Explaining the best protocol for ivf stimulation. How we can optimize the stimulation regimen to get adequate response and there by healthy baby is a challenge

1. INDIVIDUALIZED OVARIAN
STIMULATION PROTOCOLS IN
IVF
Dr Raju Nair, Mitera Hospital
Kottayam, Kerala

2. Ovulation
induction
IUI
IVF/ICSI
TI

3. monofollicular
multifollicular
Ovulation
induction
Non ART
ART

4. Ovulation induction
4
Ovulation rate
• Monofollicular
• Multi follicular
Live birth
• Healthy oocyte
• Top quality embryo
• Healthy baby
PREVENTION OF
COMPLICATIONS
• Prevention of OHSS
• Prevention of
multiple pregnancy
Ideal end point
of OI

5. What is success in IVF treatment
• Live birth
• Safety :OHSS, Multifoetal pregnancy
• Dropout rates
• Cumulative success rates per started treatment
• Health outcomes for the woman and her Baby
• Burden of treatment
• Cost.

6. Novel concepts of ovulation induction…
• Reduce cancellation due to poor response
• Reduce cancellation and hospitalization due to OHSS
• Reduce multiple pregnancies
• Minimize stimulation burden
• Achieve high chance of live pregnancy

7. Ovulation induction - individualised
• Patient profile
• Age, type of infertility, cause..
• Past history
• Past treatment cycles
• PCO / non PCO
• BMI

8. Individualization…
Age-dependent ovarian
aging (physiologic)
Premature
(nonphysiologic)
reductions in the
oocyte pool

11. Why we need bio markers?
Treatment planning
Prediction of response to COH
Identification of poor/ hyper responder
Minimize complication
Counselling tool
Ovarian surgery planning
Understanding the reality
Prognostication of infertility treatment
To understand option of oocyte donor cycles
Family planning tool
Menopause prediction

12. Ovarian reserve test…
• FSH, Clomiphene citrate
challenge test, Inhibin-B, Anti-
Mullerian Hormone (AMH)
Hormonal
Biomarkers
• Antral Follicle Count (AFC)
Functional
Biomarkers
• Single Nucleotide Polymorphisms
for FSH-R; LH/LH-R; E2-R; AMH-R
Genetic
Biomarkers

13. Clinical usefulness AMH..
•
• Reflect both the number of small growing follicles and
the primordial pool at gonadotropin-independent
folliculogenesis

14. AFC
Direct Biomarker of Functional Ovarian Reserve:
 Sum of antral follicles in both ovaries on TVUS at early follicular phase (D2-D4):
 2-10 mm (mean diameter)
 Greatest 2D-plane
 Decrease in the number of detectable (TVUS) antral follicles with aging
 Reflect the number of antral follicles in the ovaries at a given time that can be stimulated by
exogenous gonadotropins
Moderate to Low Inter-cycle Fluctuations
High Inter- and Intra-observer Reproducibility

16. Ovulation induction
ART situation

18. • Normo responder
• Poor responder
• Hyper responder

20. 2013

22. Ideal start….

24. New terminologies….
Less is more More is better
Less is more
More is better
Once and done

26. Fertility and Sterility® Vol.
107, No. 2, February 2017
Denis A. Vaughan M.D.
• CONCLUSION
• In this study we propose the concept of one-and-done, where a single cycle of COH to retrieve a maximal
number of oocytes could better serve couples. This approach, however, depends on each individual patient's
response to stimulation. In this study, approximately one in four couples could achieve two live births and
complete their theoretical nuclear family. The cohort of patients who do achieve two live births are ultimately
better-responding patients

27. Hyper responder
• Antagonist protocol
• Dose : 150- 225 IU
• Agonist trigger
• Freeze all
• Aim : Less complication

28. Normo responder
• Antagonist cycle
• R-fsh / HMG
• Dose : 150-225 iu
• Aim : Cumulative Preg

29. • Less is more
• More is better
• live birth rates (in fresh embryo transfer IVF cycles only) increased when up
to 11 oocytes were retrieved and then evened out.
• Cumulative live birth rates per oocyte retrieval (including fresh and all
subsequent frozen embryo transfer cycles) increased up to approximately
20 oocytes, but the incidence of severe OHSS increased significantly with
the number of oocytes retrieved, particularly if more than 18 oocytes were
retrieved.
• Patient discomfort, side effects, cumulative cycle outcomes and cost were
not addressed.

30. Poor responder
• Most enigmatic group
• Lot of research happening in this field
• Many unanswered questions

31. Optimal
fertility Declining
fertility End of
fertility Menopause
Irregular
cycles
Increasing Maternal Age Is Associated With Decline in Follicle
Number and Oocyte Quality
Klinkert ER, 2005 PhD Thesis University of Utrecht.
Number
of
follicles
Poor-quality
oocytes
(%)
107
106
105
104
103
102
25
50
75
100
0 10 20 30 40 50 60
Age (y)

32. Determinants of Declining Fertility With
Advancing Age in Women
• Declining oocyte number and
ovulatory disturbances
• Declining oocyte quality and
increasing chromosomal and genetic
mutations
• Luteal phase dysfunction
• Impaired fertilization rates
• Implantation failures
• Poor-quality embryos and genetic
abnormalities
• Impaired endometrial receptivity
• Higher incidence of age-related
gynecologic problems, including uterine
fibroids and polyps
• Declining sexuality
• Increased pregnancy wastage
• Early implantation failures and preclinical
losses
• Clinical losses
• Increased incidence of general medical
problems accompanying aging (eg, type
2 diabetes mellitus, hypertension)
• High incidence of obstetric complications
and poor
pregnancy outcomes
Pal. Endocrinol Metab Clin North Am. 2003;32:669.

33. •Quality of
oocyte
Age
•Quantity of
oocyte
Diminished
ovarian
reserve

37. 2011-2017
• The common belief in ‘the more oocytes, the better’, that was derived
from large cross-sectional studies.
• Sunkara et al., 2011; Drakopoulos et al., 2016; Polyzos et al., 2018
• But Now
• This require serious reconsideration

38. predicted low responders…
• High FSH dosage may increase the number of retrieved oocytes by, on
average, one to two more oocytes and substantially reduces the rate of
cycle cancellations for insufficient follicular growth
• (Youssef et al., 2016; van Tilborg et al., 2017b).
• But ….increase in oocyte number and reduction in cycle cancellation rate
do not actually improve the (cumulative) probability of a live birth.
• Recruiting the few oocytes that have the potential to fertilize and develop into a
competent embryo with a high implantation capacity therefore seems to be more
important than striving for a maximal response with additional oocytes that do not
fertilize or develop into good-quality embryos.

42. OPTIMIST trial- ‘one-size fits all’
• The OPTIMIST trial reported that individualized FSH doses (225/450
IU/day for predicted poor responders or 100 IU/day for predicted
hyper responders) for ovarian stimulation results in similar cumulative
livebirth rates (LBRs) when compared with a standard dose of FSH
(150 IU/day) in women undergoing their first IVF/ICSI cycle.
• (Oudshoorn et al., 2017)

45. AFC Criteria

52. Hum Reprod Open, Volume 2020, Issue 2, 2020, hoaa009, https://doi.org/10.1093/hropen/hoaa009
The content of this slide may be subject to copyright: please see the slide notes for details.
Figure 1 Schematic overview of the guideline ‘ovarian stimulation
for IVF/ICSI’. AMH: anti-Müllerian Hormone; AFC: ...

53. To sumup…

55. Take home messages…
• Age of the patient is one of the best predictor of success of biological
parenthood
• AFC and AMH are the best biomarkers to predict ovarian response to
ovarian stimulation.
• AMH will be the ovarian reserve test of choice for the future
• Biomarkers will help in – “True personalization” of ovarian
stimulation.

58. • ‘more is better’ (conventional protocol) versus ‘less is best’ (mild
protocol) approaches to ovarian stimulation.
• Both protocols are associated with benefits and challenges, and
physicians must consider the needs of the individual patient when
determining the best treatment options

59. New Mindset
i- COS
• Don’t think
• Hyper-stimulation..Think stimulation
• Think Preparing the Ovary for Egg Collection
• Normoresponder :Antagonist cycle with regular
dose
• Hyper responder: Antag with low dose,Freeze all
• One size fits all :needs validation
• Think Patient Oriented Treatment
• Always Minimise Trauma to Patients

60. Thank you