1. Gab Kovacs
International Medical Director, Monash IVF
Hawthorn Victoria, Australia
Declared speakers fees from MSD and Bayer; being a stakeholder in Monash IVF, ISIS
FERTILITY ACT
2. L1: In vitro fertilization and factors affecting success
Professor Gab Kovacs AM,
International Medical Director,
Monash IVF
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7. How to improve your ART
success rates?
• Based on an “Evidence Based Review”
• 48 Chapters- each written by a leading expert
• Written in late 2010
• Published by Cambridge University Press
8. Possible factors
• Patient preparation
• Stimulation Regimens
• Monitoring
• Laboratory aspects
• Embryo transfer
• Ancillary treatment
10. Patient preparation (1)- Hormonal
screening and Ultrasound
• AMH-
– predicts ovarian response
– Warns of likely OHSS
– Can be measured any time in cycle
• Thyroid screening
• Pelvic ultrasound
– Antral follicle count (AFC)
– Uterine abnormalities- fibroids, polyps, senechiae
11. Patient preparation (2)- surgery
• Hysteroscopy- If pathology suspected
• Fibroids-
– Submucous – Definite
– Intramural- Maybe
– Subserous- no
• Laparoscopy- not routinely
– If hydrosalpinges present
• Salpingectomy and tubal occlusion performed prior to
the IVF treatment improve subsequent pregnancy
rates
– Endometrioma/ Dermoids
• May be beneficial to remove
12. Patient preparation (3)-
Vitamins and other nutrients
• There is evidence on the effects of folic acid
and iodine supplementation preconception
and during pregnancy.
• There is limited evidence as to the effect of
other micronutrients on improving pregnancy
rates and obstetric outcomes.
13. Patient Preparation (4) Weight
control
• Thinness and obesity have a negative impact
on reproduction.
• Not just for getting pregnant but staying
pregnant and having a healthy child.
• Weight control and/or reduction will improve
chances of success
14. Patient preparation (5)-
Thrombophilia screening
• Haematological- suggested tests:
– Protein C, Protein S
– Antithrombin
– Lupus anticoagulant
– Anti Cardiolipinis
– Factor 5 Leyden
– Prothrombin Gene mutation
– Fasting homocysteine
– Full Blood Examination /platelet count
16. Patient preparation (7)
Immunological Screening :NK
Cells
• NK cells are lymphocytes with a CD3-CD56+ phenotypic profile
• produce cytokines (IFN-γ, TNF-β, IL-10, and GM-CSF).
• Can be tested in Blood or Endometrium-
– What is “normal”
• treatment with immune therapy (on an empirical basis) is not
necessarily confined to women with high NK cells
• No conclusive evidence for any benefit
17. Conclusion: Immunological/
Thrombophilia
• No good evidence that these factors are
significant
• No definite evidence that treatment of any of
these factors improves outcomes
• (steroids, anticoagulants, albumin, intralipid)
18. Patient Preparation (7)- Metformin in
PCOS
• The current evidence would support the use
of metformin as an adjunct to IVF treatment
– particularly in the context of the long agonist
protocol.
– as adjunct to the short antagonist protocol
requires further clarification.
• metformin may not necessarily improve the
„take home baby rate‟ but reduces the
incidence of moderate-severe OHSS
20. Stimulation Regimens
• No significant difference between Agonist and
Antagonist
• Marginal benefits for hMG vs rFSH
• Pretreatment with OC
– Benefits exceed disadvantages
21. Stimulation regimens- poor
responders
• DHEA-
• Limited evidence that DHEA may improve
oocyte numbers ?quality
• LH addback-
• Maybe some subgroups
• Growth Hormone
• Some evidence for benefit. RCT in progress
22. Rationale for using LH “add-back”
• FSH and LH both secreted in natural ovulatory cycle
• During natural menstrual cycles, FSH levels initially rise and
then, primarily under the influence of oestradiol, decline,
whereas LH is secreted in pulses, rising during the mid
follicular phase of the cycle.
• With the use of
– rFSH
– Agonist/antagonist protocols, levels of LH very low (<1.2IU/L)
23. Summary- role of LH addback
• In women with HH, it is generally accepted that LH supplementation is
needed for normal, healthy follicular development and oocyte
maturation.
• In a general population of normogonadotrophic women undergoing ART,
irrespective of whether a GnRH agonist or GnRH antagonist is co-
administered, the addition of r-hLH to treatment protocols does not
appear to provide any additional benefits.
• Subgroups of normogonadotrophic women who may receive benefit
from r-hLH supplementation for IVF and ICSI include the following:
– women aged ≥35 years and
– women who are hyporesponsive to FSH.
The latter group of women may be further identified by specific genetic
biomarkers that are currently being investigated.
25. Monitoring
• optimized by adopting an individualized, patient-
centred approach to COH.
• selection of
– appropriate COH protocol,
– close monitoring of follicle growth and serum E2 levels,
– adjustment of gonadotrophin dose to avoid hyper-response,
– individualized timing of hCG injection.
• This approach to IVF can
– improve oocyte and embryo quality, pregnancy and implantation rates,
– minimizes the risk of OHSS
26. Monitoring
• No evidence that intensive monitoring gives
better results than a “minimalist” approach
28. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Embryo selection
• Metabolomics
• Morphokinetics
–Assisted hatching
–PGD
29. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Embryo selection
• Metabolomics
• Morphokinetics
–Assisted hatching
–PGD
30. Sperm preparation
• Only use ICSI if indicated
• Use most viable, motile, functional
spermatozoa- IMSI Feldberg
• Discontinuous gradient centrifugation or a
new electrophoretic approach
• Select least damaged DNA containing
31. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Metabolomics
–morphokinetics
–Assisted hatching
–PGD
32. Addition of Co-factors
• Has the potential to improve the development of
zygotes to the blastocyst stage
• Might mimic the autocrine and paracrine factors
• Perhaps the use of microfluidic culture systems
would be more applicable
• Much research and controlled studies are required
before these co factors can be routinely used
33. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Embryo selection
• Metabolomics
• Morphokinetics
–Assisted hatching
–PGD
34. Embryo Transfer- cleavage or
blastocyst
• When laboratory conditions are not ideal, then it
would be more appropriate to place the embryos
into the uterus sooner than later.
• The available literature indicate that embryo
transfer on day 5 is associated with better
outcomes
• Day 5 ET the preferred option with increasing move
to single embryo transfer
35. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Embryo selection
• Metabolomics
• Morphokinetics
–Assisted hatching
–PGD
36. Metabolomics-
• a non-invasive assessment of embryo culture media
to aid in the prediction of embryo viability.
• determine more subtle embryo characteristics
• rapid metabolic or metabolomic assessment tool will
be part of the routine procedure used to select an
embryo for transfer.
37. • Theory: the differences between viable and sub-viable
embryos are reflected by metabolism activity.
• Take a small sample of the culture medium where the
embryo has been growing, and measure amino acids, etc.
38. • Eg: glucose, pyruvate, amino amino acids.
• Currently several methods being trialled to
measure these molecules. Most popular is
Near Infrared Spectoscopy (NIR).
• Expected time-frame for commercial
availability: 1-2 years.
39. Laboratory aspects
–Sperm preparation and selection
–Culture media and culture of embryos
–Extended culture
–Embryo selection
• Metabolomics
• Morphokinetics
–Assisted hatching
–PGD
43. Could time-lapse embryo imaging
reduce the need for biopsy and
PGS?
Swain JE. J Assist Reprod Genet. 2013 Jul 11.
Multiple morphologic endpoint assessments
and developmental timings and refinement
of modeling systems may improve the
predictive ability to determine embryonic
aneuploidy.
44. Possible factors
• Patient preparation
• Stimulation Regimens
• Monitoring
• Laboratory aspects
• Embryo transfer
• Ancillary treatment
45. Embryo transfer
• Dummy transfer beneficial
• Position-mid fundus
• Ultrasound monitoring
• Catheter soft but malleable
• Bed rest- no help
• Intercourse may help
48. Immunological/ Thrombophilia
• The best randomized controlled trials do not
support the use of heparin and aspirin in aPL
positive patients with IVF failure.
49. Hormone Supplements
• On the basis of the currently best available
evidence:
• The addition of E2 supplementation in the
luteal phase does not improve IVF outcomes in
long protocol/antagonist cycles.
– excluding antagonist trigger
50. Prednisolone
• Normal IVF patients do not significantly
improve their chances of pregnancy when
subjected to additional glucocorticoid
treatment in the IVF cycle.
• In patients who present a previous
autoimmune pathology and in whom it does
seem that corticoid treatment might be
beneficial.
