What`s New in IVF - Conceptions Reproductive Associates of Colorado

What’s New in IVF
Mark R. Bush, MD, FACOG, FACS
Medical Director
Conceptions Reproductive Associates of
Colorado
Sky Ridge, Littleton, Denver, Lafayette
www.conceptionsrepro.com
Expanded coverage of these topics with references
available on our website
Four Landmark Innovations
• ICSI (Intra-cytoplasmic sperm injection)
Optimizes fertilization
• Blastocyst Culture
Allows for developmental selection
• CCS (Complete Chromosomal Screening)
Determines which embryos have the normal 23 pairs of
chromosomes
• Vitrification
Superior freezing technique allows for outstanding survivability of
embryos and therefore a delayed transfer (FET) with higher
implantation rates over a fresh transfer
Vitrification and subsequent FET
Vitrification and subsequent FET
Comparing platforms
• ICSI and day 3 embryo transfer
12 eggs/ 10 mature/ 8 fertilize
Eight 6-8 cell embryos on day 3
Multiple embryo transfer, risk of multiples, decreased pregnancy
rates, poor prognosis embryos cryopreserved
• ICSI, blastocyst culture, CCS, subsequent FET
12 eggs/ 10 mature/ 8 fertilize
Four ~ 150 cell blastocysts on day 5/6
Three determined to be euploid
One transferred in a subsequent FET with 70+ % FHT rate
Excellent prognosis embryos cryopreserved
CCS Patients at Conceptions Through 10/22/2014
Thawed Embryos from Trophectoderm CCS Testing Patients 10/1/2010 thru 10/22/14
<35
35-37
38-40
41-42
43-44
252
159
117
47
30
Percentage of transfers resulting in pregnancies (FHT)
75.4%
78.0%
66.7%
76.6%
70.0%
Percent with single embryo transfer
72.2%
76.1%
78.6%
80.9%
93.3%
Implantation Rate
72.0%
74.6%
63.8%
73.2%
71.9%
1.27
1.24
1.21
1.19
1.07
24.4%
41.7%
35.0%
58.3%
73.4%
Number of transfers (total = 605)
Average number of embryos transferred
Percentage of patients with AMH < 1.5
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Rate of positive chemical pregnancy that does not progress to heartbeat
Unscreened FET 11.7%
CCS FET 5.4%
Rate of + FHT in a CCS transfer not progressing to live birth 1.7%
24 CHROMOSOME ANEUPLOIDY SCREENING AND FET
ALLOWS FOR HIGH PREGNANCY RATES AND THE
OPPORTUNITY FOR ELECTIVE SINGLE EMBRYO TRANSFER
Proctor, J. Glenn
Wilson, J. Michael
Swanson, Michael S.
Bush, Mark R.
AAB Meeting, Las Vegas, May 2014
Literature Comparison: Frozen Versus Fresh Embryo Transfer
Outcome
Parameter
Frozen ET Frozen ET
Better Than Equal to
Fresh
Fresh
# Studies
Frozen ET
Worse Than Fresh
Reviewed
Clinical Pregnancy
Rate
8
3
0
11
Implantation Rate
7
3
0
10
Ectopic Rate
3
0
0
3
Miscarriage Rate
1
0
0
1
Birth Defects
0
1
0
1
Perinatal
Complications
2
1
0
3
Twin Rate
1
1
0
2
Kiehl, M., Natera 10.13
Why Complete Chromosome Screening?
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Advanced maternal age
Repeat IVF cycle(s)
Recurrent pregnancy loss
Prior pregnancy with a chromosome abnormality
Ability to screen prior frozen embryos
Eliminate the number one cause of failed IVF, miscarriage,
abnormal amniocentesis
Enables single embryo transfer
24-Chromosome Screening
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Conceptions uses a SNP array platform
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Whole chromosome abnormalities (trisomies and monosomies)
Polyploidy
Large deletions or duplications
Autosomal recessive gene disorders
Autosomal dominant gene disorders
Cost effective for the patients
o Large percentage of patients utilizing technology lowers IVF package
costs
o Eliminates ET and medication fees if all aneuploidy
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Ability to confirm parentage
Ability to detect DNA contamination
Live birth outcome with trophectoderm biopsy, blast vitrification,
and single-nucleotide polymorphism microarray-based
comprehensive chromosome screening in infertile patients
Schoolcraft et al, Fertil Steril, Vol. 96, No. 3, Sept. 2011
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The combination of TE biopsy, blastocyst vitrification, and SNP
microarray – based CCS technology results in:
o High implantation rates
o Low miscarriage rates
o The realization of the expected benefit of aneuploidy screening in
ART
24 Chromosome Aneuploidy Screening and FET Allows for High
Pregnancy Rates and the Opportunity for Elective Single
Embryo Transfer
Proctor, et al, AAB Meeting, Las Vegas, 5/2014
Methods
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Retrospective cohort study. 396 patients undergoing IVF from 10-12010 thru 1-1-2014 at Conceptions in Colorado were offered a CCS
cycle with subsequent FET.
These data include all patients that desired to use their own oocytes
with ICSI.
Embryos were cultured in sequential media to day 5 or 6, hatched,
and laser biopsied.
Biopsied embryos were vitrified using a closed system and stored for
subsequent FET.
SNP analysis was performed by Natera (San Carlos, CA).
1-2 embryos were warmed and transferred (FET)at a later date when
the uterine environment was optimal
24 Chromosome Aneuploidy Screening and FET Allows for High
Pregnancy Rates and the Opportunity for Elective Single
Embryo Transfer
Proctor, et al, AAB Meeting, Las Vegas, 5/2014
Uterine preparation for FET
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BCP, lupron overlap in preceding month
With menses, baseline ultrasound for ovarian cysts, p4/ e2
If clear, start vivelle dot 1/2/4 (1 dot for 6 days, 2 dots for 4 days, 4
dots for 4 days, then back down to 2 dots) + estrace 2mg PO BID from
day 1
Day 5 lining check, e2, dose adjustments as needed, including
consideration of vaginal estrace
Day 10 lining check, e2 > 300, 5K trigger if lining >/= to 8 mm and
triple layer
Start PIO at 50/d day after trigger, then 75/d from 2 days after trigger
FET CCS blast transfer 6 days after trigger
Results
Pregnancy Rates (FHT)
90.0%
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
< 35 (156)
35-37 (106)
38-40 (86)
41-42 (31)
43-44 (17)
CCS Allows for Fewer Embryos Transferred
# Embryos Transferred
1.12
1.35
< 35
35-37
38-40
1.23
1.27
1.22
41-42
43-44
% SET
100.0%
90.0%
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
< 35 35-37 38-40 41-42 43-44
Implantation Rates
90.0%
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
< 35
35-37
38-40
41-42
43-44
Percent Aneuploidy (Patients with ET)
45.0%
40.0%
35.0%
30.0%
25.0%
20.0%
15.0%
10.0%
5.0%
0.0%
< 35
35-37
38-40
41-42
43-44
Percentage of Patients with AMH< 1.5
90.0%
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
< 35
35-37
38-40
41-42
43-44
Percentage of Patients with No Biopsy Due to D5 Development
Age
< 35
35 - 37
38 - 40
41 – 42
43 -44
% No Bxy
12.3 %
15.5 %
19.1 %
37.0%
23.1 %
• Due to arrest from day 3 to 5
• Poor quality blastocyst development
• Patients electing to discontinue biopsy testing
Percentage of Patients with a Biopsy but No Euploid
50.0%
48.3%
50.0%
40.0%
30.0%
20.0%
10.0%
5.8%
14.0%
20.6%
0.0%
< 35
35-37
38-40
41-42
43-44
Conclusion
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24 chromosome aneuploidy screening with vitrification allows
patients the opportunity to obtain embryos with high
reproductive potential while ensuring endometrial synchrony.
A significant percentage of embryos were aneuploid,
particularly in women of advanced reproductive age and/or
possessing decreased ovarian reserve.
Identifying aneuploid embryos before transfer allows for the
elimination of the number one cause of failed IVF, miscarriage
and abnormal amniocentesis.
Chromosome screening allows for patients with an AMH < 1.5
the ability to achieve a viable pregnancy utilizing elective
single embryo transfer.
Translocation and septum
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26 yo g2p1s1 with spontaneous conception, bleeding in the 1st
trimester to 25 weeks, PPROM at 26 weeks, hospitalized until
PTD at 32 weeks. Prior 1st trimester miscarriage.
Sister with 1st trimester miscarriage x2, stillbirth x1
Found to have balanced translocation, 14/21, and a uterine
septum
Septolysis followed by SET of euploid female devoid of
unbalanced translocation
Subsequent uncomplicated gestation and vaginal delivery of
healthy 8#9oz girl at term
Translocation and septum
Translocation and septum
Translocation and septum
Translocation and septum
Translocation and septum
Translocation and septum
Autosomal dominant disorder (non-disclosure)
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29 yo nullip, husband with vasectomy
Husband’s father dying of Huntington’s, his brother and sister
also carry the disease
Husband has a 50% chance of having the disease, but does
not want to know if he has it
Underwent IVF with PESA, ICSI, blast CCS
With Natera SNP platform, we determined which embryos
came from husband’s mother’s chromosome #4
SET of euploid male (with chromosome #4 from his unaffected
grandmother and not his affected grandfather)
Delivery of healthy boy
Huntington’s extinguished in this family line
Autosomal dominant disorder (non-disclosure)
Autosomal dominant disorder (non-disclosure)
Autosomal dominant disorder (non-disclosure)
Finer Points
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SNP microarray evaluates 300K random BP changes in the
non-coding regions of the chromosome, compares data with
parental samples, integrates known data from the Human
Genome Progect.
aCGH flourescently labels embryo DNA (red), reference DNA
(green), samples mixed and hybridized to an array which
contains multiple probes corresponding to each chromosome.
Trisomies red, monosomies green.
aCGH can have up to an 8.5 – 11.5 false negative rate (calling
an embryo normal when it is not) b/c it cannot detect
haploidy (set missing, n =23), some forms of triploidy (extra set,
n = 69), UPD (both sets from one parent), del/dup.
If UPD of an imprinted (methylated/silenced) gene region,
then Angelmen, Prader-Willi.
Finer Points
Natera SNP advantage over aCGH
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Individual confidences for accuracy of each call
Parental source of aneuploidy
Simultaneous single gene testing and 24 chromosome PGS on single
cell
Haploidy, polyploidy and UPD detection
Corrects for contaminant DNA
Confirmation of parentage
aCGH advantage over Natera SNP
• Chance of homozygosity in chromosome regions (blood relationship
in the couple can result in multiple areas of homozygosity and
potential for no-call across a particular chomosome)
Oocyte vitrification
Costs
20K for ovarian stim, retrieval, vit (x1), storage, thaw, fert, embryo culture, transfer.
Conservative number. Some women may need to stim, retrieve and vit more than once.
Efficacy
20% LB rate for women who freeze 6 eggs at 35
Medical v. “social”
If all women 35 who freeze 6 eggs use them in the future, at a 20% LB rate, at 20K per
cycle, then the NNT (number needed to treat) for 1 live birth is 5 at a cost of 100,000
- Table and tabulations of the 6 vit studies from Abusief and Adamson, OBG Mgmt, Feb 2015, v.27 No.2
Donor oocyte vitrification
Proven Success Rates – My Egg Bank (MEB) program has demonstrated success equal
to traditional fresh egg donation. Current CRA stats are 67% FHT for donor oocyte
vit transfers.
Economical – Full benefit of services with a significantly less out of pocket expense
than if using a fresh egg donor. $20,019 for 6 mature vitrified donor eggs, complete
MD/Nursing management of donor egg cycle, unlimited cycle laboratory assays
and ultrasound, thawing of eggs, sperm isolation, ICSI, culture of embryos to
blastocyst and transfer.
Convenience – Avoids the often lengthy match process and cycle coordination when
using a fresh donor. Expansive donor selection – large selection of frozen eggs from
donors that have passed rigorous medical, genetic and psychological testing.
College educated and come from diverse ethnic and racial backgrounds.
MEB offers a guarantee to its affiliate clinics. At least 3 oocytes must survive the thaw,
and that at least 1 - 6 cell, day 3 embryo is available. Failure to achieve either one
of these criteria and the recipient may choose another donor.
CCS is also available.
Quality/ Cost
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Conceptions is one of the premier IVF centers in the country
offering outstanding pregnancy rates with cutting edge
therapy in a patient-centered, compassionate and inclusive
environment accepting most all insurances and offering
extremely competitive package rates for care.
Optum Center of Excellence for the last 5 years in a row
Patient’s Choice Award 2012 – 14 by vitals.com
For the third year in a row, Conceptions is ranked the #1 IVF
clinic in Colorado by ivfreports.org
Quality/ Cost
CASH PRICING 2015
CRA
UNIVERSITY
CCRM
Difference
IVF/ICSI
IVF/ICSI/CCS/FET
$12,094
$20,381
$12,850
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$16,130
$23,855
$756/4,036
$ - /3474
HSG
Semen Analysis
Initial Consult
O-HSC
D&C SAB
POC Natera
Anesthesia
Follicle Scan
Sperm Wash
$500
$75.00
$175
$350
$500
$95/$399
$400
$161
$86
$940 (FemVue)
$116
$200
$1,500
performed at hospital
$175
$116
$600
$120+110
$295
$700
$2,670
$430
$190
$275
$440/100
$41/155
$25/120
$1,150/350
$2,170
$30
$24/$29
$30/189
AMH/RFC
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RFC < 8, RFC > 8, RFC 12 - 18
Ameliorating OHSS
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Lupron triggers where GnRH antagonist clears pituitary receptors and
the agonist (lupron) is able to induce endogenous LH surge (t ½ 20
minutes) and avoid or minimize use of hCG (t ½ 34 hrs, Mannearts, 98)
as surrogate surge
VEGF induces VP (vascular permeability)1,2
Effects of cabergoline (Cb2 – dopamine agonist) attributable to VEGF
receptor dephosphorylation3
Cb2 prevents VP in a dose dependent manner without affecting
angiogenesis and implantation in humans (n = 35 treated in face of
OHSS)4
Cb2 reduced the amount of ascites, hemoconcentration and
incidence of moderate-severe OHSS5
Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger
Low dose prednisone
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In women with RPL, safety and efficacy of prednisone 10mg BID thru
12 weeks demonstrated a livebirth rate of 77% in 80 women with
therapy as opposed to a 35% pregnancy rate in 52 matched women
without therapy. Concurrent use of 5mg folate QOD, 100mg ASA QD
(Tempfer et al, Fertil & Steril 2006, Vol 86(1) p. 145).
Reznikoff-Etievant et al, Human Reproduction 1999, Vol 14(8) p. 2106
also demonstrated safety of prednisone at 20mg/d in 277 women.
Women with recurrent loss had significantly more uNK than controls (p
= 0.008).
Prednisone treatment (20 mg/d for 21 days) significantly reduced the
number of CD56 cells in the endometrium, from a median of 14%
before to 9% after treament (p = 0.0004).
Demonstrated that high numbers of uterine natural killer cells in
preimplantation endometrium of women with recurrent miscarriage
can be reduced with the administration of prednisone (Quenby et al,
Fertil & Steril 2005, 84: p 980-4).
Endometrial optimization
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“Scratch” data based on setting up a non-infectious inflammatory
response involving events that accompany wound healing to include
secretion of cytokines and growth factors known to be involved in
implantation
360 degree cold loop reduction of functionalis layer preserving
basalis layer for synchonous regeneration concurrent with resection
of irregular endometrium/polypectomy/myomectomy
Antecedent normal O-HSC has revealed polyp on biopsy
Integrin biopsy: If not in phase and/or integrins absent, 8 weeks
lupron with 0.625 e2 add-back to influence deleterious
peritoneal/pelvic inflammation (endometriosis)
Hydrosalpinx: Direct embryotoxic effect (2), decreased endometrial
receptivity, mechanical disruption of implantation by fluid. Based on
the results from 3 trials, ongoing pregnancy rate after salpingectomy
or proximal occlusion is two-fold higher than controls, 34% v. 17% (3)
Endometrial optimization
Endometrial optimization
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