Justification and benefit of adjuvant therapy in IVF/ICSI

1
Justification and benefit of adjuvant therapy in
IVF/ICSI

• Prof. dr. sc. Miro Kasum
• Klinika za ženske bolesti i porode
• Petrova 13, Zagreb

2
Factors

• 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

4
Indications 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

5
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

6
Indications 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

7
Maternal factors and other methods

• Aspirin
• Glucocorticoids
• Growth hormone(GH)
• Dehydroepiadrosterone (DHEAS)
• Sildenafil
• Heparin
• Intravenous immunoglobulin (IVIg)
• Antibiotics

• Acupuncture
• Endometrial biopsy

8
Aspirin

• Properties
• Arachidonic acid
• lt Cyclooxigenase
• lt Prostacyclin (PGI2)
• ltlt Thromboxane A2 (TXA2)
• Effects
• Vasodilatatory
• Anti-inflammatory
• Platelet aggregation inhibition

9
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

10
Glucocorticoids

• 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

11
Glucocorticoids 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

12
Growth 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

13
GH 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

14
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
• 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

15
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

• 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

16
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

17
Sildenafil 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

18
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
• 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

19
Heparin 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

20
Immunoglobulin (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

21
IgG 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

22
Antibiotics

• 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

23
Controversial 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

24
Acupuncture

• 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

25
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

• 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

26
Endometrial 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

27
Benefits 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

28
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