Who is the MOST Important for
Successful ART Outcome?
Glenn L. Schattman, M.D., F.A.C.O.G.
Associate Professor
Cornell Institute for Reproductive Medicine
The Weill Medical College of Cornell University
Disclosures
• I am a clinician
• I do not understand all aspects of the magic
that occurs in the IVF laboratory
• Outcome of interest is “Live Birth”
• I have been married for ~24 years so ….
I admit that I am always to blame!
Pre-IVF Couple Evaluation
• Patient presents to clinician
• Evaluation
~ Cause of infertility
y
– Ovarian reserve testing
– Evaluation of uterine cavity
– ? Evaluation of tubal status
– Semen analysis
– Blood tests
– ?pregnancy loss
Treatment
• Ovarian stimulation
~ Monitoring of response
~ Timing
Ti i off HCG trigger
t i
~ Timing of retrieval
• Laboratory personnel receive the oocytes and
maintain the embryos under stringent
conditions with appropriate Quality Controls.
Treatment
• The laboratory personnel then hand over the
embryos to the clinician who places them in the
uterine cavity (hopefully!)
Weakest Link Breaks Chain
Hydrosalpinx
SM fibroid
Sub-optimal
SubStimulation
DOR
Patient Evaluation
Laboratory
Scenario A
• 5 clinicians, 10 embryologists
• 200 IVF cycles/year for last 10 years
• 2000
2000--2009
~ Consistent LBR/started cycle = 35%
• 2010
~ LBR/started cycle = 22%
• Who’s problem is it?
Scenario A
• Clinician: related to stimulation?
~ New MD in practice
~ Change in pre
pre--IVF evaluation: SIS instead of HSG
• Embryologist: related to laboratory conditions?
~ New incubators, change in media
~ Training new staff
• Change in patient population
~ 2000
2000--2009 = mean age 32
~ 2010 = mean age 37
Scenario B
• Same statistics as program A
• 34 YO G0, unexplained infertility
• Failed conventional treatments
• IVF
IVF-- FSH+antagonist
FSH+antagonist.. HCG 2 follicles ≥17
• 22 oocytes, 22 MII
• 18 2PN2PN- grade 4, with vacuoles, fragmentation
Assumption:
• Maximal pregnancy rate for any given patient
=100%
~ 50% delivery rate for age <32
~ 15% delivery rate for ages 4040-42
• Any intervention (or lack of) can only have a
negative impact on patient’s maximal
probability of pregnancy
• Can only correct deficiencies to return rate
back to 100%
Improving Outcomes in ART
• Patient evaluation
~ Ovarian reserve testing
~ Identify underlying conditions
– Tubal disease, endometrial abnormalities
• Physiologic ovarian stimulation and timing
• Optimal embryo culture
• Embryo selection
• Embryo transfer
Optimal Evaluation of Infertile Female
• “Examination of the uterine cavity is an
integral part of any thorough evaluation of an
infertile couple”
• “Evaluation of tubal patency is a key
component of the diagnostic workwork-up in
infertile couples”
• “Evaluation of ovarian reserve should be
performed in selected patients to obtain
prognostic information…influence treatment..”
ASRM PC Fertil Steril 2006;86:S264
Ovarian Reserve Testing
• Day 2/3 FSH/E2
• AFC
• AMH
~ Best used for determining initial stimulation
protocol
~ Both AMH and AFC have limited value in
predicting “non“non-pregnancy”*
– Should NOT be used to exclude treatment
– Should be used to provide an ageage-adjusted “expectation”
*Broer SL, et al Fertil Steril 2009;91:705
2009;91:705--14
Scott R Fertil Steril 2008; 89:868-78
Anti-Müllerian Hormone (AMH)
• Linear correlation between AMH levels and response
to gonadotropin stimulation
• AMH also correlated with AFC and # oocytes
retrieved
• No significant correlation between AMH level and
pregnancy
• AMH can be measured at any time during the cycle
• Decline in AMH over time precedes FSH, Inhibin B
and AFC
Van Rooij IAJ Human Reprod 2002;17:3065-71
Antral Follicle Count
Hydrosalpinx
• Direct effect on embryo
• Alteration in endometrial receptivity
• Mechanical flushing
• Example: male factor infertility
~ SIS or hysteroscopy
~ Tubes not evaluated
Hydrosalpinx
• ~ 50% reduction in ART success compared to
patients without tubal disease
~ Seen with both fresh ET and FET
~ Effect greatest in patients with U/S visible
hydrosalpinges
Zeyneloglu HB et al Fertil Steril 1998;70:492
Laparoscopic Surgery: OPR
Tubal Obstruction: OPR
Aspiration of Hydrosalpinx
Tubal Surgery: Miscarriage
Fibroids
• 20
20--50% of reproductive aged women
~ Monoclonal tumors
~ Location is critical
– Intra
Intra--mural
– Sub
Sub--serosal
– Sub
Sub--mucosal
– Altered blood flow
– Endometrial alterationsalterations- atrophy, inflammation, etc
Fibroids: Endometrial Blood Flow
• 50 patients with “small” fibroids/ 50 controls
• No endometrial distortion
• 3D U/S on day of retrieval
• No difference in uterine artery PI/RI
• No difference in endometrial/
endometrial/subendometrial
subendometrial
~ Vascularization
Vascularization,, pulsatility or resistance index
Ng EHY et al Human Reprod 2005;20:501
Sub-mucous Fibroids
• Most studies reveal that fibroids distorting
endometrial cavity have a deleterious effect on
ART outcome.
~ Fahri and EldarEldar-Geva showed significant reduction
in IR and PR with fibroids distorting endometrial
contours
~ Surrey demonstrated no difference in patients S/P
resection of SM or IM/SM fibroids
Non--cavityNon
cavity-distorting Intramural Fibroids vs. No Fibroids:
Implantation Rate
Sunkara S K et al. Hum. Reprod.
Reprod. 2010;25:4182010;25:418-429
Non--cavityNon
cavity-distorting Intramural Fibroids vs. No Fibroids:
Clinical PR
Sunkara S K et al. Hum. Reprod.
Reprod. 2010;25:4182010;25:418-429
Non--cavityNon
cavity-distorting Intramural Fibroids vs. No Fibroids:
Miscarriage Rate
Sunkara S K et al. Hum. Reprod.
Reprod. 2010;25:4182010;25:418-429
Non--cavityNon
cavity-distorting Intramural Fibroids vs. No Fibroids:
Live Birth Rates.
Sunkara S K et al. Hum. Reprod.
Reprod. 2010;25:4182010;25:418-429
Non--cavityNon
cavity-distorting Intramural Fibroids vs. No Fibroids:
<37 years, Live Birth Rates
Sunkara S K et al. Hum. Reprod.
Reprod. 2010;25:4182010;25:418-429
Uterine Cavity Evaluation?
• 1475 patients S/P 2 failed ET’s
• “normal” uterine cavity on HSG <12 months
prior to 1st IVF cycle
• 540 patients (37%) had abnormal findings
~ 246 polyps (17%)
~ 184 adhesions (12%)
~ 13 septum (1%), 2 fibroids (1%)
• OPR 27% vs 22% (controls)
Makrakis E et al JMIG 2009;16:181
Uterine Evaluation
• Multiple studies identified between 26% and
50% of patients who fail IVF to have uterine
abnormalities.
• Treating the abnormality signifcantly
increased pregnancy rates over patients with
prior failed cycle without an identified
abnormality.
Kirsop R et al Aust NZJ Obstet Gynecol 1991;31:263
Schiano A et al Contr Fertil Sex 1999;27:129
Oliveira FG et al Fertil Steril 2003;80:1371
Demirol A et al Reprod Biomed Online 2004;8:590
Rama Raju GA et al Arch Obstet Gynecol 2006;274:160
Embryo Transfer
• 10 RCT’s comparing “Soft” to “firm” ET
catheters*
~ “Soft”
Soft catheters result in a significant increase
(39%) in PR compared to “firm” catheters
• Recent RCT suggests operator dependent**
~ “B” significantly better results with soft catheter
~ “C” significantly better results with firm catheter
*AbouAbou-Setta AM et al Human Reprod 2005;20:3114
**Yao Z et al. Human Reprod 2009;24:880
• Norfolk group in the
80’s compared follicle
size and maturity of
oocytes obtained
• 18 mm size was the best
(P < 0.01)
Percent Matu
ure
Follicle Size to Trigger
90
80
70
60
50
40
30
20
10
0
<15
15-17 18-20
>21
Scott et al FS 1989
Prospective Trial to Evaluate
Timing of hCG
• Clark et al. evaluated 57 women in a prospective trial
to evaluate the timing of hCG in patients with Flare
GnRH--a protocols
GnRH
• Group 1 – standard timing of hCG at two follicles at
least 17mm
• Group 2 – one day later
Clark Fertil Steril 55:1192
Prospective Trial to Evaluate
Timing of hCG
Group 1
Group 2
P
Number
31
26
Age (yrs)
31.7 + 3.9
32 + 4.0
NS
Day of hCG
8.9 + 2.3
9.1 + 1.7
NS
Max E2 (pg/mL)
1416
1901
NS
Number Oocytes
7.7 + 5.2
8.4 + 5.7
NS
Clark Fertil Steril 55:1192
Preg rate/ET
T (%)
Prospective Trial to Evaluate
Timing of hCG
45
40
35
30
25
20
15
10
5
0
P < 0.05
1
2
GROUP
Clark Fertil Steril 55:1192
Prospective Trial to Evaluate
Timing of hCG
• Prospective RCT
• GnRH
GnRH--antagonists/ recFSH
• Mean Age 32.5
• HCG ≥3 follicles ≥17mm or 2 days later
Clin Preg /Ret
Ongoing /ET
Implantation Rate
Group 1
(n=205)
35.6
39.2
22.6
Group 2
(n=208)
25.0
27.7
15.1
P Value
0.027
0.024
0.009
Kolibianakis Fertil Steril 2004;82:102
Delay in HCG Administration
• 10 Oocyte donors (rFSH
(rFSH//antag)
antag)
• HCG given when
~ 3 follicles ≥ 17 mm
~ +2 days
• Endometrial biopsies (at retrieval) revealed
advancement of endometrium in all biopsies by
2-3 days in patients delayed by 2 days
Kolibianakis E et al Human Reprod 2005;20:2453
Early HCG
• 120 patients randomized (rFSH
(rFSH//antag)
antag)
• HCG given when
~ ≥3 follicles ≥16 mm
~ 1 day later
• Early HCG groupgroup- fewer oocytes (6.1 vs 9.2)
• No difference in pregnancy rate (30 vs.36.7)
Kryou D et al Fertil Steril 2011;96:1112
“Patient Friendly” ART
~ Isn’t friendly if the patient does not get pregnant
~ Physiologic stimulation
– Reduce risk of complication like OHSS
~ Singleton pregnancy
~ Collaborative effort between the clinical staff
(MD’s, RN’s, ancillary) and laboratory personnel
Who is More Important?
Failure to treat Sub
Sub--optimal
underlying disorders Stimulation
50%
10%
Accurate prognosis Laboratory
Sub-optimal
Sub15%
Traumatic ET
Patient Evaluation
5%
15%