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29TH ANNUAL IN VITRO FERTILIZATION AND EMBRYO TRANSFER
“A COMPREHENSIVE UPDATE – 2016”
FOCUS SESSION – ALTERNATIVES TO FULL STIMULATION AND FRESH TRANSFER
WITH VITRIFICATION AND DEFERRED TRANSFER,IS CLOMIPHENE CITRATE THE NEW “NATURAL” CYCLE?
BILL YEE, M.D.
CLINICAL PROFESSOR DEPT OF OB/GYN
UNIVERSITY OF CALIFORNIA, IRVINE
POOR RESPONDERS/DEMINISHED OVARIAN RESERVE
POOR RESPONDERS/DEMINISHED OVARIAN RESERVE
2013 CDC NATIONAL ART SUMMARY
• 93,787 IVF STIMULATION STARTS
• 8,943 CYCLES WERE CANCELLED
• CANCELLATION RATE OF 9.5%
• ASSUMING A COST OF $5,000 PER CANCELLED CYCLE (DRUGS, ULTRASOUNDS, BLOODS)
• $44.5 MILLION DOLLARS SPENT ON CANCELLED CYCLE IN 2103
STIMULATION FOR POOR RESPONDERS• TRY A DIFFERENT STIMULATIONS PROTOCOL
NO BIRTH CONTROL PILLS/MIDLUTEAL ESTROGEN
SWITCH FROM AGONIST TO ANTAGONIST
MICRO OR MINI‐FLARE PROTOCOL
CLOMIPHENE WITH GONADOTROPINS
ADJUNCTS (ASA, GH, ANDRODERM, DEX)
• META‐ANALYSIS OF 22 RCT’S OF POOR RESPONDERS FOUND NO SIGNIFICANT INCREASE IN SUCCESS RATES WITH SUBSEQUENT CYCLES
• LAST RESORT, RECOMMEND DONOR EGGS OR ADOPTION
• HOWEVER, MANY COUPLES WANT A “CLOSURE” CYCLE BEFORE PROCEEDING WITH DONOR EGGS
CLOMIPHENE FOR POOR RESPONDERS• “A POOR RESPONDER WILL ALWAYS BE A POOR
RESPONDER”
• OUR APPROACH WITH THESE PATIENTS IS ENTIRELY DIFFERENT
• INSTEAD OF A LARGE AMOUNT OF MEDICATIONS TO STIMULATE MULTIPLE EGGS IN ONE CYCLE
• WE PERFORMED MULTIPLE RETRIEVALS INSTEAD, RECOVERING 1‐2 EGGS AT A TIME, AND FREEZE ALL RESULTING EMBRYOS
• FOLLOWED BY FET CYCLE AND TRANSFER ALL EMBRYOS IN A SINGLE TRANSFER
• STRATEGY – ACCUMULATION AND DEFERRED TRANSFER
WHY CLOMIPHENE ALONE??
• LOW PRICE (USD $100‐200 vs $5,000)
• IT IS AN ORAL MEDICATION
• WIDELY AVAILABLE, EASILY OBTAINED
• MORE EGGS THAN A NATURAL CYCLE
CLOMIPHENE CITRATE SUCCESS RATES
• TROUSON (1981) – LIVE BIRTH RATE OF 17% PER EMBRYO TRANSFER
• MARRS (1983) – PREGNANCY RATE OF 11% PER RETRIEVAL
• MacDOUGALL (1994) – RCT, ONGOING PREGNANCY RATE OF 13% PER CYCLE
• INGERSLEV (2001) – RCT, ONGOING PREGNANCY RATE 18% PER CYCLE
NORMAL RESPONDERS
WHY FREEZE AND BANK THESE EMBRYOS
• ANTI‐ESTROGENIC EFFECTS OF CLOMIPHENE ON THE ENDOMETRIUM SUPPORTED BY DATA FROM THE JAPANESE IVF REGISTRY
• EMOTIONAL AND PSYCHOLOGICAL TRAUMA OF LOW SUCCESS ASSOCIATED WITH A SINGLE EMBRYO BEING TRANSFER IN THIS GROUP OF PATIENTS WHO ARE POOR RESPONDERS
JAPAN SOCIETY OBSTETRICS AND GYNECOLOGY ‐2009 ART REGISTRY
STIMULATION CYCLES
NATURAL 12,124
CLOMIPHENE 19,926
FSH + CC 23,335
FSH 4,199
GnRH AGONIST 39,642
GnRH ANTAGONIST 21,413
OTHERS 7,777
TOTAL 128,416
JAPAN SOCIETY OBSTETRICS AND GYNECOLOGY ‐2009 ART REGISTRY
STIMULATION CYCLES
NATURAL 12,124
CLOMIPHENE 19,926
FSH + CC 23,335
FSH 4,199
GnRH AGONIST 39,642
GnRHANTAGONIST
21,413
OTHERS 7,777
TOTAL 128,416
JAPAN OBSTETRICS AND GYNECOLOGY 2009 ART RESULTS
DEFINITION OF POOR RESPONDERS
• PRIOR STIMULATED CYCLE (s) WITH 2 OR LESS EGGS RETRIEVED
• PRIOR STIMULATED CYCLE THAT WAS CANCELLED WITH LESS THAN 2 FOLLICLES
• ELEVATED FSH – 25mIU OR HIGHER
• MATERNAL AGE – 43 YEARS OLD OR GREATER
• AMH AND ANTRAL FOLLICLE COUNT WAS NOT USED
CLOMIPHENE ALONE PROTOCOL FOR POOR RESPONDERS
• CLOMIPHENE CITRATE 100 ‐ 150 mg FOR 5 DAYS, FROM CYCLE DAYS 5‐9
• ULTRASOUND MONITORING ALONE BEGINNING ON CYCLE DAY 12
• NO BLOOD TESTS ARE DONE• HCG, 10,000 IU AT FOLLICLE SIZE 18 mm OR WHEN URINE
LH IS POSITIVE• INDOMETHACIN 50 mg, TID ON DAY OF AND AFTER hCG• IF URINE LH IS POSITIVE, PATIENT IS SCANNED AGAIN THE
DAY AFTER HCG PRIOR TO THE O.R.• RETRIEVALS ARE AT 35 HOURS AFTER HCG
CLOMIPHENE ALONE PROTOCOL FOR POOR RESPONDERS
• ALL EGGS WERE EITHER INSEMINATED OR ICSI, AND EMBRYOS WERE VITRIFIED ON DAY 3
• PATIENTS HAD EITHER THREE RETRIEVALS OR HAVE THREE EMBRYOS VITRIFIED BEFORE FROZEN EMBRYO TRANSFER
• COST OF ONE COMPLETED CYCLE, WITH AN EMBRYO TO FREEZE, IS $5,000 ($5,500 WITH ICSI)
• THEREFORE, THE COST OF “THREE” COMPLETED CYCLES ($15,000) WAS EQUIVALENT TO “ONE” FULLY STIMULATED IVF CYCLE
CLOMIPHENE ALONE PROTOCOL FOR POOR RESPONDERS
• ALL EGGS WERE EITHER INSEMINATED OR ICSI, AND EMBRYOS WERE VITRIFIED ON DAY 3
• PATIENTS HAD EITHER THREE RETRIEVALS OR HAVE THREE EMBRYOS VITRIFED BEFORE FROZEN EMBRYO TRANSFER
• COST OF ONE COMPLETED CYCLE, WITH AN EMBRYO TO FREEZE, IS $5,000 ($5,500 WITH ICSI)
• THEREFORE, THE COST OF “THREE” COMPLETED CYCLES ($15,000) WAS EQUIVALENT TO “ONE” FULLY STIMULATED IVF CYCLE
CLOMIPHENE CITRATE FORPOOR RESPONDERS
• FROM JANUARY 2012 TO DECEMBER 2015
• 686 EGG RETRIEVALS FROM 407 PATIENTS
MEAN AGE – 41.4 YEARS OLD (32‐50)
MEAN FSH – 15.6 mIU (8‐86)
• 668 EGGS RETRIEVED
AVERAGE – 1.7 EGGS/RETRIEVAL
FROZEN EMBRYOS – 1.5/TRANSFER
ORAL AGENTS FOR POOR RESPONDERS
• AMONG THE 686 MINIMAL STIM RETRIEVAL CYCLES
CLOMID – 83.7%LETROZOLE – 16.3%
• MOST FREQUENT DOSE OF MEDSCLOMID – 100 mg (88.7%)LETROZOLE – 5 mg (84.0%)
MINIMAL STIM FOR POOR RESPONDERS
0
20
40
60
80
100
120
<35 35‐38 39‐40 41‐42 43‐44 >44
AGE
AGE
ORAL AGENTS FOR MINIMAL STIM
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
CLOMID LETROZOLE TOTAL
PREGNANCY RATE
ONGOING/DEL
SUCCESS RATES FOR POOR RESPONDERS USING MINIMAL STIM
0%
10%
20%
30%
40%
50%
60%
70%
<35 35‐38 39‐40 41‐42 43‐44 >44 TOTAL
PREGNANCY RATE
ONGOING/DEL
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%
<35 35‐38 39‐40 41‐42 43‐44 >44 total
MISCARRIAGE RATES FOR POOR RESPONDERS
AGE
ORAL AGENTS ALONE FOR POOR RESPONDERS
• THE CHANCE OF A BABY FROM A SINGLE RETRIEVAL IS 6%
• THE CHANCE OF A BABY WITH A DEFERRED TRANSFER IS 21%
• THE “OVERALL” CHANCE OF BABY WITH ANYPOOR RESPONDER IS 11%
• MUCH BETTER THAN THE 1% CHANCE WITH A NATURAL CYCLE IN “WOMEN OVER 40”
ORAL AGENTS ALONE FOR POOR RESPONDERS
• OUR DATA IS UNIQUE BECAUSE: JUST FOR POOR RESPONDERS
• UNLIKE OTHER “MINIMAL STIM” REPORTS ON POOR RESPONDERS, NO GONADOTROPINS WERE USED
• THERE NO OTHER LARGE SERIES ON POOR RESPONDERS USING CLOMIPHENE ALONE, ONLY FOR NORMAL RESPONDERS
WITH VITRIFICATION AND DEFERRED TRANSFER,IS CLOMIPHENE CITRATE THE NEW “NATURAL” CYCLE?
WITH VITRIFICATION AND DEFERRED TRANSFER,IS CLOMIPHENE CITRATE THE NEW “NATURAL” CYCLE?
YES ‐ AT LEAST FOR POOR RESPONDERS
