Presentation on theme: "Patient Friendly IVF Approach: 5 Critical Ways to Keep Them Coming Back Nick Macklon Professor of Obstetrics and Gynaecology, University of Southampton."— Presentation transcript:
1Patient Friendly IVF Approach: 5 Critical Ways to Keep Them Coming Back Nick MacklonProfessor of Obstetrics and Gynaecology, University of SouthamptonDirector, Complete Fertility Centre SouthamptonPlease use the dd month yyyy format for the date for example 11 January The main title can be one or two lines long.
2The impact of drop outs on cumulative rates Data from 4102 IVF cycles in 2130 women70605040302010123456Cycles%Drop out rateECPRRCPRSchroder et al, RBM Online 20042
3The need for patient friendly IVF Stress and Anxiety reduce cumulative pregnancy rates by increasing drop out…and reduce per cycle success rates tooMilder, more/patient friendly treatment regimens significantly reduce anxiety and treatment-related stress…and lower drop out rates increasing cumulative pregnancy rates
45 Steps Reduce the psychological burden of treatment. Reduce the physical burden of treatmentFocus on cumulative outcomes rather than single cycle outcomes4. Look beyond the fresh embryo transfer.5. Manage expectation.
5Step 1Reduce the psychological burden of treatment.
7Drop out rates from IVF are HIGH 20-40% per cycle50-60% after 3 cyclesOnly 10-20% due to active censoringOlivius et al, 2004Land et al, 1997Kristin et al, 2004
8Treatment burden as a primary reason Among 384 couples undergoing IVF treatment, 65 (17%) dropped outCauses for Drop outPhysical or psychological burden of treatmentUnknownRelational problems/divorceOthersAdoptionThe physical and psychological burdens of treatment are the most frequent cause of drop-out by women and their partners enrolled in IVF programs.Cumulative IVF pregnancy rates are compromised by the large number of couples who drop out of treatment before achieving pregnancy.In a study of 384 patients undergoing IVF treatment, the incidence of dropout from IVF treatment with either a GnRH antagonist–based protocol or a GnRH agonist–based protocol was evaluated.The GnRH antagonist–based treatment strategy included fixed daily dose of 150 IU recFSH initiated on cycle day 5. GnRH antagonist treatment was administered when at least 1 follicle of 14 mm was observed. The single best-quality embryo was transferred.The GnRH agonist–based approach included pituitary downregulation with a GnRH agonist initiated during the mid-luteal phase of the pretreatment cycle. After 2 weeks of GnRH agonist administration, ovarian stimulation was started with a daily dose of 150 IU/d recFSH. A maximum of 2 embryos were transferred.Among the 384 couples undergoing IVF treatment, 17% dropped out.Thirty-five patients elected to discontinue treatment following COS.Eight (23%) after the first cycle, 12 (34%) after the second cycle, and 15 (43%) following the third cycleThe physical or psychological burden of treatment was the most frequent (28%) reason given for voluntarily discontinuing treatment.Poor embryo qualityPoor response/signs of ovarian agingEthical objections to ICSI treatment after failed IVF treatmentNo. of patientsAdapted from Verberg et al. Hum Reprod. 2008;23:2050.Verberg et al. Hum Reprod. 2008;23:2050.8
9Impact of counselling on stress during IVF treatment: a RCT 20161284No counsellingp=0.076CounsellingDistressStartStimulationPick-upFertilizationWaitingResultTreatment PhaseDe Klerk et al Hum Reprod 2005
14Advantages of GnRH antagonist? Suppression of endogenous LH level within a few hoursNo flare-up effectNo risk of GnRH agonist-induced cyst formationNo estrogen deprivation symptomsFSH consumption reducedDuration of stimulation shortened – less costlyUnintended administration during early pregnancy avoidedSignificant reduction in severe OHSS rate1. Al-Inany et al. Cochrane Database Syst Rev 2006;3:CD0017502. Tarlatzis et al. Hum Reprod Update 2006;12:3333. Klingmuller et al. Acta Endocrinol 1993;128:154. Varney et al. J Assist Reprod Genet 1993;10:53
15GnRHa or hCG for triggering of final oocyte maturation - Why GnRHa? Significant decrease/elimination in the incidence of OHSST1/2 of endogenous LH shorter than T1/2 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 physiologicalLuteal phase steroid level closer to the physiological rangeEndogenous FSH and LH surge
16GnRHa 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 cycleEffective stimulation of final oocyte maturation and ovulation (Gonen et al., 1990; Itskovitz et al., 1991)Not applicable in cycles down-regulated with GnRHa
17Surge of gonadotropins after GnRHa triggering versus natural cycle 48hHoff et al., 1983; Gonen et al., 1990; Itskovitz et al., 1991
18What does the hCG trigger do which LH does not? Causes rise in intrafollicular P4 (Yding Andersen et al 1993)Development of multiple corpora luteaSupraphysiological estradiol and Progesterone synthesishCG 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
20Step 3Focus on cumulative outcomes rather than single cycle outcomes
21Conventional Strategy 2 embryos2 embryos2 embryosConventional Strategy200 patients200 patientsMild Strategy1 embryo1 embryo1 embryo1 embryo1 yearThese 2 treatment protocols were used in a randomized controlled trial comparing 2 treatment strategies, the standard strategy consisting of 3 standard treatment cycles and the mild strategy, consisting of 4 mild treatment cycles. 400 patients were included in the trial in 2 centers in Rotterdam and Utrecht between 2002 and 2004.400 patientsTwo-centres (Erasmus MC Rotterdam, UMC Utrecht - NL)Inclusion periodPower: 80%; α: 0.05; maximal difference non inferiority -12.5%
22GnRH Antagonist and Long GnRH Agonist strategies result in comparable cumulative pregnancy rates Proportion of pregnancies leading to cumulative term live birth within 12 months after starting IVFGnRH agonist with DETGnRH antagonist with SETleading to term live birth% of pregnanciesSingleton term live birthThe effect of a GnRH antagonist–based strategy vs a GnRH agonist–based strategy was evaluated in a randomized, noninferiority effectiveness trial.A total of 404 patients were randomly assigned to undergo either stimulation with a GnRH antagonist combined with single embryo transfer or stimulation with a GnRH agonist long protocol and transfer of 2 embryos.Primary end points were proportion of cumulative pregnancies leading to term live birth within 1 year after randomization (with a noninferiority threshold of −12.5%). Analysis was by intention to treat.Results with GnRH antagonist–based treatment vs GnRH agonist–based treatment demonstrated that the proportions of cumulative pregnancies that resulted in term live birth after 1 year were nearly identical, at 43.4% and 44.7%, respectively (P=NS)Months since randomizationAdapted from Heijnen, et al. Lancet. 2007;369:743.Heijnen et al. Lancet. 2007;369:743.
23Costs Total costs of IVF treatment per couple over 12 months (€) Mild (n=205)Standard (n=199)p*Technical procedures1083 (734)991 (584)0.16Medication1626 (1088)1737 (1069)0.3Monitoring750 (561)576 (693)0.006Indirect costs1948 (2280)1740 (1845)Pregnancy and neonatal periodMedical costs2547 (4553)4899 (10746)0.01379 (1177)802 (2270)0.03Total costs8333 (5418)10745 (11225)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.Heijnen, et al. Lancet. 2007
24Medication costs and hospital charges for IVF/ICSI treatment at the Oulu University hospital for the year 2008Cumulative costs (euros)Unit price (euros)Fresh cycleMedication1495IVF1542ICSI2158Progesterone support34FET cycle600Hormonal support66eSET periodDET periodTotal costsCosts of fresh cyclesCosts of FET cyclesTotal costs per woman56115890After 3% discounting45844942Term live births per woman0.2610.243
27IVF and the Endometrium Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantationWen-ge Ma*, Haengseok Song†, Sanjoy K. Das, Bibhash C. Paria, and Sudhansu K. Dey‡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.
28Ovarian stimulation on intra-uterine cytokine profile Performed in 41 women. Within patient comparsisons were made.With Bonferroni correction for multiple testing these mediators were significantly differentially expressed in natural and stimulated cycles. Most mediators are increased in concentration.Multivariable analysis in 203 patients showed significant relations between the number of oocytes retrieved and secretion concentrations of IL-12, Dkk-1 (positive) and IL-15 (negative).Therefore, disruptive effects seem to increase along with the number of oocytes retrieved.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 Steril28
30Relationship between serum P levels on the day of hCG and ongoing pregnancy rate A retrospective, observational, single-centre cohort studyMultivariate 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).Progesterone levelsPregnancy rate< or = 1.5 ng/ml31%>1.5 ng/ml19%P <0.001Bosch E. Hum Reprod. 2010;25:2092–2100.
31190 patientsWhen 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 pregnancywhenever progesterone levels exceeded the threshold of 1.5 ng/ml”Agonist group9.5 versus 31.8%P= 0.03Antagonist14.3 versus 34.3%P= 0.07
32Most recent meta-analysis in GnRH antagonist cycles (n=585) Patients with progesterone elevationhigher 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 pregnancyKolibianakis, et al. Curr Pharm Biotech
33Does milder stimulation reduce estradiol and progesterone levels at the end of the follicular phase? Blockeel C, et al. JCEM. 2011;96:
34Follicular characteristics and cycle outcome measures CD2 group (n = 33)CD 5 group (n = 39)PTotal dose of recFSH (IU)1364 ± 2261177 ± 295<0.01recFSH duration (days)9.1 ± 1.57.8 ± 2.0Duration follicular phase (days)10.1 ± 1.511.9 ± 2.0Blockeel C, et al. JCEM. 2011;96:
36Produce embryos in one cycle, and transfer in another?
37‘There is an alternative’ I said to Jean ‘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 1976A Matter of Life. The Story of IVF2nd edition 2011, Impression Publishing
38Three trials accounting for 633 cycles in women aged 27–33 years Mostly high responders
40Eleven studies met the inclusion criteria Singleton pregnancies after the transfer of frozen thawed embryos were associated with better perinatal outcomes compared with those after fresh IVF embryosLower relative risks (RR) and 95% confidence intervals (CI) after FET for:RR95% CIantepartum haemorrhage0.670.55–0.81preterm birth0.840.78–0.90small for gestational age0.450.30–0.66low birth weight0.690.62–0.76perinatal mortality0.680.48–0.96
41The endometrium and the baby Perinatal outcome of singleton siblings born after Assisted Reproductive Technology and spontaneous conception Danish National Sibling-Cohort studyAIM: Separate the effects of the maternal characteristics and the effects of infertilityChairman, ladies and gentlemens,Thank you for given me the opportunity to present the results from our recent sibling analysis where we have looked at the perinatal outcome in singletons where one of the siblings is born after assisted reproduction, the other child spontaneously conceivedHenningsen AA, Pinborg A, Lidegaard Ø, Vestergaard C, Forman JL, Andersen AN41
42MethodsData were obtained from the National Danish Birth and IVF registersAll 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 periodWe obtained data on the perinatal outcome from both the Danish IVF register and the Danish Birth register.We identified all women who had given birth to two consecutive singletons, where one of the children was born after either in-vitro-fertilisation or ICSI, the other child spontaneously conceived.In total we included more than children over a study period of 13 years.42
43Birthweight (g), adjusted* n=5982(64 g ↑)p<0.02n=1774(62 g ↓)p<0.07This is the difference in mean BW when we adjust for known confounders such as maternalage, parity, offspring sex etc.Again the blue linie illustrates the sibling combination where the ART pregnancy comes first, the spontaneous pregnancy second.Here you still see an increase in BW from child number 1 to child number 2 but a more moderate one of only 60 gram, compared to 160 gram in the crude analysis.But when you look at the red linie where the spontaneous conception preceeds that of ART we actually find a decrease in BW of around 60 gram from child number 1 to child number 2, indicating that the techniques of assisted reproduction does play a role regarding the BW of the children.It is this graph with the adjusted analysis for BW you should hold up against the findings from the Norwegian study by Romundstad who found an increse in BW from child number 1 to child number 2 regardless of mode and order of conception.*maternal age, parity, year of birth, sex43
44Perinatal outcomeARTSpontaneousCrude OR[95%CI]Adj. OR*BW < 2500 g5.5%3.8%1.5[ ]1.4[ ]BW < 1500 g1.1%1.1[ ][ ]GA < 37 weeks7.1%5.6%1.3[ ]GA < 32 weeks[ ]Here you see the odds ratios for prematurity and low-birth-weight.The first column at the left shows the prevalence for adverse outcomes for the ART children, - the second column for the spontaneously conceived siblings.In the ART group 5.5% of the children are born with a BW less than 2500 g, - for the spontaneously conceived siblings this is the case for only 3.8%. This gives a crude OR of 1.5, - but this elevated risk of LBW disapears when we adjust for known confounders, - and when you look at the adjusted odds ratio, there is no difference between the two groups.The same is the case for prematurity, - where a borderline significant difference disapears when adjusting.*OR adjusted for maternal age, parity, year of birth, sex, time between pregnanciesNFOG Copenhagen. June, 2010.44
45Cryo: Birthweight (g), adj.* IVF procedure or Ovarian Stimulation?Cryo: Birthweight (g), adj.*n=550(286 g ↑)p<0.004n=166(26 g ↓)p<0.82*maternal age, parity, year of birth, sex
46Step 5. Manage Expectation Highlight natures limits: and why they are thereEmphasise role of couple in determining success
48Wallace and Kelsey 2010 PLoS One 5; e8772 You can only stimulate follicles that are thereWallace and Kelsey 2010 PLoS One 5; e8772
495 Steps to keep them coming back Reduce the psychological burden of treatment.Reduce the physical burden of treatmentFocus on cumulative outcomes rather than single cycle outcomes4. Look beyond the fresh embryo transfer.5. Manage expectation.