Transcript Document

Justification and benefit of
adjuvant therapy in IVF/ICSI
Prof. dr. sc. Miro Kasum
Klinika za ženske bolesti i
porode
Petrova 13, Zagreb
Factors

Fetal
–
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Assisted hatching
Preimplantation genetic
screening
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Maternal
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–
–
–
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Other methods
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Acupuncture
Endometrial biopsy
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Aspirin
Glucocorticoids
Growth hormone
Dehydroepiandrosterone
Sildenafil
Heparin
Immnoglobulin
Antibiotics
Assisted hatching (AH)
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Before an embryo implants
into the uterus it must hatch
from the zona pellucida
Definition:
Artificial disruption
(thinning) or making a small
hole in the zona pellucida
– Easier for hatching to
occur
Methods
– Chemical
– Mechanical
– Laser
Indications and success rates
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Older women
> 37years
Poor embryo quality
Thick zona pellucida
Repeated failed IVF cycles
– 3 or more ET without
pregnancy
> FSH levels

No evidence to recommend
or determine any effect of
AH on LBR
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
Seif MM, Cochrane
Database Syst Rev 2006
Improvement in CPR with
AH means that a clinic with
a success rate of 25% could
anticipate improving the
CPR to between 29% and
49%
–
Das S, Cochrane
Database Syst Rev 2009
Preimplantation genetic screening
(PGS)
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3 days after the embryos are
created in the laboratory
Removal 1 or 2 cells
The genetic material (mainly
chromosomes)
Testing for abnormalities
(aneuploidy screening)
Embryos having both a normal
test result and physical
appearance should be
transferred
Physical appearance means
embryos should have at least 5
cells on day 3
Indications and effectiveness
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A family history of
genetic disorders
Repeated unexplained
miscarriages
Advanced maternal age
–
> 35 years
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No evidence of a beneficial
effect of PGS as currently
applied on the LBR after IVF,
but, for women of advanced
maternal age PGS significantly
lowers the LBR
Technical drawbacks and
chromosomal mosaicism
underlie this inefficacy of PGS
New approaches in the
application of PGS should be
evaluated carefully before their
introduction into clinical practice
 Mastenbroek
S, HRU, 2011
Maternal factors and other methods
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Aspirin
Glucocorticoids
Growth hormone(GH)
Dehydroepiadrosterone
(DHEAS)
Sildenafil
Heparin
Intravenous immunoglobulin
(IVIg)
Antibiotics
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Acupuncture
Endometrial biopsy
Aspirin
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Properties:
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Arachidonic acid
< Cyclooxigenase
< Prostacyclin (PGI2)
<< Thromboxane A2
(TXA2)
Effects:
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Vasodilatatory
Anti-inflammatory
Platelet aggregation
inhibition
Aspirin following ET
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Aspirin 75 mg
– Alternate days from
the day of ETuntil 18
days after retrieval
Evaluation:
– Ovarian blood flow
– Folliculogenesis
– Ovarian
responsiveness
– Uterine vascularity
and receptiveness
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RCT of 1380 women
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LBR
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27% (with aspirin)
23% (without aspirin)
–
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Waldenstroem U, FS
2004
Low-dose aspirin does not
improve IVF outcome and it
cannot be recommended for
routine clinical use
–
Revelli A, FS 2008; Duvan CL,
JARG 2006; Fratarelli JL, FS
2008; Gelbaya TA, HRU 2007
Glucocorticoids
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Immunomodulators
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> Intra uterine environment
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> Implantation rate
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< NK cells
< Cytokines
< Endometrial inflammation
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–
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Boomsma CM,
Cochrane Database
Syst Rev 2007
– Tetsuka M, JCEM
1997
– Miell JP, JE 1993
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> Ovarian response to
gonadotrophins
Dexametasone
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–
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=> enzyme 11-beta
hydroxysteroid
dehxdrogenase type 1
=> Directly influence
follicular development
=> Indirectly by increasing
serum GH, IGF-1, and
consequently follicular fluid
IGF-1 levels
Glucocorticoids and success rates
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1 mg dexamethone
10 mg prednisolone
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> Implantation rate
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> Pregnancy rate
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16.3 vs. 11.6% (NS)
26.9 vs. 17.2% (NS)
< Cancellation rate
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2,8 vs. 12,4% (SS)
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Keay SD, HR 2001
> Pregnancy rate
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Borderline (SS)
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Boomsma CM, Cochrane
Database Syst Rev 2007
Growth hormone (GH)
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> Intraovarian IGF-I
Addition of IGF-I to gonadotrophins
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> Gonadotrophin action in granulosa cells in poor responders
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Demonstration in animal and human studies
Augmentation of the activity of aromatase
Increase of E2-17 beta, P4, LH-r
Augmentation of follicular development
Increase of oocyte maturation
Hypothesis for the introduction of GH to enhance ovarian
steroidogenesis and follicular develpoment and the ovarian
response acting sinergistically with FSH
–
Yoshimura Y, BR 1996, Suikarri AM, FS 1996
GH during ovulation induction
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Mostly studied poor responders
4 -12 IU of GH
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sc
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> Retrieved oocytes
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> PR
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Starting on the day of ovarian
stimulation with gonadotrophins
7.5 vs. 3.5 (p< 0.001)
60%
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No significant differences
–
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Ibrahim ZH, FS 1991
Number of follicles and
oocytes, gonadotrophin dose,
cancellation, PR
No support for the use of GH as
adjuvant th
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Suikkari AM, FS 1996, Shaker
A, FS 1992, Kotarba D,
Cochrane Library , 2002
Dehydroepiandrosterone (DHEAS)
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Primarily adrenocortical reticularis zone origin
In high amounts during reproductive life
Progressive decline with age
Speculation that HRT in the elderly may have ageretardant effects
Essential sustrate for steroidogenesis
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< DHEAS => < testosterone, < E2-17 beta
> DHEAS (oral supplementation) => > IGF-I
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Orentreich N, JCEM 1984, McNatty KP, S 1979, Casson
PR, HR, 2000
DHEAS before ovulation induction
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Mostly studied
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–
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Women with diminished
ovarian reserve
Repeated IVF failures
Oral supplementation
75 mg daily
2 – 4 months before
ovulation induction with
gonadotrophins
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> E2-17 beta
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> IGF-I
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Particularly 35-40 years
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Trott E, FS, 1996
> CPR
< Dose of gonadotrophins
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Casson PR, E, 1998
> Outcome in CC resistency
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Casson PR, HR 2000
Barad D, HR 2006
May augment ovulation
induction
Beneficially affect oocyte
and embryo quality and PR
Sildenafil
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A potent cGMP-specific
phosphobodies-terase 5
inhibitor
–
Its selective inhibition of
cGMP catabolism in
cavernous smooth muscle
tissue augments penile
erection

–
Fagelman E, U, 2001
Vaginal sildenefil improves
uterine artey blood flow
and sonographic
endometrial appearence
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Sher G, HR 2000
Sildenafil during ovarian stimulation
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7 days of sildeneafil
– > Uterine artery blood flow
The combination of sildenafil
and estradiol valarate
– >Uterine artery blood flow
– > Endometrial thickeness
 Sher G, HR 2000
Vaginal route for 3 to 10 days
– > 2 previous > IVF failures
 > PR (SS)
– < Endometrial thickness
 > 9 mm
– Sher G, FS 2002
Promising studies *
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The addition of silldenefil to
an estrogen supplemented
regimen
Previously failed to achieve
an endometrial thickness
greater than 8 mm
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No increase in endometrial
thickness
No increase in blood flow
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Check JH, HR 2000
Sildenefil has not
demostrated a definitive role
Heparin
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Treatment of choice
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Recurrent pregnancy loss due to aPL antibodies
Heparins are involved in activities anticoagulation
and adhesion of the blastocyst to the endometrial
epithelium and subsequent invasion
aPL may be responsible
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< Phospholipid adhesion molecules of trophoblast
< hCG release
< Trophoblast invasiveness
< Trophoblast differentiation in vitro
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Fiedler K, EJMR 2004, Di Sormone N, AR 2000
Heparin and success rates
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Assumption
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< Immunological status
< Embryo implantation
at least one aPL
Heparin 5000 IU, Aspirin
100 mg daily
NO significant difference in
PR those treated and those
receiving placebo
–
Quenby S, FS
2005, Stern C, FS
2003
Seropositive women
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Seropositive women in IVF
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> 3 IVF failures
at least 1 thrombophilic
defect
Enoxaparin (Low
molecular weight heparin),
40 mg daily
> CR,> PR, > LBR/ placebo
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20,9% vs. 6,1%
31% vs. 9,6%
23,8% vs. 2,8%
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Qublasn H, HF
2008
Immunoglobulin (IgG)
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Indications
– > Embryo failure
– > Recurrent miscarriage
 > Inappropriate
immune response
 > Proinflammatory
cytokines
Preparations of IgG contain
– All humoral IgG
antibodies
– Normally in the plasma
of blood donors
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Effects of IgG:
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< Proinflammatory citokynes
> Antinflammatory cytokines
< NK cells
< Pathological antibodies
Dose:
–
500 mg iv / kg before ET
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Carp HJ, CRAI 2005
Coulam CB, EP 2000
IgG before ET
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No improve in PR
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Stephenson MD, FS
2000
> LBR (SS), meta
analysis, 3 RCT
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> PR (56% vs. 9%)
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No benefit
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Balasch J, FS 1996
Clark DA, JARG 2006
Coulam CB, EP 2000
> Outcomes in specific
group of IVF patients
with positive APA
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Sher G, AJRI 1996
Antibiotics
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Vaginal antisepsis, negative effect
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Bacterial vaginosis, negative effect
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< Quality of the oocytes and the embryos
< H2O2 producing lactobacilli
< CR
> EPL
Bacterial contamination of the ET catheter tip
Significant negative effect
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–
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< CR
< ZP
> Endometritis
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> Cytokines, > Macrophages, > Prostaglandins, > Leukocytes
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Salim R,HR 2002; Spandorfer S, JRM 2001; Moore DE, FS 2001
Controversial role of antibiotics
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Ceftriaxone +
metronidazole
At oocyte recovery
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Reduction of bacteria on
the transfer catheter clip
(78,4%)
> CR
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41,3% vs. 18,7%
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Egbase PE, Lancet 1999
Amoxycillin + clavulanic
acid 1g/1,25, RCT
At oocyte recovery + 6 days
> Pregnancy loss rate
–
21,6 % vs. 9,3%
> CPR
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33,3% vs. 20,8% (p=9,15)
Not recommend this
antibiotic prescription *
Ensure maximum catheter
sterility *
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Peikrishvili R, JGOBR
2004
Acupuncture
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Used in China for centuries
to regulate the female
reproductive system
Recent popularity in the
western world
3 potential mechanisms
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–
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> Neurotransmiters, GnRH,
FSH, E2, “O”
> Uterine blood flow
< Endogenous opioids
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Cho ZS, PNAC 1998
Beneficial effects of acupuncture
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Timing of administration:
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During ovarian stimulation
At oocyte recovery
At ET and afterward
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A number of systemic
reviews and meta-analysis
have been conducted on its
efectiveness as an adjuvant
treatment
Ng EH, BJOG 2008
> CPR, > LBR
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Manheimer E, BMJ 2008
> PR
–
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> CPR, > LBR
El-Toukhy T, BJOG 2008
> LBR
Placebo effect and small
sample size cannot be
excluded *
Not recommended as a routine
use procedure *
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Cheong YC, Cochrane
database Syst Rev 2008
Endometrial biopsy (Pipelle)
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EB vs. Local injury
> Wound-healing effect
> Decidualization
> Cytokines
> Growth factors
> Uterine receptivity
> Implantation
> PR
– Animal studies
Indications
< Endometrial receptivity
> Intrauterine adhesions
> Endometrial iregularity (US)
< Endometrial thickness (US)
–
Raziel A, FS 2007;
Basak S, AJRI 2002
Benefits of scratching (EB)
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On days 10-13 and 20-24 of
previous cycle
> genes encoding membrane
proteins important during
implantation
–
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> CR
– 27,7% vs. 14,2%
> CPR
– 66,7% vs.30.3%
> LBR
– 48,9% vs.22.5%
–

Barash A, FS 2003
> CR following excision of polyp or
thickened endometrium
–
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Kalma Y, FS 2009
Li R, FS 2008
> CR, > CPR, > LBR
–
Zhou L FS 2008
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Results are promising
Prospective controlled
studies are still needed to
confirme the procedure
Validitation in a large
randomized study may lead
to the routine performance
of EB in conjuction with IVF
Conclusions
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The expense, time, stres and
frustration felt by physicians and
15% of couples with difficulties in
conceiving are searcing for new
drugs and tecnologies that will
increase succes rates
However, progress has been
limited because none of the
available adjuvant treatments has
a clear advantage
If the embryos are genetically
abnormal, no maternal adjuvant
therapy will improve the pregnancy
rate

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Some of the therapies may prove
efficacious in subgroups of
patients
Treatment often needs to be
“tailor-made” to suit the individual
patient
Low molecular weight heparine
may be effective against
antiphospholipid antibodies,
other than LE and ACA
EB may benefit patients with thin
and nonresponsive endometrium
Ig may benefit patients with high
NK cell numbers, or enhanced
killing activity