1. Patient Friendly IVF Approach: 5 Critical Ways to Keep Them Coming Back
Nick Macklon
Professor of Obstetrics and Gynaecology, University of Southampton
Director, Complete Fertility Centre Southampton
Please use the dd month yyyy format for the date for example 11 January The main title can be one or two lines long.

2. The impact of drop outs on cumulative rates
Data from 4102 IVF cycles in 2130 women 70 60 50 40 30 20 10 1 2 3 4 5 6
Cycles %
Drop out rate
ECPR
RCPR
Schroder et al, RBM Online 2004 2

3. The need for patient friendly IVF
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

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

5. Step 1
Reduce the psychological burden of treatment.

6. mg per day
It works 6

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
Among 384 couples undergoing IVF treatment, 65 (17%) dropped out
Causes for Drop out
Physical or psychological burden of treatment
Unknown
Relational problems/divorce
Others
Adoption
The 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 cycle
The physical or psychological burden of treatment was the most frequent (28%) reason given for voluntarily discontinuing treatment.
Poor embryo quality
Poor response/signs of ovarian aging
Ethical objections to ICSI treatment after failed IVF treatment
No. of patients
Adapted from Verberg et al. Hum Reprod. 2008;23:2050.
Verberg et al. Hum Reprod. 2008;23:2050. 8

9. Impact of counselling on stress during IVF treatment: a RCT20 16 12 8 4
No counselling
p=0.076
Counselling
Distress
Start
Stimulation
Pick-up
Fertilization
Waiting
Result
Treatment Phase
De Klerk et al Hum Reprod 2005

10. 10

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

12. Drop outs from successive IVF cycles
Verberg. HR

13. Step 2
Reduce the physical burden of treatment

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:CD001750
2. Tarlatzis et al. Hum Reprod Update 2006;12:333
3. 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
T1/2 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 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
48h
Hoff et al., 1983; Gonen et al., 1990; Itskovitz et al., 1991

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. Humaidan et al., Fertil Steril, 2010; 93:847-54
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

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

22. GnRH 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 IVF
GnRH agonist with DET
GnRH antagonist with SET
leading to term live birth
% of pregnancies
Singleton term live birth
The 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 randomization
Adapted from Heijnen, et al. Lancet. 2007;369:743.
Heijnen et al. Lancet. 2007;369:743.

23. Costs Total costs of IVF treatment per couple over 12 months (€)
Mild (n=205)
Standard (n=199) p*
Technical procedures
1083 (734)
991 (584)
0.16
Medication
1626 (1088)
1737 (1069)
0.3
Monitoring
750 (561)
576 (693)
0.006
Indirect costs
1948 (2280)
1740 (1845)
Pregnancy and neonatal period
Medical costs
2547 (4553)
4899 (10746)
0.01
379 (1177)
802 (2270)
0.03
Total costs
8333 (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

24. Medication costs and hospital charges for IVF/ICSI treatment at the Oulu University hospital for the year 2008
Cumulative costs (euros)
Unit price (euros)
Fresh cycle
Medication
1495
IVF
1542
ICSI
2158
Progesterone support 34
FET cycle
600
Hormonal support 66
eSET period
DET period
Total costs
Costs of fresh cycles
Costs of FET cycles
Total costs per woman
5611
5890
After 3% discounting
4584
4942
Term live births per woman
0.261
0.243

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

27. IVF and the Endometrium
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‡
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
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 Steril 28

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).
Progesterone levels
Pregnancy rate
< or = 1.5 ng/ml
31%
>1.5 ng/ml
19%
P <0.001
Bosch E. Hum Reprod. 2010;25:2092–2100.

31. 190 patients
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”
Agonist group
9.5 versus 31.8%
P= 0.03
Antagonist
14.3 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
CD2 group (n = 33)
CD 5 group (n = 39) P
Total dose of recFSH (IU)
1364 ± 226
1177 ± 295
<0.01
recFSH duration (days)
9.1 ± 1.5
7.8 ± 2.0
Duration follicular phase (days)
10.1 ± 1.5
11.9 ± 2.0
Blockeel C, et al. JCEM. 2011;96:

35. ©2011 by Endocrine Society
Box (median values and 25th and 75th percentiles) and whisker (P5 and P95) plots representing FSH (international units per liter), LH (international units per liter), estradiol (E2; nanograms per liter), and progesterone (P; nanograms per milliliter) serum concentrations of both treatment groups. On the x-axis, the days of blood sampling are given (d 2, 6, and 8 of the cycle and day of hCG administration): CD2 group, d 2 (n = 36 patients), d 6 (n = 33 patients), d 8 (n = 33 patients), d of hCG (n = 33 patients); CD5 group, d 2 (n = 40 patients), d 6 (n = 39 patients), d 8 (n = 39 patients), day of hCG (n = 39 patients).
Blockeel C, et al. JCEM ;96:

36. Produce 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 1976
A Matter of Life. The Story of IVF
2nd 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-Thawed
Fresh
Weight
Risk Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95%CI
Study or Subgroup
Events
Total
Aflatoonian 2010 73
187 52
46.0%
1.4 [1.05, 1.88]
Shapiro 2011 – Normal 39 70 27 67
24.4%
1.38 [0.97, 1.98]
Shapiro 2011 – High 38 60 34 62
29.6%
1.15 [0.86, 1.55]
Total (95% CI)
317
316
100.0%
1.32 [1.10, 1.590
Total events
150
113
Heterogeneity: Chi2 = 1.03, df =2 (P = 0.60); I2 = 0%
Test for overall effect: Z = 3.00 (P = 0.003)
Clinical Pregnancy  78 58
47.9%
1.34 [1.02, 1.77] 42 29
24.5%
1.37 [0.99, 1.94]
27.6%
1.19 [0.88, 1.59
1.31 [1.10, 1.56]
 159
121
Heterogeneity: Chi2 = 0.60, df = 2 (P = 0.74); I2 = 0%
Test for overall effect: Z = 3.04 (P = 0.002)
Miscarriage 5 6
33.2%
0.83 [0.26, 2.68] 7
39.6%
0.82 [0.29, 2.32] 4
27.2%
0.83 [0.23, 2.93]
0.83 [0.43, 1.60] 15 18
Heterogeneity: Chi2 = 0.00, df = 2 (P = 1.00); I2 = 0%
Test for overall effect: Z = 0.56 (P = 0.57)
Roque. Elective frozen-thawed embryo transfer. Fertil Steril

40. Eleven 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 embryos
Lower relative risks (RR) and 95% confidence intervals (CI) after FET for: RR
95% CI
antepartum haemorrhage
0.67
0.55–0.81
preterm birth
0.84
0.78–0.90
small for gestational age
0.45
0.30–0.66
low birth weight
0.69
0.62–0.76
perinatal mortality
0.68
0.48–0.96

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
Chairman, 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 conceived
Henningsen AA, Pinborg A, Lidegaard Ø, Vestergaard C, Forman JL, Andersen AN 41

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
We 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

43. Birthweight (g), adjusted*
n=5982
(64 g ↑)
p<0.02
n=1774
(62 g ↓)
p<0.07
This 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, sex 43

44. Perinatal outcome
ART
Spontaneous
Crude OR
[95%CI]
Adj. OR*
BW < 2500 g
5.5%
3.8%
1.5
[ ]
1.4
[ ]
BW < 1500 g
1.1%
1.1
[ ]
[ ]
GA < 37 weeks
7.1%
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 pregnancies
NFOG Copenhagen. June, 2010. 44

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

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

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

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

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