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Nick Macklon Professor of Obstetrics and Gynaecology, University of Southampton Director, Complete Fertility Centre Southampton Patient Friendly IVF Approach:

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Presentation on theme: "Nick Macklon Professor of Obstetrics and Gynaecology, University of Southampton Director, Complete Fertility Centre Southampton Patient Friendly IVF Approach:"— Presentation transcript:

1 Nick Macklon Professor of Obstetrics and Gynaecology, University of Southampton Director, Complete Fertility Centre Southampton Patient Friendly IVF Approach: 5 Critical Ways to Keep Them Coming Back

2 Schroder et al, RBM Online 2004 Data from 4102 IVF cycles in 2130 women Cycles % Drop out rateECPRRCPR The impact of drop outs on cumulative rates

3 Stress and Anxiety reduce cumulative pregnancy rates by increasing drop out …and reduce per cycle success rates too Milder, more/patient friendly treatment regimens significantly reduce anxiety and treatment-related stress …and lower drop out rates increasing cumulative pregnancy rates The need for patient friendly IVF

4 5 Steps 1.Reduce the psychological burden of treatment. 2.Reduce the physical burden of treatment 3.Focus on cumulative outcomes rather than single cycle outcomes 4. Look beyond the fresh embryo transfer. 5. Manage expectation. 4

5 Step 1 1.Reduce the psychological burden of treatment. 5

6 mg per day It works

7 Drop out rates from IVF are HIGH 20-40% per cycle 50-60% after 3 cycles Only 10-20% due to active censoring Olivius et al, 2004 Land et al, 1997 Kristin et al, 2004

8 Treatment burden as a primary reason Physical or psychological burden of treatment Unknown Relational problems/divorce Others Adoption Poor embryo quality Poor response/signs of ovarian aging Ethical objections to ICSI treatment after failed IVF treatment Among 384 couples undergoing IVF treatment, 65 (17%) dropped out Adapted from Verberg et al. Hum Reprod. 2008;23:2050. Causes for Drop out No. of patients

9 Impact of counselling on stress during IVF treatment: a RCT p=0.076 De Klerk et al Hum Reprod 2005 No counselling Counselling Distress StartStimulationPick-upFertilizationWaitingResult Treatment Phase

10

11 Patient distress and mild IVF More physical and depressive symptoms during down regulation in conventional IVF HR 2006 HR 2007 Failed IVF results in less depressive symptoms after mild IVF

12 Drop outs from successive IVF cycles Verberg. HR

13 Step 2 1.Reduce the physical burden of treatment 13

14 Advantages of GnRH antagonist? Suppression of endogenous LH level within a few hours No flare-up effect No risk of GnRH agonist-induced cyst formation No estrogen deprivation symptoms FSH consumption reduced Duration of stimulation shortened – less costly Unintended administration during early pregnancy avoided Significant reduction in severe OHSS rate 1. Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD Tarlatzis et al. Hum Reprod Update 2006;12: Klingmuller et al. Acta Endocrinol 1993;128:15 4. Varney et al. J Assist Reprod Genet 1993;10:53

15 GnRHa or hCG for triggering of final oocyte maturation - Why GnRHa? Significant decrease/elimination in the incidence of OHSS –T 1/2 of endogenous LH shorter than T 1/2 of hCG (20 min versus 33 hours) More MII oocytes harvested in IVF ( Imoedemhe et al., 1999; Humaidan et al., 2005; Humaidan et al., 2010; 2011; Oktay et al., 2010) Higher patient convenience (Cerillo et al., 2009; Hernandez et al., 2009) Negative impact of hCG on endometrial receptivity and oocyte quality ( Forman et al., 1988; Fanchin et al., 2001, Fatemi et al., 2010 ;Valbuena et al., 2001) More physiological –Luteal phase steroid level closer to the physiological range –Endogenous FSH and LH surge

16 GnRHa trigger in GnRH antagonist co-treated cycles – How? GnRHa displaces the GnRH antagonist from the GnRH receptors in the pituitary, triggering a surge (flare-up) of both LH and FSH: Resembles the surge of gonadotrophins of the natural cycle Effective stimulation of final oocyte maturation and ovulation (Gonen et al., 1990; Itskovitz et al., 1991) Not applicable in cycles down-regulated with GnRHa

17 Surge of gonadotropins after GnRHa triggering versus natural cycle 14h 20h 48h0 Hoff et al., 1983; Gonen et al., 1990; Itskovitz et al., h 4h GnRHa Natural

18 What does the hCG trigger do which LH does not? Causes rise in intrafollicular P4 (Yding Andersen et al 1993) Development of multiple corpora lutea Supraphysiological estradiol and Progesterone synthesis hCG increases LH activity but does not reconstitute the midcycle physiologic FSH surge. Higher luteal phase levels of E2 and P induced by supraphysiological hCG concentrations

19 OHSS reduction? hCG triggering: 3/150: 2% (1 severe/2 moderate) GnRHa triggering: 0/152 Humaidan et al., Fertil Steril, 2010; 93:847-54

20 Step 3 Focus on cumulative outcomes rather than single cycle outcomes 20

21 2 embryos 1 embryo Mild Strategy Conventional Strategy 200 patients 1 year 400 patients Two-centres (Erasmus MC Rotterdam, UMC Utrecht - NL) Inclusion period Power: 80%; α: 0.05; maximal difference non inferiority -12.5% 1 embryo

22 GnRH Antagonist and Long GnRH Agonist strategies result in comparable cumulative pregnancy rates Adapted from Heijnen, et al. Lancet. 2007;369:743. GnRH agonist with DET GnRH antagonist with SET % of pregnancies leading to term live birth Months since randomization Singleton term live birth Proportion of pregnancies leading to cumulative term live birth within 12 months after starting IVF

23 Costs IVF TreatmentMild (n=205)Standard (n=199)p* Technical procedures1083 (734)991 (584)0.16 Medication1626 (1088)1737 (1069)0.3 Monitoring750 (561)576 (693)0.006 Indirect costs1948 (2280)1740 (1845)0.3 Pregnancy and neonatal period Medical costs2547 (4553)4899 (10746)0.01 Indirect costs379 (1177)802 (2270)0.03 Total costs8333 (5418)10745 (11225)0.006 Total costs of IVF treatment per couple over 12 months ( € ) Heijnen, et al. Lancet Data are mean (SD). *Independent groups t test (assuming unequal variances). Analysis includes costs of pregnancies up to 6 weeks after delivery. Mean costs for pregnancy are across the whole group, including those who did not achieve pregnancy.

24 Medication costs and hospital charges for IVF/ICSI treatment at the Oulu University hospital for the year 2008 Unit price (euros) Fresh cycle Medication1495 IVF1542 ICSI2158 Progesterone support34 FET cycle600 Hormonal support66 Cumulative costs (euros) eSET period DET period Total costs Costs of fresh cycles Costs of FET cycles Total costs per woman After 3% discounting Total costs per woman Term live births per woman

25 Step 4. Look beyond the fresh embryo transfer. 25

26

27 Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation Wen-ge Ma*, Haengseok Song †, Sanjoy K. Das, Bibhash C. Paria, and Sudhansu K. Dey ‡ Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation Wen-ge Ma*, Haengseok Song †, Sanjoy K. Das, Bibhash C. Paria, and Sudhansu K. Dey ‡ IVF and the Endometrium A scheme depicting modulation of the window of receptivity in the P4-primed uterus in response to changing estrogen levels. This scheme shows that estrogen at low threshold level extends the window of uterine receptivity for implantation, but higher levels rapidly close this window, transforming the uterus into a refractory state.

28 Ovarian stimulation on intra-uterine cytokine profile Multivariable analysis in 203 patients showed significant relations between the number of oocytes retrieved and secretion concentrations of IL-12, Dkk-1 (positive) and VEGF, IL-15 (negative). Boomsma, et al. Fertil Steril

29 What about impact of high Progesterone levels?

30 Relationship between serum P levels on the day of hCG and ongoing pregnancy rate A retrospective, observational, single-centre cohort study Multivariate regression analysis showed that daily FSH dose, number of oocytes and estradiol values on the day of hCG administration were positively associated with progesterone levels (P < for all). N=4032 Bosch E. Hum Reprod. 2010;25:2092–2100. Progesterone levelsPregnancy rate < or = 1.5 ng/ml31% >1.5 ng/ml19% P <0.001

31 When progesterone exceeded the threshold of 1.5 ng/ml, lower delivery rates: P rise >1.5 ng/ml in 24% of the antagonist group and 23% agonist group “9 out of 10 patients failed to achieve a clinical pregnancy whenever progesterone levels exceeded the threshold of 1.5 ng/ml” 190 patients Agonist group 9.5 versus 31.8%P= 0.03Antagonist14.3 versus 34.3%P= 0.07

32 Most recent meta-analysis in GnRH antagonist cycles (n=585) Patients with progesterone elevation –higher serum estradiol levels on the day of hCG (p=0.008) –more COCs retrieved (+2.9, 95% CI +1.5 to +4.4, p < 0.001) Progesterone elevation on the day of hCG administration was associated with a significantly decreased probability of clinical pregnancy per cycle (-9%, 95% CI -17 to -2, p>0.005) In conclusion, in patients treated with GnRH antagonists and gonadotrophins, progesterone elevation on the day of hCG administration is significantly associated with a lower probability of clinical pregnancy Kolibianakis, et al. Curr Pharm Biotech

33 Does milder stimulation reduce estradiol and progesterone levels at the end of the follicular phase? Blockeel C, et al. JCEM. 2011;96:

34 Follicular characteristics and cycle outcome measures Blockeel C, et al. JCEM. 2011;96: CD2 group (n = 33) CD 5 group (n = 39)P Total dose of recFSH (IU)1364 ± ± 295<0.01 recFSH duration (days)9.1 ± ± 2.0<0.01 Duration follicular phase (days)10.1 ± ± 2.0<0.01

35 ©2011 by Endocrine Society Blockeel C, et al. JCEM. 2011;96:

36 Produce embryos in one cycle, and transfer in another?

37 ‘There is an alternative’ I said to Jean. ‘We could try freezing human embryos, and keep them in store until the effects of the fertility drugs have faded away and their menstrual cycles were back to normal. The womb would then be receptive, and capable of sustaining the growth of the fetus’ The idea suddenly excited me. We could provide the mother with a whole family spaced in the way she wished, just thawing out each embryo when desired. R.G Edwards 1976 A Matter of Life. The Story of IVF 2 nd edition 2011, Impression Publishing

38 Three trials accounting for 633 cycles in women aged 27–33 years Mostly high responders

39 Meta-analysis results Ongoing Pregnancy Frozen-ThawedFresh Weight Risk Ratio M-H, Fixed, 95% CI Risk Ratio M-H, Fixed, 95%CI Study or SubgroupEventsTotalEventsTotal Aflatoonian %1.4 [1.05, 1.88] Shapiro 2011 – Normal %1.38 [0.97, 1.98] Shapiro 2011 – High %1.15 [0.86, 1.55] Total (95% CI) %1.32 [1.10, Total events Heterogeneity: Chi 2 = 1.03, df =2 (P = 0.60); I 2 = 0% Test for overall effect: Z = 3.00 (P = 0.003) Clinical Pregnancy Aflatoonian %1.34 [1.02, 1.77] Shapiro 2011 – Normal %1.37 [0.99, 1.94] Shapiro 2011 – High %1.19 [0.88, 1.59 Total (95% CI) [1.10, 1.56] Total events Heterogeneity: Chi 2 = 0.60, df = 2 (P = 0.74); I 2 = 0% Test for overall effect: Z = 3.04 (P = 0.002) Miscarriage Aflatoonian %0.83 [0.26, 2.68] Shapiro 2011 – Normal %0.82 [0.29, 2.32] Shapiro 2011 – High %0.83 [0.23, 2.93] Total (95% CI) %0.83 [0.43, 1.60] Total events15 18 Heterogeneity: Chi 2 = 0.00, df = 2 (P = 1.00); I 2 = 0% Test for overall effect: Z = 0.56 (P = 0.57) Roque. Elective frozen-thawed embryo transfer. Fertil Steril

40 RR95% CI antepartum haemorrhage –0.81 preterm birth –0.90 small for gestational age –0.66 low birth weight –0.76 perinatal mortality –0.96 Singleton pregnancies after the transfer of frozen thawed embryos were associated with better perinatal outcomes compared with those after fresh IVF embryos Lower relative risks (RR) and 95% confidence intervals (CI) after FET for: Eleven studies met the inclusion criteria

41 The endometrium and the baby Perinatal outcome of singleton siblings born after Assisted Reproductive Technology and spontaneous conception Danish National Sibling-Cohort study AIM: Separate the effects of the maternal characteristics and the effects of infertility Henningsen AA, Pinborg A, Lidegaard Ø, Vestergaard C, Forman JL, Andersen AN

42 Methods Data were obtained from the National Danish Birth and IVF registers All women who have given birth to two consecutive singleton siblings conceived in different ways: A) Fresh IVF/ICSI — spontaneous (n=7756) B) Fresh IVF/ICSI — FER (n=716) Study period

43 Birthweight (g), adjusted* *maternal age, parity, year of birth, sex n=5982 (64 g ↑) p<0.02 n=1774 (62 g ↓) p<0.07

44 Perinatal outcome ARTSpontaneousCrude OR[95%CI]Adj. OR*[95%CI] BW < 2500 g5.5%3.8%1.5[ ]1.4[ ] BW < 1500 g1.1% 1.1[ ]1.1[ ] GA < 37 weeks7.1%5.6%1.3[ ]1.3[ ] GA < 32 weeks1.1% 1.1[ ]1.1[ ] NFOG Copenhagen. June, *OR adjusted for maternal age, parity, year of birth, sex, time between pregnancies

45 Cryo: Birthweight (g), adj.* *maternal age, parity, year of birth, sex n=550 (286 g ↑ ) p<0.004 n=166 (26 g ↓ ) p<0.82 IVF procedure or Ovarian Stimulation?

46 46 Step 5. Manage Expectation Highlight natures limits: and why they are there Emphasise role of couple in determining success

47 Habit 3: Understand nature’s limits (Macklon et al, Hum Reprod Update, 2002) 30% 15% 25% 30% Spontaneous Pre-implantation loss Post-implantation loss Miscarriage Live Birth 30% 10% 30% CONCEPTIONS (Boomsma et al, Hum Reprod, 2009) IVF 30% 15% Miscarriage Live Birth 25% 10% Post-implantation loss 15% Pre-implantation loss 50% CONCEPTIONS

48 Wallace and Kelsey 2010 PLoS One 5; e8772 You can only stimulate follicles that are there

49 5 Steps to keep them coming back 1.Reduce the psychological burden of treatment. 2.Reduce the physical burden of treatment 3.Focus on cumulative outcomes rather than single cycle outcomes 4. Look beyond the fresh embryo transfer. 5. Manage expectation. 49


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