INDIVIDUALIZED IVF TREATMENT BY DR. JUDE E. OKOHUE MBBS, FWACS, FMCOG, DMAS, FICS, Cert (USS) GYNESCOPE SPECIALIST HOSPITAL PORT HARCOURT. +2348037275377 WWW.GYNESCOPESH.COM

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

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

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

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

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

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

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?

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)

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)

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

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

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

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

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)

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

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

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

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

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

Strategies Progesterone Estradiol Ascorbic acid Aspirin Prednisolone hCG Naxolone

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

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