Title: Justification and benefit of adjuvant therapy in IVF/ICSI
1Justification and benefit of adjuvant therapy in
IVF/ICSI
- Prof. dr. sc. Miro Kasum
- Klinika za ženske bolesti i porode
- Petrova 13, Zagreb
2Factors
- Fetal
- Assisted hatching
- Preimplantation genetic screening
- Other methods
- Acupuncture
- Endometrial biopsy
- Maternal
- Aspirin
- Glucocorticoids
- Growth hormone
- Dehydroepiandrosterone
- Sildenafil
- Heparin
- Immnoglobulin
- Antibiotics
3 Assisted hatching (AH)
- 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
4Indications and success rates
- Older women
- gt 37years
- Poor embryo quality
- Thick zona pellucida
- Repeated failed IVF cycles
- 3 or more ET without pregnancy
- gt FSH levels
- No evidence to recommend or determine any effect
of AH on LBR - 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
5Preimplantation genetic screening (PGS)
- 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
6Indications and effectiveness
- A family history of genetic disorders
- Repeated unexplained miscarriages
- Advanced maternal age
- gt 35 years
- 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
7Maternal factors and other methods
- Aspirin
- Glucocorticoids
- Growth hormone(GH)
- Dehydroepiadrosterone (DHEAS)
- Sildenafil
- Heparin
- Intravenous immunoglobulin (IVIg)
- Antibiotics
- Acupuncture
- Endometrial biopsy
8Aspirin
- Properties
- Arachidonic acid
- lt Cyclooxigenase
- lt Prostacyclin (PGI2)
- ltlt Thromboxane A2 (TXA2)
- Effects
- Vasodilatatory
- Anti-inflammatory
- Platelet aggregation inhibition
9Aspirin following ET
- 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
- RCT of 1380 women
- LBR
- 27 (with aspirin)
- 23 (without aspirin)
- 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
10Glucocorticoids
- Immunomodulators
- gt Intra uterine environment
- gt Implantation rate
- lt NK cells
- lt Cytokines
- lt Endometrial inflammation
- Boomsma CM, Cochrane Database Syst Rev 2007
- Tetsuka M, JCEM 1997
- Miell JP, JE 1993
- gt Ovarian response to gonadotrophins
- Dexametasone
- gt enzyme 11-beta hydroxysteroid dehxdrogenase
type 1 - gt Directly influence follicular development
- gt Indirectly by increasing serum GH, IGF-1, and
consequently follicular fluid IGF-1 levels
11Glucocorticoids and success rates
- 1 mg dexamethone
- 10 mg prednisolone
- gt Implantation rate
- 16.3 vs. 11.6 (NS)
- gt Pregnancy rate
- 26.9 vs. 17.2 (NS)
- lt Cancellation rate
- 2,8 vs. 12,4 (SS)
- Keay SD, HR 2001
- gt Pregnancy rate
- Borderline (SS)
- Boomsma CM, Cochrane Database Syst Rev 2007
12Growth hormone (GH)
- gt Intraovarian IGF-I
- Addition of IGF-I to gonadotrophins
- Demonstration in animal and human studies
- gt Gonadotrophin action in granulosa cells in poor
responders - 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
13GH during ovulation induction
- Mostly studied poor responders
- 4 -12 IU of GH
- sc
- Starting on the day of ovarian stimulation with
gonadotrophins
- gt Retrieved oocytes
- 7.5 vs. 3.5 (plt 0.001)
- gt PR
- 60
- Ibrahim ZH, FS 1991
- No significant differences
- Number of follicles and oocytes, gonadotrophin
dose, cancellation, PR - No support for the use of GH as adjuvant th
- Suikkari AM, FS 1996, Shaker A, FS 1992, Kotarba
D, Cochrane Library , 2002
14Dehydroepiandrosterone (DHEAS)
- Primarily adrenocortical reticularis zone origin
- In high amounts during reproductive life
- Progressive decline with age
- Speculation that HRT in the elderly may have
age-retardant effects - Essential sustrate for steroidogenesis
- lt DHEAS gt lt testosterone, lt E2-17 beta
- gt DHEAS (oral supplementation) gt gt IGF-I
- Orentreich N, JCEM 1984, McNatty KP, S 1979,
Casson PR, HR, 2000
15DHEAS before ovulation induction
- Mostly studied
- Women with diminished ovarian reserve
- Repeated IVF failures
- Oral supplementation
- 75 mg daily
- 2 4 months before ovulation induction with
gonadotrophins
- gt E2-17 beta
- Casson PR, HR 2000
- gt IGF-I
- Casson PR, E, 1998
- gt Outcome in CC resistency
- Trott E, FS, 1996
- gt CPR
- lt Dose of gonadotrophins
- Particularly 35-40 years
- Barad D, HR 2006
- May augment ovulation induction
- Beneficially affect oocyte and embryo quality
and PR
16Sildenafil
- 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 - Sher G, HR 2000
17Sildenafil during ovarian stimulation
- 7 days of sildeneafil
- gt Uterine artery blood flow
- The combination of sildenafil and estradiol
valarate - gtUterine artery blood flow
- gt Endometrial thickeness
- Sher G, HR 2000
- Vaginal route for 3 to 10 days
- gt 2 previous gt IVF failures
- gt PR (SS)
- lt Endometrial thickness
- gt 9 mm
- Sher G, FS 2002
- Promising studies
- The addition of silldenefil to an estrogen
supplemented regimen - Previously failed to achieve an endometrial
thickness greater than 8 mm - No increase in endometrial thickness
- No increase in blood flow
- Check JH, HR 2000
- Sildenefil has not demostrated a definitive role
18Heparin
- Treatment of choice
- 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
- lt Phospholipid adhesion molecules of trophoblast
- lt hCG release
- lt Trophoblast invasiveness
- lt Trophoblast differentiation in vitro
- Fiedler K, EJMR 2004, Di Sormone N, AR 2000
19Heparin and success rates
- Assumption
- lt Immunological status
- lt Embryo implantation
- Seropositive women in IVF
- 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
- gt 3 IVF failures
- at least 1 thrombophilic defect
- Enoxaparin (Low molecular weight heparin), 40 mg
daily - gt CR,gt PR, gt LBR/ placebo
- 20,9 vs. 6,1
- 31 vs. 9,6
- 23,8 vs. 2,8
- Qublasn H, HF 2008
20Immunoglobulin (IgG)
- Indications
- gt Embryo failure
- gt Recurrent miscarriage
- gt Inappropriate immune response
- gt Proinflammatory cytokines
- Preparations of IgG contain
- All humoral IgG antibodies
- Normally in the plasma of blood donors
- Effects of IgG
- lt Proinflammatory citokynes
- gt Antinflammatory cytokines
- lt NK cells
- lt Pathological antibodies
- Dose
- 500 mg iv / kg before ET
- Carp HJ, CRAI 2005
- Coulam CB, EP 2000
21IgG before ET
- No improve in PR
- Stephenson MD, FS 2000
- No benefit
- Balasch J, FS 1996
- gt LBR (SS), meta analysis, 3 RCT
- Clark DA, JARG 2006
- gt PR (56 vs. 9)
- Coulam CB, EP 2000
- gt Outcomes in specific group of IVF patients with
positive APA - Sher G, AJRI 1996
22Antibiotics
- Vaginal antisepsis, negative effect
- lt Quality of the oocytes and the embryos
- Bacterial vaginosis, negative effect
- lt H2O2 producing lactobacilli
- lt CR
- gt EPL
- Bacterial contamination of the ET catheter tip
- Significant negative effect
- lt CR
- lt ZP
- gt Endometritis
- gt Cytokines, gt Macrophages, gt Prostaglandins, gt
Leukocytes - Salim R,HR 2002 Spandorfer S, JRM 2001 Moore
DE, FS 2001
23Controversial role of antibiotics
- Ceftriaxone metronidazole
- At oocyte recovery
- Reduction of bacteria on the transfer catheter
clip (78,4) - gt CR
- 21,6 vs. 9,3
- gt CPR
- 41,3 vs. 18,7
- Egbase PE, Lancet 1999
- Amoxycillin clavulanic acid 1g/1,25, RCT
- At oocyte recovery 6 days
- gt Pregnancy loss rate
- 33,3 vs. 20,8 (p9,15)
- Not recommend this antibiotic prescription
- Ensure maximum catheter sterility
- Peikrishvili R, JGOBR 2004
24Acupuncture
- Used in China for centuries to regulate the
female reproductive system - Recent popularity in the western world
- 3 potential mechanisms
- gt Neurotransmiters, GnRH, FSH, E2, O
- gt Uterine blood flow
- lt Endogenous opioids
- Cho ZS, PNAC 1998
25Beneficial effects of acupuncture
- Timing of administration
- During ovarian stimulation
- At oocyte recovery
- At ET and afterward
- A number of systemic reviews and meta-analysis
have been conducted on its efectiveness as an
adjuvant treatment
- gt CPR, gt LBR
- Manheimer E, BMJ 2008
- gt PR
- Ng EH, BJOG 2008
- gt CPR, gt LBR
- El-Toukhy T, BJOG 2008
- gt LBR
- Placebo effect and small sample size cannot be
excluded - Not recommended as a routine use procedure
- Cheong YC, Cochrane database Syst Rev 2008
26Endometrial biopsy (Pipelle)
- EB vs. Local injury
- gt Wound-healing effect
- gt Decidualization
- gt Cytokines
- gt Growth factors
- gt Uterine receptivity
- gt Implantation
- gt PR
- Animal studies
- Indications
- lt Endometrial receptivity
- gt Intrauterine adhesions
- gt Endometrial iregularity (US)
- lt Endometrial thickness (US)
- Raziel A, FS 2007 Basak S, AJRI 2002
27Benefits of scratching (EB)
- On days 10-13 and 20-24 of previous cycle
- gt genes encoding membrane proteins important
during implantation - Kalma Y, FS 2009
- gt CR
- 27,7 vs. 14,2
- gt CPR
- 66,7 vs.30.3
- gt LBR
- 48,9 vs.22.5
- Barash A, FS 2003
- gt CR following excision of polyp or thickened
endometrium - Li R, FS 2008
- gt CR, gt CPR, gt LBR
- Zhou L FS 2008
- 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
28Conclusions
- 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
- 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