The old IVF patient: An evidence based approach Stratis Kolibianakis MD MSc PhD Unit for Human Reproduction 1 st Dept Ob/Gyn Aristotle University of Thessaloniki
No conflict of interest
How old is old?
How old is old? Great inconsistency in the literature regarding the definition of older mothers Klitzman 2016 >35 y, >38 y, >40 y The definition can vary depending on the decade of publication A 35-year-old woman in the 1980s is described as an older mother Robinson et al 1987 In 2007, women of the same age are considered to be part of the younger cohort McMahon et al 2007
No universal definition of the old IVF patient
How frequently do we encounter old IVF patients?
European data EIM 2016 (2011) Aspirations % Age 34 35-39 40 IVF 45.9 36.9 17.1 ICSI 45.6 36.2 18.1 Kupka et al 2016
SART 2014 Age group < 35 35-37 38-40 41-42 > 42 Cycles 40805 21137 20274 10870 8514 % 40.2 20.8 19.9 10.7 8.4
Approximately 1/5 of all IVF cycles are performed in patients > 40 years of age
The old IVF patient: An evolving problem Proportion of IVF / ICSI cycles performed in women >40 years of age in Europe (2002-2011) 20 18 16 14 IVF ICSI 12 10 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
The old IVF patient: An evolving problem Proportion of egg donation cycles performed in women >40 years of age Europe (2002-2011) ED 60 59 58 57 56 55 54 53 52 51 50 2006 2007 2008 2009 2010 2011 ED
Explanations for the increasing proportion of old IVF patients Low awareness of the rapid decrease in fertility with age in reproductive-aged men and women Bretherick et al 2010 Overestimation of the age that women's fertility decreases, and of the odds of success of IVF treatments Peterson et al 2012 Improvement in pregnancy rates leads to a shift towards more older patients in IVF programs Gleicher et al 2006
What is the probability of live birth in the old IVF patient?
European data EIM 2016 (2011) Deliveries Age 34 35-39 40 IVF 28.6 20.9 9.9 ICSI 25.6 18.4 7.5 Kupka et al 2016
SART 2014 Live birth Age group < 35 35-37 38-40 41-42 > 42 Cycles 40,805 21,137 20,274 10,870 8514 Live birth % 48.6 38.3 24.3 12.3 3.8 95%CI 48.2-49.1 37.7-39.0 23.7-24.9 11.7-12.9 3.4-4.2 All transfers performed with embryos fresh or frozen originating from a single oocyte retrieval
Outcome of 1114 ICSI and embryo transfer cycles of women > 40 years of age Significant decrease in delivery rates per transfer per year No PGS, no blastocyst culture Ciray et al 2006
Klipstein et al 2006 2,705 IVF cycles in 1,263 women age > 40 years Live birth p<0.001 Age 40 41 42 43 44 45 46+ Cycles 775 661 590 380 230 52 17 Live birth /cycle started 13.9 9.7 9.2 7.6 2.6 1.9 0 Tsafrir et al 2007 1,217 IVF/ICSI in 381women > 40 years FSH <20 IU/L Live birth p<0.0001 Age 40 41 42 43 44 45 46-47 Cycles 209 230 237 199 150 143 49 Delivery /cycle started 9.1 4.3 6.3 4 2.7 0.7 0
Serour et al 2010 2,386 IVF/ICSI cycles in 1,645 women > 40 years FSH<20 IU/L AMH >0.6 ng/ml Live birth p<0.001 Age 40 41 42 43 44 >45 Cycles 742 595 429 251 150 219 Live birth /cycle started 10 7 5 2 0.7 0.5
The probability of live birth in women >40 years of age is small and decreases significantly with each additional year
What is the probability of cumulative live birth in the old IVF patient?
Cumulative delivery rates after ICSI 116 pts 26 pts 236 cycles 66 cycles FSH<15 IU/L Osmanagaoglu et al 2002
Cumulative live birth rates after IVF in 66 women aged 41-43 AFC >5, basal FSH <15 IU/l, regular cycles If during the first IVF/ICSI cycle 3 oocytes were retrieved, a second cycle was not initiated 125 cycles Cycle 1 Cycle 2 Cycle 3 Patients at risk 66 60 19 Live births 6 4 0 Cumulative Live birth 9.1 18.4 18.4 95%CI 2-16 8-29 8-29 van Disseldorp et al 2007
Cumulative pregnancy rates in 1,217 IVF treatment cycles in 318 women > 40 years All patients, FSH < 20 IU/L Tsafrir et al 2007
The cumulative probability of pregnancy in women >40 years of age is small (5.7% after 3 cycles)
What is the probability of live birth in IVF patients >45 years?
Delivery rates in women > 45 years (288 cycles) Only patients with a reasonable chance of achieving a pregnancy were included 19.8%: cancelled due to elevated FSH or ovarian cyst 30.0%: cancelled due to low or no response (<3 follicles) Age Cycles with OPU 45 116 COCs 2pn 7.0 5.5 Embryos transferred 2.9 Delivery 4.3 46 29 6.1 5.6 3.4 0 47 11 7.0 5.2 3.5 0 48 4 5.8 1.8 1.8 0 49 1 2 1 1 0 Up to seven embryos were replaced when available Spandorfer et al 2007
The old IVF patient Costs implications
Cost per live birth from IVF increases with maternal age and order of attempts Griffiths et a 2010 Incremental cost per live birth by maternal age and treatment cycle
The cost for treating old IVF patients need to be considered in counseling these patients
How many embryos to transfer in the old IVF patient?
How many embryos to transfer in the old IVF patient? Age Embryos transferred 40 41 42 43 44 Live birth 1 2.7 1.5 0 0 0 2 10.9 5.9 5.1 3.8 3.8 3 20.6 11 11.9 13.8 0 4 24 19.3 19.2 12.7 5.4 An increase in the number of embryos transferred is associated with an increase in the probability of live birth rate (p < 0.001), even after adjusting for age at cycle start Klipstein et al 2006
Number of embryos transferred and probability of multiple pregnancy in the old IVF patient Klipstein et al 2006 2,705 IVF cycles in 1,263 women > 40 years Live birth p<0.001 Age 40 41 42 43 44 45 46+ Twins 16.7 17.2 7.4 13.8 0 0 0 Triplets 1.8 1.6 0 0 0 0 0 Klipstein et al 2006
The more embryos transferred the higher the probability of live birth in patients > 40 years of age, however, twins and triplets are still possible
The old IVF patient Can we identify predictive factors for the achievement of live birth?
Prognostic factors for live birth in the old IVF patient (>40 years) Serum AMH tertiles ng/ml Low <0.48 Middle 0.49-1.22 High >1.23 Cycles 21 38 57 Age 42.8 41.1 41.3 COCs 2.4 4.7 8.1 Embryos obtained 1.8 3.1 4.8 Embryos transferred 1.6 2.6 3.2 Viable pregnancy/cycle 0 23.7 17.5 p<0.05 Lee et al 2011
Prognostic factors for live birth in the old IVF patient Cut-off AMH level ng/ml ROC AUC p Cycle cancellation 0.68 0.77 0.0001 Non-pregnancy 1.05 0.65 0.0022 Lee et al 2011
Prognostic factors for live birth in the old IVF patient Live birth Age (years) 40 41 42 43 Overall Cryopreservation 21.1 31.6 20 30.8 23.5 No cryopreservation 13.2 8.4 8.8 6.5 8.9 Significantly higher live birth rates in patients with cryopreservation, after adjusting for age at cycle start and number of embryos transferred (p <0.02) Klipstein et al 2006
The availability of embryos for cryopreservation after a fresh transfer is associated with a significantly higher probability of live birth in patients > 40 years of age AMH can be used to predict cycle cancellation and non pregnancy in patients > 40 years of age
The old IVF patient A viscous cycle Decrease in oocytes number Increase in aneuploidy rates
Declining follicle number with advancing age Faddy et al 1992
Decreased euploidy rates with increasing maternal age 46,439 embryo biopsies from 6,365 IVF cycles 24-chromosome single-nucleotide polymorphism Demko et al 2016
Miscarriage rates in women > 40 years of age Age Cycles Spontaneous abortion % Overall loss % 40 775 23.9 37.2 41 661 35.4 45.8 42 590 36.5 44.9 43 380 38.3 48.2 44 230 53.8 70 45 52 66.7 75 46+ 17 n/a n/a All >40 32.6 44 Klipstein et al 2006
Can PGS be used to manage the old IVF patient?
PGS for aneuploidies Advanced maternal age Live birth rate per woman randomised 38.8 vs. 38.0 40.5 vs. 40.6 38.0 vs.. 37.9 38.2 vs.. 38.3 40.1vs.. 39.9 Twisk et al 2011
The effect of preimplantation genetic screening on implantation rate in 150 women over 35 years of age FISH Moayeri, et al 2016
PGS by FISH is associated with a significantly lower probability of live birth in patients with advanced maternal age
Interventions to increase ovarian response Directly or indirectly increase FSH levels Increase in the sensitivity of the developing follicles to FSH
Interventions to increase ovarian response Directly or indirectly increase FSH levels Increased doses of FSH, FSH initiation in the luteal phase, long acting FSH, letrozole, short GnRH agonist protocol, GnRH antagonist protocol or different types of FSH
Increase in FSH dose Study Age years Comparison COCs Cedrin-Durnerin 2000 n=96 - Decremental dose 300-150 IU vs. high FSH fixed dose 450 IU 6.4 vs. 6.3 Klinkert 2005 n=52 40.4 vs. 42.2 150 IU vs. 300 IU 3 vs. 3 no significant differences Berkkanoglu 2010 n=119 35.6 vs. 35.3 vs. 34.1 300 IU vs. 450 IU vs. 600 IU 5.2 vs. 6.3 vs. 6.6 Lefebvre 2015 n=356 37.9 vs. 37.8 450 IU vs 600 IU 5 vs. 5 38-40 4 vs. 3 (MIIs)
Long acting FSH vs. daily FSH 79 poor responders COCs 40.5 years Long acting FSH 3.0 vs. daily FSH 2.0 41.0 years p=0.26 Kolibianakis et al 2015
Long acting FSH vs. daily FSH Kolibianakis et al 2015
Initiation of FSH during the luteal phase Study Age years comparison COCs luteal vs follicular Rombauts et al 1998 n=40 33.8 vs. 32.6 Initiation of FSH 150 IU during the luteal phase vs after the onset of menses 5 vs. 5.5 Kansal Kalra et al 2008 n=18 36.0 vs. 35.0 150 IU subcutaneously twice a day, 9 days after spontaneous LH surge On day 1 of menses, the dose was increased to 300 IU twice a day Patients in the follicular arm began rfsh at the maximum dose (300 IU twice a day) 2.5 vs 3.0
Antagonists-letrozole vs micro dose flare up High dose FSH 300-450 IU
AL vs. MF COCs % Study Year SMD (95% CI) Weight 33.5 vs. 33.8 Davar 2010-0.59 (-1.01, -0.18) 52.99 38.1 vs. 38.3 Mohsen 2013 0.02 (-0.49, 0.52) 47.01 Overall -0.31 (-0.90, 0.29) 100.00-1.01 0 1.01 favours Letrozole
GnRH agonists vs. GnRH antagonists Griesinger et al 2006 Xiao et al 2011 Pu et al 2013
GnRH agonists vs. GnRH antagonists COCs 36.6 vs. 36.2 37.3 vs. 37.2 37.1vs. 35.6 36.3 vs. 36.0 39.0 vs. 38.8 35.9 vs. 37.7 37.9 vs. 38.3 36.2 vs. 36.2 Kolibianakis et al unpublished
Short versus long protocol COCs Age: 39.2 vs. 38.5 Age: 36.9 vs. 36.7 WMD +0.66 95%CI: +0.29 to +1.02
GnRH antagonists versus no pituitary suppression Akman et al 2000 40 patients GnRH antagonists/fsh+hmg vs. FSH+HMG Age: 37.3 Age: 38.2 COCs 3.25 vs. 3.46 p=ns
Interventions to increase ovarian response Increase in the sensitivity of the developing follicles to FSH Androgens/androgen-modulating agents (Testosterone, DHEA, aromatase inhibitors, rec LH,rec hcg) By influencing the somatotropic axis (GH, pyridostigmine, oral L-arginine)
Interventions to increase ovarian response Increase in the sensitivity of the developing follicles to FSH Androgens/androgen-modulating agents (Testosterone, DHEA, aromatase inhibitors, rec LH,rec hcg) by influencing the somatotropic axis (GH, pyridostigmine, oral L-arginine)
Addition of testosterone 37.3 vs. 36.9 37.9 vs. 37.8 37.6 vs. 38.3 42.5 vs. 41.5 WMD: +0.87 COCs 95%CI: +0.18 to +1.57 Bosdou et al ESHRE 2016
DHEA DHEA pretreatment COCs % Study Year COCs WMD (95% CI) Weight 36.5 vs. 37.0 Artini 2012 0.91 (-1.23, 3.05) 10.27 37.1 vs. 37.4 Moawad 2012 2.40 (1.29, 3.51) 38.19 37.0 vs. 36.0 Yeung 2014 0.50 (-2.44, 3.44) 5.44 39.7 vs. 40.1 Ktob 2016 1.10 (0.09, 2.11) 46.10 Overall 1.54 (0.86, 2.23) 100.00 WMD: +1.54 95%CI: +0.86 to +2.23 WMD: +0.29-4 -2 0 2 4 95% CI: -0.40 to +0.79 Kolibianakis et Kolibianakis al unpublishedet al ESHRE 2016 Favours DHEA 329 patients
Aromatase inhibitors COCs 37.9 vs. 38.2 36.2 vs. 37.3 WMD: -3.04 95% CI: -9.39 to +3.31 Kolibianakis et al unpublished
rlh addition COCs 31.7 vs. 31.5 30.4 vs. 31.5 <37 y 36.3 vs. 33.0 41.8 vs. 42.1 38.6 vs. 38.3 WMD +0.75 95%CI: +0.14 to +1.36 Lehert et al 2014
hcg addition 48 women received 600 IU of rec FSH + 75 IU of rec hcg, 51 women received only 600 IU of rec FSH hcg, age: 35.2 years vs. no hcg, age: 34.9 years MIIs 3.8 vs. 5.6 p=0.19 Berkanoglu 2007
Interventions to increase ovarian response Increase in the sensitivity of the developing follicles to FSH using androgens/androgen-modulating agents (Testosterone, DHEA, aromatase inhibitors, rec LH,rec hcg) By influencing the somatotropic axis (GH, pyridostigmine, oral L-arginine)
Addition of growth hormone COCs % Study Year WMD (95% CI) Weight Bergh 1994-2.50 (-5.51, 0.51) 21.21 35.0 vs. 33.0 Dor 1995-3.11 (-4.95, -1.27) 24.96 35.8 vs. 35.2 Kuzuk 2008 3.24 (2.34, 4.14) 27.15 36.0 vs. 36.2 Eftechar 2013 1.30 (0.14, 2.46) 26.68 Overall -0.08 (-2.91, 2.75) 100.00-5.51 0 5.51 Bosch et al 2016
Addition of Pyridostigmine Kim et al, 70 patients Addition of pyridostigmine versus no addition COCs Pyridostigmine: 5.9 vs. no pyridostigmin: 3.7 Age: 36.7 Age: 38.2 WMD +2.2 95% CI: +0.73 to + 3.67 Kim et al. 1999
Addition of L-arginine Addition of L-arginine versus placebo 34 women, mean age: 40.2 COCs: L-arginine: 4.1 vs. Placebo:1.6 WMD = +2.5 95% CI: +1.53 to +3.47 Battaglia et al.,1999
Can ovarian response be improved in patients with low ovarian reserve? Various interventions Addition of aspirin
Addition of aspirin Lok et al., 2004-60 patients GnRH-agonists/HMG Age: 36.0 Aspirin versus placebo Age: 36.9 COCs 3.0 vs. 4.0 WMD: -0.23 95%CI: -2.0 to +1.6
Interventions to increase ovarian response Intervention Control COCs Studies Patients Addition of pyridostigmine no addition +2.2 1 70 Addition of L-arginine no addition +2.5 1 34 Long agonist Short agonist +0.66 2 122 DHEA No DHEA +1.51 4 329 Testosterone pretreatment no testosterone +0.87 5 362 GnRH agonists GnRH antagonists +0.27 7 933 Addition of reclh to FSH no addition +0.75 12 1077
There is evidence from RCTs to suggest that certain interventions are associated with a small increase in ovarian response, the clinical significance of which, however, is debatable..
Various interventions in the old IVF patient
Laser-Assisted Hatching in women of advance age Live birth 39.0 vs 38.5 38.3 vs 38.5 39.8 vs 40.0 Favours AH Martins 2011
Laser-Assisted Hatching Age 35-42 Shi et al 2016
Assisted hatching does not increase the probability of live birth in women with advanced maternal age
The old IVF patient Oocyte donation
Oocyte donation at advanced maternal age Success rates decline in older recipients Age Live birth % 34 56.7 35-39 55.7 40-44 55.8 45-49 52.7 50 48.6 SART data: Yeh et al 2014
Oocyte donation at advanced maternal age Live birth rate Age Cycles Adjusted OR 95% CI p 34 2987 1.05 0.97-1.14 0.24 35-39 5920 1 0.94-1.07 0.88 40-44 12218 ref 45-49 5872 0.88 0.83-0.94 <0.001 50 962 0.75 0.65-0.85 <0.001 SART data: Yeh et al 2014
Does the probability of pregnancy decrease with maternal age after oocyte donation? Live birth rate Age Cycles Adjusted OR 95% CI P 45 1975 ref 0.88-1.14 46 1548 1 0.74-1.00 0.98 47 1073 0.86 0.05 48 741 0.77 0.65-0.91 <0.003 49 535 0.83 0.69-1.01 <0.06 SART data: Yeh et al 2014
The probability of live birth after oocyte donation is high in old IVF recipients but decreases with increasing maternal age
Obstetric risks in the old IVF patient
Obstetric outcomes in women less or more than 35 years of age (6619 women with singleton pregnancies) Wang et al 2011
Obstetric outcomes in women less or more than 40 years of age (16,427 women) Chan et al 2008
Pre-eclampsia in 330 women >40 years of age using their own oocytes after IVF or natural conception 41,5 y 32.5y 41,2 y 32.1y Toshimitsu et al 2014
Obstetric outcomes in donor oocyte pregnancies 380 women >43 years of age Risk of preeclampsia Adjusted OR 95% CI Incidence No IVF 1 3.8 IVF without oocyte donation 2.3 0.7-8.3 10 IVF with oocyte donation 3.3 1.2-8.9 19.2 Le Ray et al 2012
Obstetric outcomes in 71 donor oocyte pregnancies compared with 108 advanced maternal age in in-vitro fertilization pregnancies Krieg et al 2008
Obstetric risks are increased in women with advanced maternal age The risk of preeclampsia is increased after oocyte donation compared to natural conception in women with advanced maternal age The risk of caesarean section and abnormal placentation are increased after oocyte donation compared to IVF using autologous oocytes in women with advanced maternal age
How old is old? Is there an age limit above which IVF/oocyte donation should not be offered?
How old is old? HFEA Australia No specification for an upper age limit for treatment. Clinics make their own determinations about patients Australia bars IVF after the average age of natural menopause, usually interpreted at 52 years of age ASRM No recommendation about upperage limits for women using their own eggs Guidelines: futility as interventions with less than a 1% likelihood of a live birth, very poor prognosis as odds of >1% but <5% 2004 Postmenopausal pregnancy should be discouraged, but physicians should carefully consider the specifics of each case 2013 Providers should implant embryos in women >50 years only after medical evaluation and should discourage women >55 years from doing so
Indian woman in her 70s gives birth to healthy baby boy on third attempt of oocyte donation www.theguardian.com
Conclusions No universal definition of the old IVF patient exits Approximately 1/5 of all IVF cycles are performed in patients > 40 years of age The probability of live birth women >40 years of age is small and decreases significantly with each additional year The cumulative probability of pregnancy in women >40 years of age is small (5.7% after 3 cycles)
Conclusions The increasing costs for treating old IVF patients need to be considered in counseling these patients The more embryos transferred the higher the probability of live birth in patients > 40 years of age, however, twins and triplets are still possible The availability of embryos for cryopreservation after a fresh transfer Is associated with a significantly higher probability of live birth in patients > 40 years of age
Conclusions AMH can be used to predict cycle cancellation and non-pregnancy in patients > 40 years of age PGS by FISH is associated with a significantly lower probability of live birth in patients with advanced maternal age There is evidence from RCTs to suggest that certain interventions are associated with a small increase in ovarian response, the clinical significance of which, however, is debatable
Conclusions The probability of live birth after oocyte donation Is high in old IVF recipients but decreases with increasing maternal age Obstetric risks are increased in women with advanced maternal age undergoing IVF
Acknowledgements Chairman: Prof. B.C. Tarlatzis Clinical Academics Prof Dr. G. Grimbizis Prof Dr. G. Pados Prof Dr. H. Bili Prof Dr. L. Zepiridis Unit for Human Reproduction 1 st Dept of OB/Gyn, Aristotle University of Thessaloniki PhD fellows J Bosdou MD MSc Z Oikonomou N Tarlatzi Embryologists Prof K. Chatzimeletiou A. Mitsoli Head Nurse D Savvaidou