1. INDIVIDUALIZED IVF TREATMENTBY
DR. JUDE E. OKOHUE
MBBS, FWACS, FMCOG, DMAS, FICS, Cert (USS)
GYNESCOPE SPECIALIST HOSPITAL
PORT HARCOURT.

2. INTRODUCTION
Louise Brown 1978
IVF technology has grown in leaps and bounds
Success rates have improved drastically
5 million babies delivered worldwide as at 2012 (ESHRE)
Success:
Innovations in ART laboratory
Optimized by applying an individualized patient directed approach especially in the mgt of women undergoing COH

3. Differences in body physiology and response to IVF medications
Prior to the first IVF cycle, it is sometimes difficult predicting the method(s) that suits the needs of any particular patient

5. Relevant Details Following A Prior IVF Cycle
Type of protocol used
Type/Number of Amps of stimulation drug
Number of days on controlled ovarian stimulation
Number of oocytes retrieved
Type of treatment (IVF/ICSI)
Number of eggs fertilized
Number of ET/Day of ET
Luteal phase support
Outcome

6. Strategies For Individualizing IVF Treatment
Individualizing IVF treatment should commence the moment the patient presents to the ART practitioner
History:
Helps build patients’ confidence
General and specific questions
History of abortion and previous surgeries
Azoospermic men/ STI
Children outside wedlock

7. Every practitioner develops his/her own skills
Patients depend on the dexterity of the practitioner in obtaining relevant information
Individualized physical examination
Same principle
Should not be considered as routine
Investigations
Retinue of investigations
Individualized to meet patients’ needs

8. Controlled Ovarian Stimulation
The most important component of individualized IVF treatment
Era of ovarian stimulation with gonadotropins commenced in the early 80’s
Key components for choosing the appropriate regimen for COH
Selection of the appropriate COH protocol and gonadotropin dosage
Close monitoring of follicular growth and serum estradiol levels

9. Adjustment of gonadotropin dosage to avoid hyper response and therefore OHSS
Individualized timing of hCG injection
Central Question: Will the woman have a good or poor response to gonadotropin stimulation?

10. Predictive Factors of Ovarian Response
Patient characteristics: Age, Parity, Reproductive history, BMI, Previous response to ART treatment
Endocrine markers of ovarian response: Day 2 or 3 FSH, AMH, Estradiol, Inhibin B
Ultrasonic markers: AFC, Ovarian volume, Ovarian blood flow
Dynamic evaluation of ovarian reserve: Clomiphene citrate challenge test, GnRH agonist stimulation test, Exogenous FSH ovarian test. (Limited predictive value – Maheshwani et al, 2009)

11. AMH and AFC are the most accurate predictors of ovarian response to COH (Broer S. C. et al, 2011)
Consistent serum levels throughout the menstrual cycle
Minimal cycle to cycle variability (Fanchin, 2005)
<0.99ng/ml = 100% sensitivity and 73% specificity in predicting poor response (Jayaprakason k. et al, 2010)

12. TREATMENT REGIMEN BASED ON PERCEIVED RESPONSE
Normal Responders
Favourable Prognostic factors
Age <35years
Normal BMI
Adequate ovarian reserve (day 2/3 FSH <10miu/ml, Estradiol <75pg/ml)
AFC between 6 and 10
Short duration of infertility
Previous live birth
Previous successful IVF

13. 2. High responders: Greatest risk is OHSS
Protocol: GnRH agonist short or long protocols GnRH antagonist protocols
2. High responders: Greatest risk is OHSS
Factors That Increase The Risk of OHSS:
Young age
PCO on USS (+ BCH evidence)
Previous OHSS
High dose of gonadotropins
Estradiol levels >3000pg/ml
Rapidly rising Estradiol levels

16. Protocols (Aim for 5 – 15 follicles)
GnRH antagonist protocol in combination with GnRH agonist ovulatory trigger. 1,500iu hCG after GnRH agonist trigger reduces OHSS (Humaidan P. et al, 2013)
OCP GnRH dual suppression protocol
Start with a small dose/few amps of gonadotropins
Stimulation drugs with very low LH in PCOS pt
Long GnRH agonist protocol (longer down regulation)
Coasting, reduce hCG dose, freezing, cancel Rx

17. 3. Poor Responders No universally acceptable definition
Prevalence: 10 – 25% (CDC, 2011)
Determinant Factors
Age > 40years
High FSH >10iu/l
AMH <1.1ng/ml
Previous cancelled cycles
Prolonged duration of COH
Increased daily and total gonadotropins (>44)
<3 to <5 oocytes retrieved

18. ESHRE consensus working group 2011, defined poor responders as having at least 2 of the following 3 features
Advanced maternal age > 40years or any other risk factor for diminished ovarian reserve
Previous history of poor ovarian response (<3 oocytes retrieved with conventional IVF)
Abnormal ovarian reserve test (AFC <5 or AMH < 1.1ng/ml)

20. Cryopreservation of embryos
Protocols
GnRH antagonist protocol
Co-flare and micro-flare protocols
Japanese Minimal Stimulation Protocol (Mini IVF)
Clomid on day 3
Low dose hMG days 8,10 and 12
GnRH agonist trigger
Cryopreservation of embryos
ET with natural cycle

21. Agonist/Antagonist conversion protocol
Can start with OCP
GnRH agonist after at least 10 days
Half dose (0.125mg) of GnRH antagonist when menses starts
Gonadotropin stimulation after a few days
Continue antagonist and stimulation drugs until hCG trigger.
DHEA

22. Timing and dose of hCG
Should be individualized based on the following:
Leading follicle diameter
Estradiol level
Prior cycle response and embryo quality
Type of COH protocol

23. Normal responders: >2 follicles reach 17mm or larger/estradiol level >400pg/ml for 5 days
Previous mostly immature oocytes: Allow leading follicles to reach 19 – 20mm
Clomiphene citrate or Letrozole COH protocols:
aim for 19 – 20mm
Previous poor oocytes or embryo quality especially with a high proportion of polyspermic fertilization: Suspect postmaturity and give hCG at smaller lead follicle diameter
Plateau or doubling estradiol on consecutive days with leading follicle >16mm: Give hCG

24. Luteal Phase Support
Stimulated IVF cycles are associated with LPD
No agreement regarding the optimal supplementation scheme (Faterini et al, 2006)
Lack of RCT on the issues of LPS and the causes of LPD

25. Strategies
Progesterone
Estradiol
Ascorbic acid
Aspirin
Prednisolone
hCG
Naxolone

26. SUMMARY Individualized IVF treatment optimizes success rate
While history, physical examination and investigations have roles to play in individualizing IVF treatment, the mainstay is individualized controlled ovarian stimulation
AFC and AMH are the most important predictors of ovarian response

27. Normal responders can use the long or short GnRH agonist or GnRH antagonist protocols
High responders benefit from GnRH antagonist protocol with GnRH agonist ovulation trigger as this reduces OHSS
While there is no universally acceptable definition of poor responders, the Japanese mini IVF shows promising results and should be further investigated