1. The modern approach in ARTThe modern approach in ART
today and tomorrowtoday and tomorrow
Daniel S. Seidman, MDDaniel S. Seidman, MD
Department of Ob/GynDepartment of Ob/Gyn
Sheba Medical CenterSheba Medical Center
Sackler School of MedicineSackler School of Medicine
Tel-Aviv UniversityTel-Aviv University
5. The most common IVFThe most common IVF
StrategyStrategy
•Historically, to compensate for low rates
of implantation for individual embryos
and achieve ‘‘acceptable’’ pregnancy
rates, multiple embryos have been
transferred to the majority of IVF
patients.
Fert Steril 2012;97:835–42
8. Elective single-ET
vs. double-ET in IVF
• Patients were randomized to eSET or DET.
• The ongoing pregnancy rates
• eSET 28%
• DET 43%
(RR 0.64; P<.001)
N Engl J Med 2004;351:2392–402
Twins 1%
Twins 30%
13. Why should we avoid Twins?
• 8% Delivery <32 wk
• 10.5% Neonates <1,500 g
• Risk of at least one handicapped
child is: ~1 in 13 pairs of twins
14. New IVF StrategyNew IVF Strategy
•Advocated as the only effective
means to avoid multiple pregnancy
in IVF cycles
15. Elective SET is defined in the SART
reporting guidelines as:
• ‘‘an embryo transfer in which more than
one high-quality embryo exists but it was
decided to transfer only one embryo.’’
18. eSET strategy ineffective?
•By reducing pregnancy chances and
eliminating second twins, a rigorous eSET
program eliminates approximately one-
third of potential newborns.
19.
20. Incorrect statistics
• Based on incorrect statistical
methodology, twins after IVF have come
under attack as “adverse” outcomes.
• The correct study should compare one
twin pregnancy to two consecutive
singleton pregnancies.
21. Elective Single Embryo
Transfer
(eSET(
• USA ~10%
• Europe 20%
• Slovenia 30%
• Denmark 33%
• Japan 46%
• Belgium 48%
• Finland 50%
• Australia and New Zealand 57%
• Sweden 69%
24. What determines eSET rates?
• Cost - Is IVF coverage mandated
• Patient populations
• Legislation
• Guideline recommendations
• Culture
25. In 2010, eSET comprised 5.6% of
all fresh transfers, representing an
eightfold increase since
publication of first guidelines in
2004 recommending eSET.
27. Proportions of transfers of one, two, three, or four or more
embryos among all IVF cycles performed in the USA, 1999–
2008.
Practice Committee. eSET. Fertil Steril 2012
Major Strategy: DET
28. Proportions of all liveborn children resulting from
ART in the USA that were members of multiple
births
Practice Committee. eSET. Fertil Steril 2012
Major Strategy: DET
Many Twins -> Fewer Triplets
29.
30. Cost of eSET per deliveryCost of eSET per delivery
ImmediateImmediate
CostCost
•Higher
Long-termLong-term
CostCost
•Lower ?
Hum Reprod 2006;21:2090–7
31. Cost of multiple birthsCost of multiple births
ImmediateImmediate
CostCost
•Maternal
hospitalization
•Neonatal intensive care
Long-termLong-term
CostCost
•Chronic illness
•Rehabilitation
•Special education
32. LIMITING RESOURCES TO ART
PHYSICIANS PATIENTS
Higher competition Increased pressure
among ART clinics for immediate
success
Demand for higher pregnancy rates
Higher number of embryos transferred
More multifetal pregnancies
33. MORE RESOURCES TO ART
PHYSICIANS PATIENTS
Less competition Less pressure
for immediate
success
More cauation
More eSET
Fewer multifetal pregnancies
35. Elective single-ET + FET
vs. double-ET in IVF
• Patients were randomized to eSET+FET or DET.
• The ongoing pregnancy rates
• DET 43% Twins 30%
• eSET 28% Twins 1%
(RR 0.64; P<.001)
• eSET+FET 39% (RR 0.90; P=.30)
N Engl J Med 2004;351:2392–402
36. Potential disadvantages of
eSET + FET
•Need for good cryopreservation program
•Not all thawed embryos survive
•Demands two ET procedures
•Additional costs
37. New Strategy:
Single Blastocyst transfer
• Patients were randomized to eSET or DET.
• The ongoing pregnancy rates (RR 0.80; P=NS):
• eSET 61%
• DET 76%
Fertil Steril 2004;81:551–5
Twins 0%
Twins 47%
38. Potential disadvantages of
Blastocyst transfer
•Monozygotic twin rate 2–5-fold higher
•Increased risks of epigenetic mutations in
offspring
•Increased risk for adverse neonatal
outcomes compared with children
conceived naturally
(OR 1.53, 95% CI 1.23–1.90)
•Higher lab costs
Fertil Steril 2010;94:1680–3
39. Time for a new embryo
transfer strategy?
Fertil Steril 2011; 95:1691-5
40. Blastocyst-stage embryos on day
5
Before
vitrification
0 hours after
warming
16 hours after
warming,
fully hatched
42. Conclusion(s(
• Vitrified-warmed BT cycles resulted in
statistically significantly higher CPR and IR
compared with fresh BT cycles.
• A new embryo transfer strategy is therefore
proposed whereby fresh BT would be avoided
in the initial ovarian stimulation cycle.
• Instead, all the patient’s available blastocysts
would be vitrified-warmed and transferred in
subsequent cycles.
43. NEW METHODS FOR EMBRYONEW METHODS FOR EMBRYO
SELECTIONSELECTION
• Traditionally, human eggs fertilized in vitro are
selected for implantation based on visual
assessments of embryonic fitness made at any
of three developmental checkpoints: days 1, 2
or 3, and 5
52. •Proton NMR spectroscopy identified
implantation/pregnancy with a sensitivity
of 88.2% and a specificity of 88.2%
53. • Raman spectral
analysis of culture
media segregates
embryos that
implanted and led to
delivery (red) and
those that did not
implant (blue).
Metabolomic analysis
of embryo culture media
70. Eeva (Early Embryo Viability Assessment), in
combination with D3 morphology
significantly improved their ability to
identify embryos that would reach the
usable blastocyst stage
72. Embryoscope
• Time-lapse enabled assessment
- Dynamic observation for better decision
• Constant surveillance of all embryos
- Undisturbed culture in stable environment
• Flexible evaluation
- Do it when you want, never miss anything
• Complete 4D documentation
- Knowledge building through retrospective analysis
81. The three classes of aneuploidy risk (low,
medium and high) based on time from
insemination to a full blastocoele
blastocyst has not yet started expansion (tB)
hpi = hours post insemination
time from
insemination to
start of
blastulation
(tSB).
89. Representative aCGH data obtained from
human blastocysts via trophectoderm
biopsy performed on post-fertilization day 5
normal
chromosomal
status (46,XX)
abnormal
chromosomal
status (45,XY,-12)
90. Detail of aCGH results derived
from aneuploid blastocysts
(n = 191) in Group A
91. Comparison of laboratory findings and clinical
outcome among IVF patients undergoing SET with
embryo assessment by aCGH + morphology (Group
A) and blastocyst morphology alone (Group B(
92. Conclusion
• The observed discordance between ploidy
status and morphology means embryo
selection without the benefit of information
gained from aCGH would allow the transfer of
a reproductively incompetent—albeit
morphologically normal—embryo.
93.
94. OBJECTIVE
•To determine whether blastocyst biopsy
and rapid quantitative real-time
polymerase chain reaction (qPCR)-based
comprehensive chromosome screening
(CCS) improves in vitro fertilization (IVF)
implantation and delivery rates.
96. • Objective: To determine whether performing
comprehensive chromosome screening (CCS) and
transferring a single euploid blastocyst can result
in an ongoing pregnancy rate that is equivalent to
transferring two untested blastocysts while
reducing the risk of multiple gestation.
97.
98.
99.
100.
101.
102. • IVF patients should be counseled that the
benefits of aCGH screening will likely come at
the cost of sharply limiting the number of
surplus embryos available for
cryopreservation.
106. "The work of Palini and co-workers is
provocative and fascinating for it raises the
possibility of a new era in diagnosis of genetic
abnormalities in preimplantation embryos."
Jacques Cohen
Gedis Grudzinskas
Martin H. Johnson
108. Period of imaging in Cambell et a., 2013
(1 frame every 1 min)
Optimal IVF Strategy?
109. Better embryo selection
strategies?
• Screening for chromosomal abnormalities
(nuclear component )
• Pronuclear morphology
• PGD / PGS
• NIPGD (?)
• Analyzing the quality of embryo metabolism, the
cytoskeleton or Ca2+ homeostasis
(cytoplasmic component)
• Analysis of metabolites
• Secreted proteins
• Cytoplasmic flows
110. Better embryo selection
strategies?
• Following the timing of embryonic cell
divisions, duration and synchrony affected by
• Improper chromosome segregation
• Cytoskeletal properties
• Energy levels
• Quick diagnosis, Combination of
• Genetic testing of the polar body
• Examination of the cytoplasmic flows
113. Non-invasive method devised
to sequence DNA of human
eggs• For the first time determined the genome sequence of human
egg cells without destroying them.
• Amplified the DNA they contained using a technique called
multiple annealing and looping-based amplification cycles
(MALBAC).
• The polar bodies and pronucleus together contain four copies
of each of a woman’s genes — two from each of her father and
her mother.
• The team showed that it could use the genetic sequence of the
polar bodies to accurately predict the genetic sequence of the
pronucleus, by counting which three versions of a gene were
contained among the polar bodies and thus deducing which
version of the gene must be represented in the pronucleus.
114.
115.
116.
117. Non-invasive method devised
to sequence DNA of human
eggs• The genome of the oocyte pronucleus,
including information regarding aneuploidy
and SNPs in disease-associated alleles, can be
accurately deduced from the genomes of PB1
and PB2.
• The MALBAC-based preimplantation genomic
screening in in vitro fertilization (IVF) enables
accurate and cost-effective selection of normal
fertilized eggs for embryo transfer.
118.
119.
120. • Single-cell genome analyses of human oocytes are important for
meiosis research and preimplantation genomic screening.
• However, the nonuniformity of single-cell whole-genome amplification
hindered its use.
• Hou e al. demonstrated genome analyses of single human oocytes
using multiple annealing and looping-based amplification cycle
(MALBAC)-based sequencing technology.
• By sequencing the triads of the first and second polar bodies (PB1 and
PB2) and the oocyte pronuclei from same female egg donors, we
phase the genomes of these donors with detected SNPs and
determine the crossover maps of their oocytes.
121.
122. CONCLUSION(S):
•Blastocyst biopsy with rapid qPCR-based
comprehensive chromosomal screening
results in statistically significantly
improved IVF outcomes, as evidenced by
meaningful increases in sustained
implantation and delivery rates.
123. Incidence (%) of major maternal
complications in multiple
pregnancies
125. Couples should be educatedCouples should be educated
according to HFEA that:according to HFEA that:
The chance of loosing each baby is:
•1 in 113 in singleton pregnancies
•1 in 21 in twin pregnancies
•1 in 12 for triplet pregnancies
The risk of at least one handicapped child is:
• ~1 in 13 pairs of twins
• 1 in 4.5 sets of triplets
126. Embryo Transfer Trends :US v. Australia/NZ
Single Embryo Transfers Two Embryo Transfers
Three+ Embryo Transfers
127.
128. Multiple pregnancies should not
be considered IVF success?!
• Maternal bonding impaired
• “Domestic overload”
• Social isolation
• Continual physical exhaustion
• Marital disharmony
• Psychological problems, depression
• Emotional stress
129. SELECTIVE FETAL
REDUCTION
• Emotional, Ethical, Legal, and Religious
Objections
• Risk of loosing all fetuses after this
procedure ~10%, with associated
adverse psychological consequences
for the couples.
130. Conclusions:
Need How to improve our pregnancy rates
Most common strategy -> transfer more
embryos
Adverse outcome: Multiple births
New Strategy -> eSET
DET better results
Need to improve embryo selection
132. RESULT(S(:
•We transferred 134 blastocysts to 72
patients in the study (CCS) group and 163
blastocysts to 83 patients in the routine
care (control) group.
•Sustained implantation rates (probability
that an embryo will implant and progress
to delivery) were statistically significantly
higher in the CCS group (89 of 134; 66.4%)
compared with those from the control
group (78 of 163; 47.9%).
133. RESULT(S(:
•61 of 72 treatment cycles using CCS led to
delivery (84.7%)
•56 of 83 (67.5%) control cycles ultimately
delivered.
134. Clinical implantation rates are
statistically significantly higher in
embryos that have undergone CCS
(P=.01).
135. Embryos selected after CCS are also
statistically significantly more likely to
progress to delivery than unscreened
embryos from the control
group (P=.01).
136. • The desire to achieve a higher per transfer pregnancy rate.
• The education of both clinicians and patients on the health and wider
societal benefits of eSET.
• The availability of health insurance coverage for IVF sufficient to
permit repeated attempts at fresh and frozen ET.
• The economic pressure on patients restricting the number of ART
cycles that they can attempt.
• The availability of effective cryopreservation protocols.
• Potential commercial competition among IVF programs to achieve
the highest fresh embryo transfer delivery rates.
• Other socioeconomic, cultural, and religious factors.
137. For which patients is the eSET
strategy best?
• Most beneficial when selectively applied according
to patient characteristics and embryo quality.
• Most appropriate for those with a good prognosis:
• age <35 years
• >1 top-quality embryo available for transfer
• first or second treatment cycle
• previous successful IVF
• recipient of embryos from donated eggs.
138. How can we offer eSET for
poor prognosis patients?
• Better embryo selection
• Blastocyst
• Embryoscope
• CGH
139.
140.
141. • Arch Gynecol Obstet. 2012 Sep;286(3):755-61. doi: 10.1007/s00404-
012-2396-1. Epub 2012 Jun 8.
• Comprehensive genetic assessment of the human embryo: can
empiric application of microarray comparative genomic hybridization
reduce multiple gestation rate by single fresh blastocyst transfer?
• Sills ES, Yang Z, Walsh DJ, Salem SA.
• Source
• Reproductive Research Division, Pacific Reproductive Center, Orange
County, 10 Post, Irvine, CA 92618, USA. dr.sills@prc-ivf.com
• Abstract
• PURPOSE:
• The unacceptable multiple gestation rate currently associated with in
vitro fertilization (IVF) would be substantially alleviated if the routine
practice of transferring more than one embryo were reconsidered.
142. New IVF StrategyNew IVF Strategy
• As implantation rates have improved, the
practice of transferring multiple embryos must
be reassessed.
• How to maximize the efficacy of eSET and
improve its acceptability and utilization among
clinicians and patients remains a challenge!
Fert Steril 2012;97:835–42
143.
144. •Owing to the high risk of multiple gestation with SO in ovulatory
•women, moving directly from CC-IUI to IVF should
•be considered
145. Patient(s(:
•A total of 886,686 fresh, nondonor cycles
reported to the National Assisted
Reproductive Technology Surveillance
System during 1999–2010, of which
17,166 met criteria for elective single ET.
146. Trends in the proportion of elective single
ET (eSET) among all fresh, nondonor
transfers, overall and stratified by age—
United States, 1999–2010.
For all trends, P<.001
147. ARTART Birth Order TrendsBirth Order Trends
• Singleton: ↑24%
• Twin: Unchanged
• Higher-order: ↓77%
Higher-Order
Twin
Singleton
E. Adashi, June, 2013
148. Embryo Transfer Trends
Embryo Transfer Fractions
•SETs: 5→18%
•DETs: 12 →55%
•3+ETs: 83 →27%
SETs
DETs
3+ ETs
E. Adashi, June, 2013
149. Result(s(:
•Compared with other ETs, elective single
ETs were nearly twice as likely to result in
a good perinatal outcome
• 37.1% vs. 18.9%, respectively
•Among women using elective single ET,
those aged <35 and 35–37 years had a
good perinatal outcome
• 40.2% and 32.5%, respectively
160. background
•A selective switch to elective single
embryo transfer (eSET) in IVF has been
suggested to prevent complications of
fertility treatment for both mother and
infants.
•We compared seven IVF strategies
concerning their cost-effectiveness using
a Markov model.
161. methods
•The model was based on a three IVF-
attempts time horizon and a societal
perspective using real world strategies
and data, comparing seven IVF strategies,
concerning costs, live births and
incremental cost-effectiveness ratios
(ICERs).
162. results
• In order to increase pregnancy probability, one cycle
of eSET one cycle of standard treatment policy [STP,
i.e. eSET in patients ,38 years of age with at least one
good quality embryo and double embryo transfer
(DET) in the remainder of patients] one
• cycle of DET have an ICER of E16 593 compared with
three cycles of eSET. Furthermore, three STP cycles
have an ICER of E17 636 compared
• with one cycle of eSET one cycle of STP one cycle of
DET, and three DET cycles have an ICER of E26 729
compared with three cycles STP.
163.
164.
165. Possible advantages of
double intrauterine
insemination
• Larger fertilization period in a non-synchronized cycle
• Longer exposure time for cycles deprived of additional intercourse
• Increased total sperm quantity introduced to the ovulating eggs
• Compensation for inferior survival rates of semen in hostile
environment
166. Possible disadvantage of
double intrauterine
insemination
• Larger fertilization period in a non-synchronized cycle
• Longer exposure time for cycles deprived of additional intercourse
• Increased total sperm quantity introduced to the ovulating eggs
• Compensation for inferior survival rates of semen in hostile
environment
167. How to improve our pregnancy rates
Cheapest transfer more embryos
Short term, but long term
Multiple births cost – prematurity
one embryo law turkey
Selection of embryos – Double transfer BLT
selection, embryoscope, GCS
More treatments
Who will pay we are paid not for pregnancy but for
treatment cycle
Less pressure? New registry?
Budget IVF
179. Who should control the desire of infertile
couples for a multiple pregnancy ?
LEGAL
REGULATION
PATIENT SOCIETAL
AUTONOMY INTERESTS
THE PHYSICIAN
180. How many embryos should beHow many embryos should be
transferred to avoid multiple pregnancy?transferred to avoid multiple pregnancy?
• The Law
• The Guidelines
• The Experts
181. HIGH COSTS RELATED TO
MULTIFETAL PREGNANCIES
LIMITING RESOURCES TO A.R.T.
182.
183.
184.
185. Total direct medical cost of selected chronic by
sex, Maccabi Healthcare Services 2006 (in
internal cost units)
191. SERVICES OFFERED
• Prenatal Genetic Diagnosis (PGD)
• Determining the sex of the baby
• Choosing the characteristics of baby ?!
• ”Designer Babies”
192.
193. •Who will pay for the new
technologies if the savings are only
long term?
194. New registry
•Will the IVF Units with lowest results
receive more funds or will they be closed
down?
195. TO THE PATIENT:TO THE PATIENT:
• Failure is defined as a negative pregnancy
test
• Surveys show patients overwhelmingly
desire multiple gestations !
Hojgaard et al., 2007
196. TO THE PHYSICIAN:TO THE PHYSICIAN:
• Live birth rate remains the overriding index of clinical excellence !?
• More aware of increased perinatal morbidity and mortality associated
with multiple births.
197. TO THE PATIENT:TO THE PATIENT:
• Failure is defined as a negative pregnancy
test
• Surveys show patients overwhelmingly
desire multiple gestations
208. After 7 years………
trying to conceive through IVF:
• How many ?
• Fulfill their dream
• Spontaneously conceive
• Forgive parenthood
• Choose to adopt
• Divorce
215. Select √ to transfer, * to
freezer and X to discard,
changes by way of colour
coding are
reflected on the
EmbryoScope screen for
the embryologist.
ביותר הטובים העוברים בחירת
זמנית בו עוברים מספר בין השוואה
העוברים דרוג
להחזרה -
הקפאה -
השמדה -
219. Karlström u. Bergh, HumRep 22: 2007
Birth rate and MBR in relation to the percentage of SET
and triple embryo transfer (TET) in Sweden 1991–2004
220. Karlström u. Bergh, HumRep 22: 2007
Birth per embryo transfer(%(
and MBR in Sweden and USA
221. §1,Abs. 1, Nr. 5
„a person fertilizing more oocytes
than he or she intends to tranfer in
the course of one treatment cycle“
§1,Abs. 1, Nr. 3
„a person transfering more than
3embryos to the womb in the
course of one treatment cycle“
Prison sentence up to three
years or financial penalty for
222. Preimplantation genetic screening (PGS)
University of Brussels
Inclusion criteria:
• 37 yrs and older
• prospective randomized controlled study
• examined chromosomes: X, Y, 13, 18, 21
223. Results PG-Screening
University of Brussels
Preimplantation genetic screening (PGS) control
Patients 86 82
Embryo transfer 48 (55%) 70 (85%)
Abnormal embryos 20
Pregnancies per embryo transfer 10 (20.9%) 18 (26.5%)
No of embryos per ET 2.1 (100) 3.1 (210)
Implantation rate per embryo 10% 8%
Devroey, 2006
224. Conclusion of the Brussels study:
A positive effect of PGS on implantation and
abortion rate of this study and others is not clearly
documented.
226. Clin. pregnancies / ET
after cryo transfer
(1996-2004)
Cryo transfer 67,257
Clin. pregnancy / ET 15.5 %
Abortion rate after cryo transfer 21.64 %
German IVF Index 2004
227.
228. after Kuwayama, RBM-online 2005, pp.300-308
a. Polypropylen strip
b. Hartplastik-Griffstück
dSchutz für LN2 Lagerung
c. Hartplastik-Schutzhülle
Cryotop for vitrification
231. פריון אי זה ?מה
•הגדרה של עניין
•?מחלה זו האם
The American Society of Reproductive
Medicine (ASRM) has defined infertility
to be “a disease of the reproductive system.”
250. PREVALENCE OF INFERTILITY BY AGE
0
5
10
15
20
25
30
15-19 20-24 25-29 30-34 35-39 40-44
Age (years(
Infertile (%(
(Menken J, Science 1986;223:1389)
251. WHY IS AGING AND REPRODUCTION A
GROWING CONCERN?
• Deferment of marriage
• Postponement of pregnancy in marriage
• Divorce and remarriage
Delayed age of childbearing
259. IVF IN ISRAEL
• How Much ?
• How Well ?
• The Effect of Age
• Micromanipulation
• International Comparisons
260. Why is it good to be an IVF
specialist in Israel?
261. IVF/ICSI Centers
per million population
• Pakistan 0.01
• China 0.02
• India 0.04
• Egypt 0.45
• Germany 1.22
• USA 1.31
• France 2.39
• Israel 3.68
Collins JA, Hum Reprod Upd
8;265, 2002
262. IVF/ICSI Cycles per Million
Population per Annum
• Pakistan 4
• China 5
• India 11
• Egypt 13
• Germany 417
• USA 126
• France 610
• Israel 1657
Collins JA, Hum Reprod Upd
8;265, 2002
264. ISRAEL NATIONAL IVF REGISTRY
• ADVANTAGES
• Continuous reporting since 1989
• Very high compliance
• No direct cost
• Data reported by age
• ART data available (GIFT, ZIFT,
SUZI, ICSI)
265. ISRAEL NATIONAL IVF REGISTRY
• LIMITATIONS
• No validation
• Chemical Vs. Clinical pregnancies
• Reporting not complete
• Data NOT reported according to etiology, ovulation
protocol
• No perinatal outcome data
• No data on multiple gestations
266.
267.
268.
269.
270.
271.
272.
273.
274. ISRAEL NATIONAL IVF REGISTRY
• 23 Centers Reporting
• Up to 2006
• 253,613 Treatment Cycles
• 48,554 Live Deliveries
277. IVF RESULTS IN ISRAELI CENTERS
Deliveries per Retrieval
0
4
8
12
16
278. IVF RESULTS BY NUMBER OF CYCLES PER
YEAR
Deliveries per Retrieval
0
4
8
12
16
>300 300
- 500
500
- 999
>1000No. of
Cycles:
%
279.
280.
281.
282. ENDEND TIDAL CARBON MONOXIDE MEASUREMENT INTIDAL CARBON MONOXIDE MEASUREMENT IN
PREGNANT WOMEN:PREGNANT WOMEN:
OBSERVATIONS AND POSSIBLE CLINICALOBSERVATIONS AND POSSIBLE CLINICAL
APPLICATIONSAPPLICATIONS
Israel Hendler, MDIsrael Hendler, MD
Dept. of Ob/Gyn, Sheba Medical Center, Tel-
Hashomer, Tel-Aviv University.
www.baby4u.co.il
283. ARE IVF RESULTS IMPROVING ?
0
4
8
12
16
20
24
28 Up to 1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
%
Pregnancies per Transfer
284. ARE IVF RESULTS IMPROVING ?
0
4
8
12
16
Up to 1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
%
Deliveries per Treatment
285. HOW DO WE AVOID MULTIPLE
GESTATION?
• Judicious use of ovulatory agents
• Limit number of embryos transferred
• Improve quality selection criteria of the
embryos
• Better in-vitro embryo culture
• Improve cryopreservation
286. DONOR AND CRYOPRESERVED OOCYTES
1990-94
NO. Deliveries per
Cycles Transfer
Israel USA
DONOR 2515 12.4% 33.7%
CRYO 2864 7.4% 15.6%
287. WHY DO ISRAELI IVF RESULTS
DIFFER FROM INTERNATIONAL
DATA ?
• Lower Skill (?!)
• Selection Bias
288. SELECTION BIAS
• Different eligibility criteria
• Distinct infertility subpopulations
• Age limit
• “End Stage” infertility
• Dropout population
• Physician decision
• Availability
• Financial constraints
289. NUMBER OF CYCLES BY
WOMEN’S AGE 19945705
2280
1369
70
0
2000
4000
6000 >36
36-40
41-45
>45
290. PREGNANCY PER RETRIEVAL BY
WOMEN’S AGE 199418.7
8
5.8
17.3
0
5
10
15
20 >36
36-39
40-44
>45
%
297. CURRENT NUMBER OF USA IVF CYCLES
Vs. ISRAELI RATES
Current
Israeli
Rate
298.
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309. THE FUTURE OF THE ISRAELI
IVF REGISTRY
• Prospective registering of results to a
centralized computerized data
collection facility
• Individual patient cycle specific data
• Complete reporting of all patient
characteristics (age, etiology,
induction protocol, etc.)
• Complete follow-up of pregnancy outcome
310.
311. PREGNANCY RATE BY NUMBER OF
EMBRYOS TRANSFERRED
8.4
20.2
26.6
0
5
10
15
20
25
1
2
3
%
HFEA 1997
312. HIGH-ORDER PREGNANCY RATE BY NUMBER OF
EMBRYOS TRANSFERRED
1.1
0.2
5.8
0
1
2
3
4
5
1
2
3
%
HFEA 1997
313. PERINATAL MORTALITY (per 1000) BY
SINGLE AND MULTIPLE BIRTHS
8.8
46.8
82.6
0
15
30
45
60
75 Single
(4782)
Twins
(1678)
Triplet
(255)
%
HFEA 1997
314. Determinants of Preterm rates in Canada
from 1981 through 1983 and from 1992
through 1994
•“The recent increase in preterm births
in Canada is largely attributable to
changes in the frequency of multiple
births….”
Joseph et al., N Engl J Med, Nov. 1998
315. Gestational age for all live births
in Canada
Joseph et al., N Engl J Med, Nov. 1998
Live Births 1981-3 1992-4
Singletons 577,013 555,351
39.4 ± 1.9w 39.2 ± 1.9w
Twins 10,725 11,769
36.5 ± 3.5w 35.8 ± 3.3w
Triplets 240 366
32.9 ± 3.9w 32.2 ± 3.3w
316. MULTIFETAL PREGNACIES IN IVF
CYCLES IN ISRAEL
1994 (n=866)
Singletons 72.4%
Twins 18.6%
Triplets 7.2%
Quadruplets 1.3%
Quintuplets 0.2%
317. HAS THE RATE OF MULTIPLE
GESTATIONS AFTER IVF INCREASED
IN ISRAEL?18.7 18.6
4.6
7.2
0.3
1.3
0
5
10
15
20
Twins Triplets Quadruplets
Israel
1982-
89
Israel
1994
%
318. HOW DOES ISRAEL COMPARE WITH
THE WORLD
18.6
24.7
29.6
7.2
4.1
6.4
0
5
10
15
20
25
30
Twins Triplets
Israel 1994
World
Collab. 1997
ASRM 1998
%
319. HOW MANY EMBRYOS SHOULD BEHOW MANY EMBRYOS SHOULD BE
TRANSFERRED TO AVOID MULTIPLETRANSFERRED TO AVOID MULTIPLE
PREGANACY?PREGANACY?
• The Law
• The Guidelines
• The Experts
320. WHAT DOES THE LAW SAY?
• In the UK there is legal restriction
which limits the number of embryos
transferred to a maximum of three
• In the USA and Israel there is no such
legal limit
321. WHAT ARE THE GUIDELINES?
• Israeli Ministry of Health guidelines limit
the number of embryos transferred to
three, or in exceptional cases, four
• ESHRE (1998) recommended transfer of
either two or three embryos depending on
female age
322. WHAT ARE THE GUIDELINES?
ASR Practice Committee Guidelines on number of embryos
transferred 1998
• Above average prognosis (e.g. age <35y) transfer no more
than three
• Average prognosis (e.g. age 35-40y) transfer no more
than four embryos
• Below average prognosis (e.g. age >40y or multiple failed
cycles) transfer no more than five embryos
323. WHAT DO THE EXPERTS SAY?
“Transfer 1 embryo”Without
selective single
embryo transfer
Selective
single
embryo
transfer
Pregnancy
Rate
30% 26%
Twins 24% 13%
Triplets 4% 2%
Coustier & Dhont, Hum Reprod, Oct., 1998
324. WHAT DO THE EXPERTS SAY?
“Transfer 2 embryos”
• “When more than four eggs were fertilized there was no
increase in the birth rate for women receiving three
transferred embryos compared with those receiving
two, but there was a considerable increase in the rate of
multiple births when three were transferred (O.R.1.6;
C.I. 1.5-1.8)” Templeton &
Morris, N Engl J Med, Aug 1998
325. WHAT DO THE EXPERTS SAY? “Transfer
more than 2 embryos”
• Most couples feel that twins would be an
ideal outcome of IVF treatment
(Murdoch, Hum Reprod, Feb.,1997)
• Possibility of relying on the “escape route”
or “safety net” of selective fetal reduction
(Murdoch, Hum Reprod, Oct., 1998)
326. WHAT DO THE EXPERTS SAY?
“Transfer more than 4 embryos”
• Compensate for predictors of poor
outcome:
Women’s age
Cause & duration of infertility
Number of ART cycle
Embryo morphology
Frozen/thawed embryos
327. HOW MANY EMBRYOS SHOULD BEHOW MANY EMBRYOS SHOULD BE
TRANSFERRED TO AVOID MULTIPLETRANSFERRED TO AVOID MULTIPLE
PREGANACY?PREGANACY?
• The Law
• The Guidelines
• The Experts
328. WHAT DOES THE LAW SAY?
• In the UK there is legal restriction
which limits the number of embryos
transferred to a maximum of three
• In the USA and Israel there is no such
legal limit
329. WHAT ARE THE GUIDELINES?
• Israeli Ministry of Health guidelines limit
the number of embryos transferred to
three, or in exceptional cases, four
• ESHRE (1998) recommended transfer of
either two or three embryos depending on
female age
330. WHAT ARE THE GUIDELINES?
ASR Practice Committee Guidelines on number of embryos
transferred 1998
• Above average prognosis (e.g. age <35y) transfer no more
than three
• Average prognosis (e.g. age 35-40y) transfer no more
than four embryos
• Below average prognosis (e.g. age >40y or multiple failed
cycles) transfer no more than five embryos
331. WHAT DO THE EXPERTS SAY?
“Transfer 1 embryo”Without
selective single
embryo transfer
Selective
single
embryo
transfer
Pregnancy
Rate
30% 26%
Twins 24% 13%
Triplets 4% 2%
Coustier & Dhont, Hum Reprod, Oct., 1998
332. WHAT DO THE EXPERTS SAY?
“Transfer 2 embryos”
• “When more than four eggs were fertilized there was no
increase in the birth rate for women receiving three
transferred embryos compared with those receiving
two, but there was a considerable increase in the rate of
multiple births when three were transferred (O.R.1.6;
C.I. 1.5-1.8)” Templeton &
Morris, N Engl J Med, Aug 1998
333. WHAT DO THE EXPERTS SAY? “Transfer
more than 2 embryos”
• Most couples feel that twins would be an
ideal outcome of IVF treatment
(Murdoch, Hum Reprod, Feb.,1997)
• Possibility of relying on the “escape route”
or “safety net” of selective fetal reduction
(Murdoch, Hum Reprod, Oct., 1998)
334. WHAT DO THE EXPERTS SAY?
“Transfer more than 4 embryos”
• Compensate for predictors of poor
outcome:
Women’s age
Cause & duration of infertility
Number of ART cycle
Embryo morphology
Frozen/thawed embryos
335. THE NUMBER OF EMBRYOS
TRANSFERRED PER IVF CYCLE NATIONAL
VS. WORLD DATA
14.4
30.4
38.5
16.7
12.8 13.7
22.4
0
10
20
30
40
50
1 2 3 4+
World
Israel
%
336. HIGH COSTS RELATED TO
MULTIFETAL PREGNANCIES
LIMITING RESOURCES TO
A.R.T.
337. LIMITING RESOURCES TO ARTLIMITING RESOURCES TO ART
PHYSICIANS PATIENTS
Higher competition Increased pressure
among ART clinics for immediate
success
Demand for higher pregnancy rates
Higher number of embryos transferred
More multifetal pregnancies
339. What are the limits of
spontaneous pregnancy?
• According to The Guinness Book ofThe Guinness Book of
World RecordsWorld Records:
A woman from Portland, Oregon,
delivered when she was
57 years and 120 days old
340. WHY DOES FERTILITY DECLINE
WITH AGE?
• Cumulative exposures to occupational and
environmental hazards
• Diseases: endometriosis, myomas,
adenomyosis
• Sexual transmitted diseases
• Decreased frequency of sexual
intercourse
342. THE RISK OF ABORTION IN
WOMEN OLDER THAN AGE 40
• Clinically recognized 34%
• Overall abortion rate
(recognized and
unrecognized) ~75%
343. Rate of spontaneous abortion in
recipients by donors’ age
14
44.5
0
10
20
30
40
50
20-24 yrs >35 yrs
%
344. REPRODUCTION IN THE OLDER MALE
• Male fertility -- immortalimmortal?!
A decline in testosterone
Increase in gonadotropins
Associated decrease in sperm production and the number of normal
sperm -- modest changes
Capacity to fertilize maintained.
345. REPRODUCTION IN THE OLDER MALE
• A paternal age >40 associated
with a 20% greater chance of birth
defects
• Advanced paternal age NOTNOT
associated with increased
frequency of trisomy 21
Lian et al., Am J Hum Genet 1986
346. PREVALENCE OF INFERTILITY BY AGE
0
5
10
15
20
25
30
15-19 20-24 25-29 30-34 35-39 40-44
Age (years)
Infertile (%)
(Menken J, Science 1986;223:1389)
347. INFERTILITY AND WOMEN’S AGE
• 1:7, age 30 - 34 yrs
• 1:5, age 35 - 39 yrs
• 1:4, age 40 - 44 yrs
348. PREGNANCY RATE BY AGE
0
4
8
12
16
20
24
28
32
<29 30-34 35-39 40-44 >45
Own Eggs
Donted Eggs%
WOMAN’S AGE
**
*
#
# p<0.05
* p<0.001 (Templeton et al., 1996)
349. ETIOLOGY OF FERTILITY
DECLINE WITH AGE
• Ovarian Factor
• Decline of oocyte reserve
• Genetic abnormalities
• Poor response to ovarian
stimulation
• Early luteinization
352. Statistics in Infertility
• The effect of maternal age
• Expectations from treatment
• Presentation of outcome
results
353. BACKGROUND
• Infertility is defined as one year of
unprotected coitus without conception.
• It affects approx. 10-15% of couples in
reproductive age group.
• One in 6 women seeks professional help
during their life time because of infertility.
354. CONCEPTION RATE PER CYCLE AFTER
IVF
24
26
28
30
32
34
36
38
41
45
0
5
10
15
20
25
30
AGE (yrs)
%
(Tan et al., 1992)
355. Pregnancy loss rate after
documentation of fetal cardiac activity
in 1570 IVF pregnancies
4.1
9.9 10.7
23.6
0
5
10
15
20
25
<31
31-34
35-39
>39
%
*
*p<.001
(Spandorfer et al., 1997)
356. IVF IN WOMEN >40 yrs
• Should not delayed long as
the patients chances to
conceive diminish quickly!
357.
358.
359.
360.
361.
362.
363. Intracytoplasmic Sperm Injection
(ICSI)
• The deposition of a single spermatozoon
directly into the cytoplasm of the oocyte,
thus bypassing the ZP and the oolemma.
• First reported by Palermo et al in 1992.
365. Innovations
0%
5%
10%
15%
20%
25%
30%
35%
40%
1980 1985 1990 1995 2000
IVF
ZIFT
ICSI
GIFT
Donor Egg
Cryopreservation
Partial Zona Dissection
Subzonal Insertion
Clinical Pregnancy / Transfer
Nuclear Transfer
Cytoplasmic Transfer
Co-Culture
Hatching
PGD
366.
367. Intracytoplasmic Sperm Injection (ICSI)
• “No other technique since IVF
itself has had such a positive and
almost explosive impact in
helping infertile patients to
achieve conception.”
Oehninger & Gosden, 2002
369. The use of ICSI
in 1999
• 43% of 258,460 ART cycles in 22
European countries
• Hum Reprod 2002 Dec;17:3260-74
• 41% of 88,077 ART cycles in the
United States
• Fertil Steril 2002 Nov;78:918-31
371. Concerns regarding ICSI
Is ICSI really the treatment of choice for
all cases of IVF?
What is the risk of transmission of
chromosomal or genetic disease
Long-term health of children conceived
after ICSI
380. INTERNATIONAL COMPARISONS
NATIONAL REGISTRIES
•US and Canada: Society of
Assisted Reproductive Technology
(SART)
•UK: Human Fertilization
Embryology Authority (HFEA)
•French In Vitro National (FIVNAT)
381.
382.
383.
384.
385.
386.
387.
388.
389.
390.
391. Cost
•Patients opted for eSET over DET 50%
more often when
• had insurance coverage
•participated in a refund guarantee
program
Fertil Steril 2009;92:1895–906
392. The cost of eSET
• In the Netherlands, Evers calculated that every
IVF offspring contributes a lifelong economic
net of $310,000 to the country’s Gross National
Product.
• Concluded that, theoretically, up to that sum
could be spent on a successful IVF cycle
without society incurring a net loss.
393. Cost of multiple births ?Cost of multiple births ?
IncreasedIncreased
•Neonatal health care
DecreasedDecreased
•No need for additional infertility treatments
•Lifelong economic contributions of second
twins to society
394. The cost of eSET
• eSET economically sound only with the
presence of medical contraindications to twin
pregnancies or when couples simply do not
wish to conceive twins.
395.
396. conclusions
•A choice has to be made between three
cycles of eSET, STP or DET.
•Depends on society’s willingness to pay
which strategy is to be preferred from a
cost-effectiveness point of view.
397. eSET should NOT be
routinely offered
•The need for a second pregnancy to
achieve equal outcome (2 children),
resulting treatment delays, increased
efforts and costs, in absence of any
guarantees that a second successful
singleton pregnancy/delivery will ever be
accomplished, invalidates eSET as a
routine procedure.
Notes de l'éditeur
NuvaRing Vaginal Contraceptive Ring
Percentage of implanting embryos with cell division parameters below or above the median values. The two panels show classification for: (i) duration of second cell cycle, cc2; (ii) synchrony of divisions from 2-cell to 4-cell stage, s2. As the limits are defined as median values for all 247 investigated embryos with known implantation outcome, each column represents the same number of transferred embryos and the frequency of implantation was significantly higher for embryos with parameter values below the median.
With increasing maternal age infertility rates increases reaching 25% at the age of 35-39y and 29% at the age of 40-44y
With increasing maternal age infertility rates increases reaching 25% at the age of 35-39y and 29% at the age of 40-44y
The ovarian factor has been attributed to: Decline of....
I will discuss each of these topics and later try to elucidate several treatment strategies for clinical application at present and future time
