Justification and benefit of adjuvant therapy in IVF/ICSI

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