Justification and benefit of adjuvant therapy in IVF/ICSI
Prof. dr. sc. Miro KasumKlinika za ženske bolesti i porode
Petrova 13, Zagreb
Factors
Fetal– Assisted hatching– Preimplantation genetic
screening
Other methods– Acupuncture– Endometrial biopsy
Maternal– Aspirin– Glucocorticoids– Growth hormone– Dehydroepiandrosterone– Sildenafil– Heparin– Immnoglobulin– Antibiotics
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
Indications and success rates
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
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)
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
A family history of genetic disorders
Repeated unexplained miscarriages
Advanced maternal age – > 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
Maternal factors and other methods
Aspirin Glucocorticoids Growth hormone(GH) Dehydroepiadrosterone
(DHEAS) Sildenafil Heparin Intravenous immunoglobulin
(IVIg) Antibiotics
Acupuncture Endometrial biopsy
Aspirin
Properties:– Arachidonic acid– < Cyclooxigenase– < Prostacyclin (PGI2)– << Thromboxane A2
(TXA2) Effects:
– Vasodilatatory– Anti-inflammatory– Platelet aggregation
inhibition
Aspirin 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
Glucocorticoids
Immunomodulators– > Intra uterine environment
– > Implantation rate – < NK cells – < Cytokines – < Endometrial inflammation
– Boomsma CM, Cochrane Database Syst Rev 2007
– Tetsuka M, JCEM 1997
– Miell JP, JE 1993
> Ovarian response to gonadotrophins
Dexametasone – => 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
1 mg dexamethone 10 mg prednisolone
> Implantation rate– 16.3 vs. 11.6% (NS)
> Pregnancy rate – 26.9 vs. 17.2% (NS)
< Cancellation rate– 2,8 vs. 12,4% (SS)
– Keay SD, HR 2001
> Pregnancy rate– Borderline (SS)
– Boomsma CM, Cochrane Database Syst Rev 2007
Growth hormone (GH)
> Intraovarian IGF-I Addition of IGF-I to gonadotrophins
– Demonstration in animal and human studies > 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
GH during ovulation induction
Mostly studied poor responders 4 -12 IU of GH
– sc Starting on the day of ovarian
stimulation with gonadotrophins
> Retrieved oocytes– 7.5 vs. 3.5 (p< 0.001)
> 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
Dehydroepiandrosterone (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
– < DHEAS => < testosterone, < E2-17 beta– > DHEAS (oral supplementation) => > IGF-I
Orentreich N, JCEM 1984, McNatty KP, S 1979, Casson PR, HR, 2000
DHEAS 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
> E2-17 beta Casson PR, HR 2000
> IGF-I Casson PR, E, 1998
> Outcome in CC resistency Trott E, FS, 1996
> CPR < Dose of gonadotrophins
– Particularly 35-40 years Barad D, HR 2006
May augment ovulation induction
Beneficially affect oocyte and embryo quality and PR
Sildenafil
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
Sildenafil during ovarian stimulation
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 *
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
Heparin
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 – < Phospholipid adhesion molecules of trophoblast– < hCG release– < Trophoblast invasiveness– < Trophoblast differentiation in vitro
Fiedler K, EJMR 2004, Di Sormone N, AR 2000
Heparin and success rates
Assumption – < Immunological status– < 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 – > 3 IVF failures– at least 1 thrombophilic
defect Enoxaparin (Low
molecular weight heparin), 40 mg daily
> CR,> PR, > LBR/ placebo 20,9% vs. 6,1% 31% vs. 9,6% 23,8% vs. 2,8%
Qublasn H, HF 2008
Immunoglobulin (IgG)
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
Effects of IgG:– < Proinflammatory citokynes– > Antinflammatory cytokines – < NK cells– < Pathological antibodies
Dose:– 500 mg iv / kg before ET
Carp HJ, CRAI 2005 Coulam CB, EP 2000
IgG before ET
No improve in PR Stephenson MD, FS
2000
No benefit Balasch J, FS 1996
> LBR (SS), meta analysis, 3 RCT
Clark DA, JARG 2006
> PR (56% vs. 9%) Coulam CB, EP 2000
> Outcomes in specific group of IVF patients with positive APA
Sher G, AJRI 1996
Antibiotics
Vaginal antisepsis, negative effect– < Quality of the oocytes and the embryos
Bacterial vaginosis, negative effect – < H2O2 producing lactobacilli– < CR– > EPL
Bacterial contamination of the ET catheter tip Significant negative effect
– < CR– < ZP– > Endometritis
> Cytokines, > Macrophages, > Prostaglandins, > Leukocytes Salim R,HR 2002; Spandorfer S, JRM 2001; Moore DE, FS 2001
Controversial role of antibiotics
Ceftriaxone + metronidazole
At oocyte recovery– Reduction of bacteria on
the transfer catheter clip (78,4%)
– > CR 21,6 % vs. 9,3%
– > CPR 41,3% vs. 18,7%
– Egbase PE, Lancet 1999
Amoxycillin + clavulanic acid 1g/1,25, RCT
At oocyte recovery + 6 days > Pregnancy loss rate
– 33,3% vs. 20,8% (p=9,15) Not recommend this
antibiotic prescription * Ensure maximum catheter
sterility * Peikrishvili R, JGOBR
2004
Acupuncture
Used in China for centuries to regulate the female reproductive system
Recent popularity in the western world
3 potential mechanisms– > Neurotransmiters, GnRH,
FSH, E2, “O”– > Uterine blood flow– < Endogenous opioids
Cho ZS, PNAC 1998
Beneficial 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
> CPR, > LBR Manheimer E, BMJ 2008
> PR– Ng EH, BJOG 2008
> CPR, > LBR El-Toukhy T, BJOG 2008
> LBR Placebo effect and small
sample size cannot be excluded *
Not recommended as a routine use procedure *
Cheong YC, Cochrane database Syst Rev 2008
Endometrial biopsy (Pipelle)
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)
On days 10-13 and 20-24 of previous cycle
> genes encoding membrane proteins important during implantation
– Kalma Y, FS 2009 > 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
– Li R, FS 2008 > CR, > CPR, > 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
Conclusions
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