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Patient Friendly IVF Approach: 5
Critical Ways to Keep Them Coming
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Nick Macklon
Professor of Obstetrics and Gynaecology, University of Southampton
Director, Complete Fertility Centre Southampton
The impact of drop outs on
cumulative rates
Data from 4102 IVF cycles in 2130 women
70
60
50
% 40
30
20
10
0
Drop out rate
1
2
ECPR
3
4
RCPR
5
6
Cycles
Schroder et al, RBM Online 2004
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
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
Step 1
1. Reduce the psychological burden of treatment.
5
25-100 mg per day
It works
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
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
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.
Impact of counselling on stress during IVF
treatment: a RCT
20
p=0.076
No counselling
Counselling
Distress
16
12
8
4
0
Start
Stimulation
Pick-up
Fertilization
Waiting
Result
Treatment Phase
De Klerk et al Hum Reprod 2005
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
Drop outs from successive IVF cycles
Verberg. HR. 2009.
Step 2
1. Reduce the physical burden of treatment
13
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
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
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
Surge of gonadotropins after GnRHa triggering
versus natural cycle
GnRHa
14h
Natural
4h
20h
14h
0
20
h
48h
Hoff et al., 1983; Gonen et al., 1990; Itskovitz et al., 1991
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
OHSS reduction?
hCG triggering:
3/150: 2% (1 severe/2 moderate)
GnRHa triggering:
0/152
Humaidan et al., Fertil Steril, 2010; 93:847-54
Step 3
Focus on cumulative outcomes rather than single cycle
outcomes
20
2 embryos
2 embryos
2 embryos
200 patients
Conventional Strategy
200 patients
Mild Strategy
1 embryo
1 embryo
1 embryo
1 embryo
1 year
• 400 patients
• Two-centres (Erasmus MC Rotterdam, UMC Utrecht - NL)
• Inclusion period 2002-2004
• Power: 80%; α: 0.05; maximal difference non inferiority -12.5%
GnRH Antagonist and Long GnRH Agonist
strategies result in comparable cumulative
pregnancy rates
% of pregnancies
leading to term live birth
Proportion of pregnancies leading to cumulative
term live birth within 12 months after starting IVF
GnRH agonist with DET
GnRH antagonist with SET
Singleton term
live birth
Months since randomization
Adapted from Heijnen, et al. Lancet. 2007;369:743.
Costs
Total costs of IVF treatment per couple over 12 months (€)
IVF Treatment
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
1948 (2280)
1740 (1845)
0.3
Indirect costs
Pregnancy and neonatal period
Medical costs
2547 (4553)
4899 (10746)
0.01
Indirect costs
379 (1177)
802 (2270)
0.03
8333 (5418)
10745 (11225)
0.006
Total costs
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
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
eSET
period
DET
period
Total costs
3 837 964 4 865 304
Medication
1495
Costs of fresh cycles
3 383 250
4 473 172
IVF
1542
Costs of FET cycles
454 714
392 133
ICSI
2158
Total costs per woman
5611
5890
34
After 3% discounting
600
Total costs per woman
4584
4942
Term live births per woman
0.261
0.243
Progesterone support
FET cycle
Hormonal support
66
Step 4.
Look beyond the fresh embryo transfer.
25
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.
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. 2010.
What about impact of high
Progesterone levels?
Relationship between serum P levels
on the day of hCG and ongoing
pregnancy rate
• A retrospective, observational, single-centre cohort study
Progesterone levels
Pregnancy rate
< or = 1.5 ng/ml
31%
>1.5 ng/ml
19%
P <0.001
• 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 < 0.0001 for all).
Bosch E. Hum Reprod. 2010;25:2092–2100.
190 patients
When progesterone exceeded the threshold of 1.5 ng/ml, lower delivery rates:
Agonist group
9.5 versus 31.8%
P= 0.03
Antagonist
14.3 versus 34.3%
P= 0.07
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”
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. 2012.
Does milder stimulation reduce
estradiol and progesterone levels at
the end of the follicular phase?
Blockeel C, et al. JCEM. 2011;96:1122-1128.
Follicular characteristics and cycle outcome measures
CD2 group
(n = 33)
CD 5 group
(n = 39)
P
1364 ± 226
1177 ± 295
<0.01
recFSH duration (days)
9.1 ± 1.5
7.8 ± 2.0
<0.01
Duration follicular phase (days)
10.1 ± 1.5
11.9 ± 2.0
<0.01
Total dose of recFSH (IU)
Blockeel C, et al. JCEM. 2011;96:1122-1128.
©2011 by Endocrine Society
Blockeel C, et al. JCEM.
2011;96:1122-1128.
Produce embryos in one cycle,
and transfer in another?
‘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.
2nd
R.G Edwards 1976
A Matter of Life. The Story of IVF
edition 2011, Impression Publishing
• Three trials accounting for 633 cycles in women aged 27–33 years
• Mostly high responders
Meta-analysis results
Ongoing Pregnancy
Frozen-Thawed
Study or Subgroup
Fresh
Weight
Risk Ratio
M-H, Fixed, 95% CI
Events
Total
Events
Total
Aflatoonian 2010
73
187
52
187
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]
316
100.0%
1.32 [1.10, 1.590
Total (95% CI)
317
Total events
Heterogeneity:
150
Chi2
Risk Ratio
M-H, Fixed, 95%CI
113
= 1.03, df =2 (P = 0.60);
I2
= 0%
Test for overall effect: Z = 3.00 (P = 0.003)
Clinical Pregnancy
Aflatoonian 2010
78
187
58
187
47.9%
1.34 [1.02, 1.77]
Shapiro 2011 – Normal
42
70
29
67
24.5%
1.37 [0.99, 1.94]
Shapiro 2011 – High
39
60
34
62
27.6%
1.19 [0.88, 1.59
Total (95% CI)
317
Total events
Heterogeneity:
316
159
Chi2
1.31 [1.10, 1.56]
121
= 0.60, df = 2 (P = 0.74);
I2
= 0%
Test for overall effect: Z = 3.04 (P = 0.002)
Miscarriage
Aflatoonian 2010
5
187
6
187
33.2%
0.83 [0.26, 2.68]
Shapiro 2011 – Normal
6
70
7
67
39.6%
0.82 [0.29, 2.32]
Shapiro 2011 – High
4
60
5
62
27.2%
0.83 [0.23, 2.93]
316
100.0%
0.83 [0.43, 1.60]
Total (95% CI)
Total events
Heterogeneity:
317
15
Chi2
= 0.00, df = 2 (P = 1.00);
18
I2
= 0%
Roque. Elective frozen-thawed embryo transfer. Fertil Steril. 2012.
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
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
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 1994-2006
Birthweight (g), adjusted*
n=5982
(64 g ↑)
p<0.02
n=1774
(62 g ↓)
p<0.07
*maternal age, parity, year of birth, sex
Perinatal outcome
ART
Spontaneous
Crude OR
[95%CI]
Adj. OR*
[95%CI]
BW < 2500 g
5.5%
3.8%
1.5
[1.2-1.8]
1.4
[1.1-1.7]
BW < 1500 g
1.1%
1.1%
1.1
[0.8-1.7]
1.1
[0.6-1.8]
GA < 37 weeks
7.1%
5.6%
1.3
[1.1-1.6]
1.3
[1.1-1.6]
GA < 32 weeks
1.1%
1.1%
1.1
[0.8-1.7]
1.1
[0.7-1.8]
*OR adjusted for maternal age, parity, year of birth, sex, time between pregnancies
NFOG Copenhagen. June, 2010.
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
Step 5. Manage Expectation
•Highlight natures limits: and why they are there
•Emphasise role of couple in determining success
46
Habit 3: Understand nature’s limits
Spontaneous
30%
Live Birth
30%
IVF
Live Birth
30%
25%
Miscarriage
15%
10%
Miscarriage
10%
15%
Post-implantation
loss
25%
30%
Post-implantation loss
15%
Pre-implantation loss
Pre-implantation loss
30%
30%
CONCEPTIONS
50%
CONCEPTIONS
(Macklon et al, Hum Reprod Update, 2002)
(Boomsma et al, Hum Reprod , 2009)
You can only stimulate follicles that are there
Wallace and Kelsey 2010 PLoS One 5; e8772
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