STATE OF THE “ART”. QUITE SIMPLE

Dr. Elmar Breitbach – Hannover - Germany

METHODS IN “ART”

It´s not just about IVF

A thorough diagnostic workup Natural family planning Clomifen Gonadotrophins and timed intercourse. Insemination with or without hormonal

stimulation

1978 – 2010: NOT MUCH OF A CHANGE?

The beginnings Natural cycle, later clomifene Laparoscopic or transvesical egg retrival No suppression of endogenous LH surge Transabdominal sonography Hormone testing via RIA or none at all

Today Convenient and timed stimulation with recombinat

gonadotrophins Transvaginal sonography and ovum pick up Fast examination of hormones Better culture media, cryopreservation ICSI for extremly low sperm counts IMSI, Hatching, IVM, Blastocysts, PID, PBD, Immunoligical

treatments, etc……… ?????

IVF: AN OVERVIEW

IVF: AN OVERVIEW

Yes, it actually (still) is that simple!

SO, WHY THAN DOESN´T IT WORK ALWAYS?

Reproduction in man does not work well in general.

So these limitations in human reproduction influence as well the treatments of infertility

Only in few cases the negative pregnancy test is a result of real pathologies

No reasons for fatalism, our goal should be to make the best out of it

LACK OF SUCCESS: REASONS

Genetically and morphological abnormal embryos are seen as main reason for low success rates

High incidence of mosaicism in human embryos

High incidence of numerical chromosomal failures mainly in elder women

Result of failures in mitotic seggregation

Can this be influenced by stimulation?

The „classical“ ultralong protocoll

STIMULATION

The alternative: the antagonist protocoll

STIMULATION

STIMULATION

Which protocoll ist the better? Long protocoll is more stable Lower cancelation rate with long protocoll Less side effects with the antagonist protocoll Lower medication use with antagonist protocoll

Depends on patient and doctor Experience with the protocoll is of great importance Usually this experience is larger with the long protocoll Therefore most studies show advantages of the long

protocoll Low responder: There might be advantages with the

antagonists There is no such thing as the “best protocoll”!

STIMULATIONNUMBER OF OOCYTES

108 Pat. < 38 years old, fertile parters (IVF) RCT 67 150 IE/die 44 225 IE/die 3 days after ovum pickup PID (FISH on two

blastomeres)

Baart EB et al.

Milder ovarian stimulation for in-vitro fertilization reduces

aneuploidy in the human preimplantation embryo: a randomized controlled trialHum Reprod. 2007 Jan 4;

STIMULATIONNUMBER OF OOCYTES

Low stimulation Higher dose

8.2 oocytes 12.2 oocytes

4.8 embryos 6.7 embryos

Normal morphology: 51%

Normal morphology: 35%

Aneuploidy: 45% Aneuploidy: 63%

37% mosaicism 65% mosaicism

1.8 euploid embryos 1.8 euploid embryos

PR: 34% PR: 23%

TINKERING

SOP on TINKERING Break your head Collect the pieces. Put them in BIN. Turn over the BIN. Go Home

STIMULATIONNUMBER OF OOCYTES

Results: There is no need for more than 10 oocytes Lower number of oocytes provides equally good

or even better embryos Due to less imprinting problems tends to have

better results > 10 oocytes only leads to more side effects

(OHSS)

So, why is it important to emphasize this?

STEP ONE: STIMULATIONNUMBER OF OOCYTES

So, why is it important to emphasize this?

Because of selective techniques to improve embryo quality and implantation Higher number of transferred embryos Blastocyst culture PID Polar body biopsy

Do they really improve the success rate?

NUMBER OF EMBRYOS

Increasing the number of transferred embryos should be the easiest way to raise PR:”The more the better, right?”

Necessity for fetal reduction, which may harm the survivers, too

Even if this results in a singleton pregnancy, the rate of complications (preterm delivery) is higher

Results are not better. There ist no way to force nature

NUMBER OF EMBRYOS

NUMBER OF EMBRYOS

„Octomum"

BLASTOCYSTS

Culture up to 5 or 6 days Sequential culture medias are used Transfer at the physiological time of

implantation Selection by longer culture in unphysiological

environment Quality of embryos better differentiable

compared to day 2 or 3 embryos Late arrests can be seen (maybe better off in

uterus?) More genetically intact embryos

BLASTOCYSTSTHE TRUTH

High numbers of oocytes arenecessary, only 50% survive untilday 5

Less than 6 oocytes: No transfer in 42 – 64% of the treatments

Reduction of genetically irregular embryos from 60% to 40%

Risks: higher incidence of OHSS. Possibly imprinting defects trough longer culture. Lower quality of the oocytes?

Birth rate in RCT 34.3% vs. 35.4% (Cochrane Database, 2005)

PID

Biopsy of two Blastomereson day 3 (8-cell-embryo)You don´t examine the embryo but

rather two cells!Mosaicism and self rescue are not

taken into accout

PID: PROBLEMS

Injury of the embryo impairs itsability to implant

PID might examine the wrong blastomeres because of mosaicism

Only up to 10 Chromosomes can be examined with “FISH”. CHIP technique might improve this.

Tests are made for chromosomes, which are responsible for pregnancy loss, not implantation failure.

PID: RCT

408 women 35 – 41 PID: 206 no PID: 202 434 treatments with PID, 402 without Ongoing pregnancy rate with PID:

25%without PID 37% which is statistically significant.

S. Mastenbroek, M. et al.In Vitro Fertilization with Preimplantation Genetic ScreeningNew England Journal of Medicine. Volume 357:9-17

PID

Again: Need for higher number of oocytes without proven positive effect on the outcome when merely used as a screening method.The necessary higher stimulation impairs oocyte quality.

OK, WHAT ELSE DO WE HAVE TO IMPROVE THE SUCCESS RATE?

IMSI Hatching Acupuncture

IMSI

IMSI: intracytoplasmic morphologically selected sperminjection

Based on the microscopic examination of cell organelles of the sperms (MSOME)

IMSI is done with high magnification (x 6000)

IMSI

IMSI

Berkowitz et al. provide the only data in a peer reviewed journal

Other Studies show no significant differences Very low sperm count (cryptozoospermia)

might be an indication for this additional method

ASSISTED HATCHING

The embryo has to leave the zonapellucida to implant

This can be accomplished by reducingthe zona

ASSISTED HATCHINGKNOWN INDICATIONS

Might help in cases of thick zona Seems to be helpful in

cryopreserved embryos Older patients: > 38 y After repeated implantation failure

Cochrane database

ACUPUNCTURE

ACUPUNCTURE

There might be a positive effect following acupunture on the day of transfer

The baby take home rate is improved up to 13%, hence there ist no statiistical difference to controlgroups

Studies are not comparable (Timing, needle points, controlgroups)

Data and their interpretation are inconsistent

El-Toukhy et al. BJOG. 2008 Sep;115(10):1203-13.

AND WHAT ABOUT…

IVM? (In Vitro Maturation)

Pregnancy rates in average just beyond 20%. In very seldom cases of “uncontrollable” PCOS there might be an indication.

AND WHAT ABOUT…

Aspirin?

AND WHAT ABOUT…

Aspirin?

AND WHAT ABOUT…

Aspirin? No Routine medication Almost no sideeffects (if given after ovum

pickup!) Maybe of use in

Recurrent implantation failure Recurrent abortion Antiphospholipidsyndrome

AND WHAT ABOUT…

Heparin? No routine medication Useful in cases of proven thrombophilia In severe cases of OHSS

CONCLUSION I

There are many helpful medication/therapies Blastocyst culture PID IMSI Hatching Acupuncture ASS Heparin

All of them might improve the success rates in certain cases. But none of them makes sense in routine therapy.

CONCLUSION II

And none of them makes sense, if you don´t have good quality oocytes.

The fate of an embryo is decided before the ovum pickup occurs - not later

You can´t improve the fate of an D-grade embryo with additional treatment

The main clue for success is the right stimulation. And this means “not more than necessary”.

IF THE BASE IS STRONG ENOUGH THE REST IS LESS IMPORTANT

Dr. Elmar Breitbach

Deutsche KlinikBad MünderHannover

THANK YOU!