embryo transfer technologies and luteal phase support to maximize pregnancy rates
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Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy Rates
Sandro Esteves ANDROFERT - Brazil
Learning objectives At the completion of this presentation, participants should be able to: • Implement embryo transfer (ET) technologies
and luteal phase support (LPS) as per quality management perspective
• Individualize embryo transfer and luteal phase support according to different patient segments
“Process”: the only objective and measurable aspect of quality
Process = Any activity or set of activities that uses resources to transform raw material, supplies and labor (inputs) into products or services (outputs)
Quality of ET and LPS can be measured, but how?
Using indicators for the most important quality dimensions in infertility care…
Safety
Patient- centeredness
Effectiveness
What are the most effective, safe and patient-centered strategies in ET and LPS?
• Effectiveness: technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumulative LBR)
• Safety: complications (OHSS), adverse effects, risks (patient & offspring), errors/mistakes
• Patient-centeredness: physical burden and invasiveness of techniques
What the doctor want to know
Clinical Needs
Standard Operating Procedures
Results
How to offer the most effective,
safest and patient-centered ET process?
• Catheter type, soft vs. rigid • US-guided ET • Full bladder • Removal of cervical mucus • Best embryo placement position • Antibiotics, Acupuncture • Post-ET interventions, etc.
Moderate to high-quality evidence
Buckett Fertil Steril. 2006; Abou-Setta et al Reprod Biomed Online 2007; Brown et al Cochrane Database Syst Rev 2010
Abou-Setta et al. Cochrane Database 2009; Derks et al Cochrane Database Syst Rev. 2009; Bontekoe et al Cochrane Database 2014
Moderate to high-quality evidence
Cheong et al Cochrane Database Syst Rev. 2013; Craciunas et al Fertil Steril 2014; Gaikwad et al Fertil Steril 2013
Moderate to high-quality evidence
Are they beneficial as routine?
• Antibiotics pre-ET
• Intrauterine hCG • Pre-cycle hysteroscopy • Trial transfer • Endometrial scratching
Limited evidence to
draw firm conclusion
Mansour et al Steril 2011; Santibañez et al Reprod Biol Endocrinol. 2014; Pundir et al Reprod Biomed Online 2014
ET SOP at Androfert
• Modified-trial ET Outer sheath of soft catheter advanced to just past internal os
• Abdominal US-guided Full/half-full bladder
• Soft catheter Sydney IVF ET catheter set
sequence of standardized steps, which is used every time a given task is done, to ensure it is done the same way each time
ET SOP at Androfert (cont.) • Two-step ET
– Outer catheter sheath advanced to just past internal os – Embryo(s) loaded into catheter
• Air-medium interface (small volume ~15 microliters) – Loaded catheter inserted into uterine cavity
• Placement mid-portion of the uterus • Two-step catheter withdrawal
– Catheter removed while outer sheath remains into canal – Laboratory check – Outer sheath removed and checked
ET SOP at Androfert Double-check (DC) and Double-witness (DW)
1
2
3
4
5
6
Nurse check patient/couple identity upon entering ET room Doctor double-check identity (DC), explains embryos status, and give recommendation for ET
Embryologist and doctor/nurse check filled form (DC)
Tagged catheter (patient name, No. embryos to be replaced) is given to doctor by embryologist; doctor checks info (DC), witnessed by nurse (DW)
Embryologist removes embryo(s) from incubator, and loads ET catheter, witnessed by another embryologist (DW)
Couple fill in a form (name, date, consent for No. embryos to be replaced)
Procedures Effectiveness Safety Patient-centeredness
Soft catheter ✔ ✔ US-guided ✔ ✔ Mid-uterine embryo placement
✔
ET SOP (DC & DW) ✔
Luteal Phase Supplementation to Support Implantation
Luteal phase in stimulated cycles is abnormal
• Normal corpus luteum function dependent on pulsatile LH release from pituitary
• Supraphysiologic steroid levels (by multifollicular development) inhibits LH secretion
• Low LH levels causes luteolysis, implantation failure and shortened luteal phase
Jones 1996; Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Fauser & Devroey 2003; Trinchard-Lugan et al 2002; Sherbahn 2013
LPS mandatory in stimulated cycles
• hCG vs. Placebo or No treatment: Higher ongoing PR (OR=1.75; 95% CI: 1.09-2.81)
• Progesterone vs. Placebo or No treatment: Higher clinical PR (OR=1.83; 95% CI: 1.29-2.61) Higher ongoing PR (OR=1.87; 95% CI: 1.19-2.94) Higher live birth rates (OR=2.95; 95% CI: 1.02-8.56)
Level 1a
Clinical Needs
Standard Operating Procedures
Results
How to offer the most effective,
safest and patient-centered LPS
process?
• Agents • Routes of administration • Dose • When to start • When to stop
Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011
High-quality evidence
Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011
Progesterone alone enough for LPS (only natural P should be used; synthetic P not safe)
• Natural hormone secreted by corpus luteum
• In the presence of estrogen, P transforms proliferative in secretory endometrium
• Progesterone increases endometrium
receptivity • Once an embryo is implanted,
progesterone helps to maintain the pregnancy
van der Linden M et al. Hum. Reprod. Update 2012 van der Linden et al Cochrane Database 2011
Co-treatments do not improve outcome, except for GnRH agonists*
*moderate quality
P routes & types Evidence Effect Conclusion
Vaginal as effective as IM/oral
13 RCT; 2 MA; >2,000
cycles Similar CPR, LBR
& miscarriage True
Vaginal safer and more patient-friendly than IM/oral
3 RCT; 1 MA; >2,000
cycles
Lower side effects; Increased patient
satisfaction True
Among vaginal P, patients prefer gel
7 RCT; 1 MA; >2,400
cycles
Easier to use; better adherence; lower discharge
True Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010;
van der Linden et al Cochrane 2011
High-quality evidence
0
5
10
15
20
25
30
35
40
IM P Vaginal P
ng/mL
Endometrial Levels
0
0.5
1
1.5
2
2.5
3
3.5
IM P Vaginal P ng
P/m
g pr
otei
n
Serum Levels P<0.0001 P<0.0001
Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3
P in oil (50mg) vs. Crinone 8% (90 mg)
1 hour
3 hours
2 hours
4 hours Time
Bioadhesion of vaginal P is essential because it takes ~4h to reach steady state in the uterus (first-pass effect)
Bulletti C et al. Hum Reprod 1997
aqueous
lipid
tissue
micronized progesterone in an ‘oil-in-water’ emulsion (Crinone® 8%)
Summary evidence on P preparations and routes of administration
• Comparable cycle outcomes among natural P preparations (Vaginal, IM, Oral)
• Vaginal route provides higher endometrial P levels and is associated with fewer side effects than IM/oral route
• Despite similar pregnancy outcome with different vaginal preparations (capsules, pressaries, tablets, ring) patients prefer gel
Clinical Needs Procedures Results
What is the most effective, safe and patient-centered
LPS?
• Agents • Routes of administration • Dose • When to start • When to stop
Similar outcome in low vs. high dosage Crinone 8% (90 mg/d) vs. 200-800 mg/d (capsules;
tablets; pressaries)
No. studies No. OR; 95% CI
Live birth 2 1485 1.01; 0.81-1.26
Clinical PR 12 4973 1.04; 0.92-1.17
Miscarriage rate 8 2350 1.27; 0.85-1.89
Multiple PR 4 905 0.95; 0.57-1.58
Van der Linden et al Cochrane 2011
Similar outcome early vs. late LPS onset Day hCG vs. OCP vs ET
23% 28% 29%
hCG OPU ET
Clinical Pregnancy
20% 21% 20%
hCG OPU ET
Live birth
RCT (N=385; GnRH down-regulated cycles); Mochtar et al. Hum Reprod. 2006;21:905-8.
Vaginal P started at the time of OPU reduces uterine contractions at the time of ET
4.6
2.8
4.5 4.2
UC on day of hCG UC on day of ET
Crinone started on the day of OPU (n=43) Crinone started on the evening of ET (n=41)
P<0.001
Fanchin et al. Fertil Steril 1999
Similar outcome early vs. late cessation pregnancy test or clinical pregnancy vs. 6-7 week
gestation
Outcome Evidence Conclusion
OPR 2 RCT; 1 MA; >350 cycles No difference
Miscarriage 6 RCT; 1 MA; >1,000 cycles No difference
LBR 8 RCT; 1 MA; >1,200 cycles No difference
Liu et al. Reprod Biol Endocrinol. 2012; 10:107
Luteal-placental shift on P production occurs around 7-12th gestational week
0
100
200
300
400
500
600
700
800
900
0
10
20
30
40
50
60
70
80
4 5 6 7 8 9 10
E2
(pg/
mL)
P (n
g/m
L)
Gestational age in weeks P E2
Scott et al. Fertil Steril 1991; 56:481
Vaisbuch et al. Reprod Biomedicine Online 28: 330-5, 2014.
Prolonged progesterone seems useful for preventing miscarriage (≥3 events)
Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2013
No significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby
Summary evidence on P dosage and when to start & stop LPS
• Comparable cycle outcomes using low and high doses vaginal P
• Similar outcome regardless of LPS onset
• Evidence supports early LPS cessation, but for patients with recurrent miscarriage
Effective-ness
Safety Patient-centeredness
P at least until day of positive pregnancy test ✔ ✔ Progesterone alone ✔ ✔ ✔ Low-dose vaginal P gel ✔ ✔ Prolonged P use if recurrent miscarriage history
✔ ✔ ✔
LPS SOP at Androfert
• Vaginal progesterone in gel (applicable to cycles with hCG trigger and fresh ET)
– 90 mg daily – Onset day OPU – Cessation at ~9th gestational week – No serum measurement of P or E2
sequence of standardized steps, which is used every time a given task is done, to ensure it is done the same way each time
Bleeding before P discontinuation consequence (not a cause) of non-
pregnancy state
• Reflect lack of a viable pregnancy rather than deficient LPS
• Usually seen in women with lower estradiol levels
Onset of menses following HCG (day 0) in non-pregnant women n = 63
Roman E et al. Hum Reprod. 2000
How to individualize ET and LPS to different patient segments
Safety
Patient- centeredness
Effectiveness
What to do?
Normal responder
High responder
Poor responder
Day 2 transfer
Day 3 transfer
Blastocyst transfer Freeze all
Type of LPS
D2 D3 p RD
No. ET 2.0 ± 0.8 1.7 ± 0.8 0.003 +0.30 95% CI +0.11; +0.49
Cancelled cycles (%) 4.3 10.8 0.04
OPR per OCP (%) 27.7 16.2 0.02 +11.4
95% CI +1.6; +21.0
Bahceci M et al, Fertil Steril 2006
RCT (n=281); Long or short GnRH agonist + recFSH
D2 ET may offer better results for poor responders in conventional COS
31% vs 39%
Higher LBR with blastocyst in fresh transfers
Glujovsky et al. Cochrane Database Syst Rev. 2012:11;7:CD002118
Glujovsky et al. Cochrane Database Syst Rev. 2012:11;7:CD002118
63% 41%
D3 D5
Embryo Freezing Rate
3% 9%
D3 D5
Failure to Transfer any Embryo
OR: 2.88 (95% CI: 2.35-3.51) OR: 0.35 (95% CI: 0.24-0.51)
Overall better outcome with blastocyst transfers but…
Higher cumulative PR (fresh + frozen) with D2-3 ET in fresh cycles
46% vs 57%
Glujovsky et al. Cochrane Database Syst Rev. 2012:11;7:CD002118
Each additional warming cycle increases the chance of achieving a live birth
40.4% 48.0%
ET #3 (FET) 49
ET #2 (FET) 239
ET #1 (fresh) 822
50.5% +18.8%
+25.0% Female Age ≤38
ANDROFERT
332/822 63/239 17/49
LBR after vitrified-warmed ET: influence of freezing and transfer days
*p<.001
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
D2/D3 D3/D4 D2/D5 D3/D5 D5/D5-6
Day embryo freezing/Day ET warming cycle
LBR
Androfert 2012-2013; N= 415 warming cycles; Age ≤38
* *
Selected cases* (fresh ET) PGS/PGD
FET cycles
DET (fresh ET) Optimize
cumulative PR D2 ET poor
responders (cCOS)
One size does not fit all
*Meet eligibility criteria; eSET
GnRH-agonist vs hCG LH trigger
Fresh autologous cycles Moderate/
severe OHSS OR 0.10, 0.01-0.82
Live birth OR 0.44 0.29-0.68
Youssef et al. Cochrane Database Syst Rev. 2011
Patients at risk of OHSS
Fresh ET Freeze all
GnRH-a trigger
One size LPS also does not fit all…
Courtesy of Peter Humaidan
No. follicles day OPU 1500 IU hCG at OPU & 1000
OPU+5 & standard LPS ≤ 14
1500 IU hCG at OPU + standard LPS 15-25
1000 IU hCG at OPU + standard LPS or Freeze all 26-30
Freeze all >30
14h
14h 20h
48h 0 20 h
4h
GnRHa Natural
Luteal phase defect
LH Surge
Modified LPS alternative for fresh ET in GnRH-a trigger cycles
Freezing all embryos with transfer in a later non-stimulated cycle may improve outcome
Roque et al. Fertil Steril. 2013; 99: 156-162
Ongoing PR
Freeze-all embryo policy: is it for all? • Non-inferior in effectiveness, but…
– cumulative LBR in normal responders not yet assessed
• Safety – Increase ART unit workload – Perinatal outcome
• Favor frozen-thawed (Maheshwari FS 2012) • Higher rate of large for gestational age (Wennerholm HR 2013)
• Patient-centeredness – Psychological & cost burden
In FET cycles, all of the current methods of endometrial preparation appear to be
equally effective in terms of ongoing pregnancy rate*
• Meta-analysis from 20 comparative studies • ~13,000 cycles • Natural and artificial cycles with and w/o GnRH agonist • Safety and patient-centeredness not addressed Groenewoud ER et al. Hum Reprod Update. 2013;19:458-70 *in eumenorrhoic patients
Conclusions • Our ultimate goal is to deliver the highest
quality in infertility care • Consider safety and patient-centeredness, in
addition to effectiveness, when choosing procedures/techniques for ET and LPS
• These quality dimensions offer an unique opportunity to better individualize ET and LPS according to different patient segments
ET Technologies and LPS to Maximize Pregnancy Rates
Obrigado Thank you Gracias
This presentation is available at http://www.slideshare.net/
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