGE (ROCOURT)

2 Plan Epidemiological data of reproduction Fertility throughout life Assisted Reproductive Technology over 40, over 45? What dreams are realistic?

3 Epidemiologic data

4 Epidemiologic data

5 Epidemiologic data 29 y in Brussels 27,3 y in Wallonie 28,2 y in Vlaanderen Delivery over 35 : 12 % (2000) 20 % (2011)

6 Epidemiologic data: Wallonie-Brussels + 266%

7 Epidemiologic data: Vlaanderen-Brussels Verlossing Geboorte van één of meer kinderen met een gewicht van Q 500 gram uit één moeder. Studiecentrum voor Perinatale Epidemiologie (SPE)

8 Why so late? Completing education Establishing a career Independence Over 40? Economic? A stable relationship (72 % over 35 y, Maheshawari et al. FS 2008) Second couple!

9 Why so late? Source: Etude de l histoire familiale (EHF), Insee, 1999

10 Fertility throughout life

11 Fertility throughout life Number of oocytes in the ovaries declines naturally and progressively through the proccess of atresia: 1-2 milions at birth at puberty at 37 y 1000 at 51 y Quality decline from 32 Y with exacerbation at 37 Y Child-bearing usually ends 10 y before menopause Cycle irregularity: 6-7 y before Broeckmans, et al., HRU 2006 ASRM report, FS 2008 Clinical guideline, Int j GO, 2012

12 Fertility throughout life Populations not using contraception Sexual activity also declines with age How to separate sexual behavior from age?

13 Rate of involuntary chidlessness % Average age of last birth: ranged from 40,9 to 45,7 y 87 to 99 % of women were infertile at 45 y Menken at al., Science, 1986 Tietze et al., FS 1957 Laufer et al., FS 2004

14 Fertility throughout life Schwarts and Mayaux NEJ 1982: AID age < > 35 CPR /12 74 % 62 % 54 %

15 IIU with donor sperm Botchan et al., HR, cycles ( 1001) «Age is the most important determinant of success» age < > 40 cycles PR/C 15.3 % 8.7 % 5.5 % Delivery 12.6% 6.3% 2.2 %

16 IIU with donor sperm 87% 52 %

17 IIU with partner sperm Haebe at al., FS, cycles ( 106 over 40 y) 27% Belgium 8.5 % 9.8 % : % > 43 No correlation with FSH (10U)

18 Fertility throughout life: second couple?

19 Fertility throughout life: Oocytes level Wang et al., HR 2012

20 Fertility throughout life: cells level Pacella et al., in press, FS 2012

21 Fertility throughout life: molecular and gene levels... McReynaolds et al., in press FS 2012

22 Fertility throughout life: patient s belief... Maheshwariet al., FS 2008

23 ART: a solution?

24 Assisted Reproductive Technology over 40 Studiecentrum voor Perinatale Epidemiologie (SPE)

25 Number of cycles per year in Belgium

26 ART over 40:etiology v

27 ART over 40 Luke et al., NEJ Women Cycles Natural conception: 20 % /month 45 % after 3 months 65 % after 6 months 85 % after 12 months 74,6% 63,3% 27.8% 11.3% 18.6% 6.6%

28 ART over 40 Wang et al., HR initiated first autologous cycles Conclusions: Advancing woman s age was associated with a decline in success rate. If women aged 35 years or older had had their first autologous treatment 1 year earlier, 15% more live deliveries could be expected.

29 ART over 40: Belgium

30 ART over 40: Belgium

31 ART over 45: cost of live birth Sullivan et al., HR ART cycles Women > fresh autologous oocytes cycles 71 % early pregnancy loss Live birth rate of 0. 5 % Remember the Belgian law: OPU allowed until 45 y

32 ART over 40: why poor results in IVF? Bromer et al., RBMO, 2009 SART LBR: 9.7 % 3,7 embryos SART LBR: 10,6 % 3,2 embryos

33 ART over 40: why poor results in IVF? Embryo wastage: number embryos that fail to produce live birth - SART data

34 donation Oocytes cryopreservation Realistic dream

35 Why oocyte donation?

36 Number of oocyte recipients in Belgium

37 Oocyte donation: Belgium

38 Sullivan et al, HR 2008 Oocyte donation: limits?

39 Is the implantation rate age related? Zegers-Hochscild et al., FS 2010 Latin american Registry (RLA) pregnancies after autologous ART and 6024 after in oocytes recipeints Implantation rate is affected by age: uterin senescence?

40 Oocyte donation: difficulties? Availability of oocytes!! Some drawbacks: Synchronization between donor and recipients Complicated organization of treating several recipients with one donor Difficulties of matching one donor and several recipients Safety for transmission of infectious diseases (no quarantine) oocyte-banking!

41 Realistic dreams: oocyte cryopreservation Rienzi, L et al., HR 2010 Prospective randomized sibling oocytes study Primary outcome: Fertilization rate after ICSI - Survival rate after VITRIFICATION: 96.8 %

42 Realistic dreams: oocyte cryopreservation Cobo et al. HR 2010 prospective randomised triple blind simple center study IVI valencia 600 recipients

43 Dream is realistic Oocyte cryopreservation for age-related fertility loss is now possible! (cryopreservation of semen is a routine for preserving male gametes) Stoop et al., HR 2011 Oocyte freezing as protection against the decline in fertility with aging Survey among 1914 women of reproductive age

44 Freezing for non medical reason? ESHRE TASK Force Ethics and Law HR, 2012 The arguments against social oocytes freezing allowing the application of the technology are not convincing. Fertility specialists should refrain from passing judgment on a woman s motives for postponing childbearing and requesting fertility preservation. The recommendations include the need for adequate information of women interested in oocyte cryopreservation, also in order to avoid raising false hopes. The message must remain that women s best chances of having a healthy child are through natural reproduction at a relative early age. Centres offering this service must have the necessary expertise to employ oocyte cryopreservation efficiently with the so far non-standardized protocols. As data about long-term safety is still lacking, centres also have a responsibility to contribute to the collection of these data.

45 «to dream practically» Vitrification: >90% survival rate per oocyte after thawing 75% fertilization rate 10 % ongoing implantation rate per thawed oocytes One live birth per vitrified oocytes Cryopreservation ideally before 35 y and not recommended over 38 y Safety? Noyes et al. RBM, 2009 A total of 58 reports ( ) reviewed 609 live born babies (308 < slow freezing, 289 < vitrification, 12 <both methods). Additionally, 327 other live births were verified. Of the total 936 live borns, 1.3% (12) birth anomalies: 3 ventricular septal defects, 1 choanal, 1 biliary atresia, 1 Rubinstein-Taybi syndrome, 1 Arnold-Chiari syndrome, 1 cleft palate, 3 clubfoot and1 skin haemangioma. Compared with congenital anomalies occurring in naturally conceived infants, no difference was noted.

46 Take home message Inform your patients! The decline of fertility already start after 30 Decrease of ART efficiency with own fresh oocytes over 35 and dramatically over 40! Efficiency of oocyte donation, the difficulty to recrute donors The possibility to cryopreserve own oocytes at 35!

47 Thank you for attention

48 Predictive factors Ovarian aging is a multifactorial governed by several factors including medical, lifestyle(smoking), genetic, autoimmune and idiopathic. Heritability has a major influence on ovarian aging. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) biomarkers seems to be the most reliable predictors of ovarian aging, but none has demonstrated conclusive evidence to predict pregnancy achievement in an ART setting.

49 Predictive factors Rosen et al., Reprod Endoc, 2012 Broer et al.,fs 2009

50 Pregnancy outcome: general population BDMS from ONE 2009 NCHS 2009

51 Pregnancy outcome: general population Pregnancy at or beyond age 40 years is associated with an increased risk of fetal death and other adverse outcomes ( AJOG 2007)

52 Pregnancy outcome: oocytes donation After own oocytes vitrification? Comparable of natural pregnancy over 40 How does it compare of IVF pregnancy for infertility? After oocytes donation HTA and pree : 24.7% >< 7.4%, P<.01, and 16.9% ><4.9%, p=.02 Premature deliver 34% ><19%, after controlling for MG, OR: 2.6 Cumulative risk of oocytes donation and age: More hypertensive disease!

53 Pregnancy outcome: oocytes donation 1 study for patient from 45 to 56 y: 45 Singletons, 24 twins in, and 5 triplets birth weight was 3218 g for the singletons, 2558 g for the twins, and 1775 g for the triplets. delivery time was at 38 weeks for the singletons, 36 weeks for the twins, and 34.5 weeks for the triplets. 38 % antenatal complications 12 % preterm labor, 16 % hypertensive desease (6 % HEELP and PreE) gestational hypertension, 8 % gestational diabetes, 4 % preterm rupture of membranes, 4 % placenta previa, 3 % placenta accreta, and 3 % carpal tunnel syndrome (n = 2).

54 How to choose a partner over 40?

55 How to improve ART results? PGD? no Stassens et al., HR 2008 Growth factor: yes Androgen: most promising treatment Other? No EBM Fertil steril, 2011