This document discusses methods and techniques used in assisted reproduction over the past 30+ years. It notes that while some techniques have advanced, such as use of recombinant gonadotropins and transvaginal ultrasound retrieval, the basic principles remain the same. The document examines various stimulation protocols and concludes there is no single best approach, and lower stimulation typically provides better quality embryos. It also reviews techniques like blastocyst culture, preimplantation genetic diagnosis, and acupuncture, finding some benefits in limited cases but no clear evidence they routinely improve success rates. The key factor, it determines, is optimizing oocyte quality through appropriate ovarian stimulation.

1. STATE OF THE “ART”. QUITE SIMPLE
Dr. Elmar Breitbach – Hannover - Germany

2. 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

3. 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……… ?????

4. IVF: AN OVERVIEW

5. IVF: AN OVERVIEW
Yes, it actually (still) is that
simple!

6. 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

7. 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?

8. STIMULATION
The „classical“ ultralong protocoll

9. STIMULATION
The alternative: the antagonist protocoll

10. 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”!

11. STIMULATION
NUMBER 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 trial
Hum Reprod. 2007 Jan 4;

12. STIMULATION
NUMBER 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%

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

14. STIMULATION
NUMBER 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?

15. STEP ONE: STIMULATION
NUMBER 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?

16. 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

17. NUMBER OF EMBRYOS

18. NUMBER OF EMBRYOS
„Octomum"

19. 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

20. BLASTOCYSTS
THE TRUTH
 High numbers of oocytes are
necessary, only 50% survive until
day 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)

21. PID
 Biopsy of two Blastomeres
on day 3 (8-cell-embryo)
You don´t examine the embryo but
rather two cells!
Mosaicism and self rescue are not taken
into accout

22. PID: PROBLEMS
 Injury of the embryo impairs its
ability 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.

23. 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 Screening
New England Journal of Medicine. Volume 357:9-17

24. 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.

25. OK, WHAT ELSE DO WE HAVE TO
IMPROVE THE SUCCESS RATE?
 IMSI
 Hatching
 Acupuncture

26. 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)

27. IMSI

28. 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

29. ASSISTED HATCHING
 The embryo has to leave the zona
pellucida to implant
 This can be accomplished by reducing
the zona

30. ASSISTED HATCHING
KNOWN 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

31. ACUPUNCTURE

32. 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.

33. 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.

34. AND WHAT ABOUT…
 Aspirin?

35. AND WHAT ABOUT…
 Aspirin?

36. 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

37. AND WHAT ABOUT…
 Heparin?
 No routine medication
 Useful in cases of proven thrombophilia
 In severe cases of OHSS

38. 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.

39. 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”.

40. IF THE BASE IS STRONG ENOUGH
THE REST IS LESS IMPORTANT

41. Dr. Elmar Breitbach
Deutsche Klinik
Bad Münder
Hannover
THANK YOU!