Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy Rates
Sandro EstevesAndrofert, 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 perspectiveIndividualize embryo transfer and luteal phase support according to different patient segments
The ‘process’ is 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 strategy can be measured…
We should use indicators for the most important quality dimensions in infertility care…
Safety
Patient centeredness
Effectiveness
Basic question in a quality perspective is…
What is the most effective, safe and patient-centered ET technique and LPS we should apply?Effectiveness includes technical aspects to deliver the best possible outcome (cumulative LBR)Safety includes complications (OHSS), adverse effects, risks (patient and offspring), errors/mistakesPatient-centeredness relates to physical burden and invasiveness of techniques for ET and LPS
What the doctor want to know
Clinical Needs
Determine procedures Write SOP
Standard Operating Procedure
sequence of steps that have been standardized to execute a task, which is used every time a given task is done, to ensure it is done the same way each time
What is the most effective, safe and patient-centered
ET/LPS?
• Catheter type, soft vs. rigid• US-guided ET• Full bladder• Removal of cervical mucus• Best embryo placement position• Antibiotics • Acupuncture• Post-embryo transfer interventions• Etc.
What is the most effective, safe and patient-centered ET technique we should apply??
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
Moderate to high-quality evidence Peri-ET
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 Peri-ET
Cheong et al Cochrane Database Syst Rev. 2013; Craciunas et al Fertil Steril 2014; Gaikwad et al Fertil Steril 2013
Are they beneficial as a routine?
Antibiotics pre-ET
Intrauterine hCGPre-cycle hysteroscopy
Trial transferEndometrial scratching
May be beneficial;
Limited evidence to draw firm
conclusionMansour et al Steril 2011; Santibañez et al Reprod Biol Endocrinol. 2014;
Pundir et al Reprod Biomed Online 2014
ET SOP at Androfert
Abdominal US-guided Full bladder
Soft catheter Sydney IVF, Cook
Air-medium interface Small transfer volume ~15 microliters
Modified-trial ET (previous cycle)Outer sheath of soft catheter advanced to just past the internal os
ET SOP at Androfert (cont.)
Two-step ET Outer sheath soft catheter advanced to just past internal osEmbryo load into the catheterInsertion of the loaded soft catheter into the uterine cavity
Placement mid-portion of the uterus
Two-step catheter withdrawalSoft catheter removed first (pressure on the syringe plunger maintained) while outer sheath withdrawn past internal osLaboratory check Rigid outer sheath removed and checked
Double-checking (DC) and Double-witness (DW) SOP at Androfert
Identification by the nurse of the patient arriving at the ET room;Patient and husband fill in a form (name, dates of retrieval and ET)
1
Nurse and doctor
performing the ET check ID info
(DC)
2
Doctor explains embryos profile,
and give recommendation
for ET
3
Couple fill in No. embryos to be replaced and cryopreserved (in conformity
with legislation)
4
Embryologist and
doctor/nurse check
information written (DC)
5
Embryologist removes couple’s embryos from
incubator, and loads ET catheter,
witnessed by a 2nd embryologist
(DW)
6
Catheter tagged with patient name and No. embryos is given to
doctor, who checks info
(DC),
witnessed by a nurse
(DW)7
Effectiveness Safety Patient-centeredness
Soft catheter ✔ ✔
US-guided ✔ ✔
Mid-uterine embryo placement
✔
ET SOP (DC & DW)
✔
Luteal Phase Support
Luteal phase of stimulated cycles is abnormal
Supraphysiologic steroid levels (by multifollicular development) inhibits LH secretionNormal corpus luteum function dependent on pulsatile LH release from pituitaryLow LH levels causes luteolysis, implantation failure and shortened luteal phase
Adapted from Jones-1996 by Fauser and Devroey-2003
Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000;Trinchard-Lugan et al 2002; Sherbahn 2013
hCG vs. Placebo or No treatmentHigher ongoing PR; OR=1.75 (95% CI: 1.09-2.81)
Progesterone vs. Placebo or No treatmentHigher 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)
LPS mandatory in all stimulated cycles
Level1a
van der Linden et al, Cochrane Database Syst Rev 2011:CD009154
Quality of LPS strategy can be measured…
Agents and routes of administration
Which dose and when to start and stop LPS
What the doctor want to know
Clinical Needs
Determine procedures Write SOP
What is the most effective, safe and patient-centered
LPS?
High-quality evidence on LPS
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
LPS with Progesterone is critical
P alone enough for LPS Progesterone is a natural hormone secreted by the corpus luteumIn the presence of estrogen, P transforms a proliferative into a secretory endometrium
Progesterone increases the receptivity of theendometriumOnce an embryo is implanted,progesterone acts to maintainthe pregnancy
Routes/Type Evidence Effect Conclusion
Vaginal P as effective as IM/oral?
13 RCT; 2 MA; >2,000
cyclesSimilar CPR, LBR,
miscarriage True
Vaginal P safer and more patient-friendly?
3 RCT; 1 MA; >2,000
cycles
Lower side effects; Increased patient
satisfactionTrue
Among vaginal P, patients prefer gel?
7 RCT; 1 MA; >2,400
cycles
Easier to use; better adherence; lower discharge
True
High-quality evidence on LPS
Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips Fertil Steril. 2009; Polyzos et al Fertil Steril 2010;
van der Linden et al Cochrane 2011
Higher endometrial P levels with vaginal administration
IM P Vaginal P0
5
10
15
20
25
30
35
40 ng/mL
Endometrial Levels
IM P Vaginal P0
0.5
1
1.5
2
2.5
3
3.5
ng
P/m
g p
rote
in
Serum LevelsP<0.0001
P<0.0001
Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3
P in oil (50mg) vs. Crinone 8% (90 mg)
First-pass uterine effect of P gel
1 hour
3 hours
2 hours
4 hoursTime
Time-dependent diffusion of Crinone 8% from the cervix to the fundus of the uterus
Bulletti C et al. Hum Reprod 1997
aqueous
lipid
tissue
micronized progesterone in an ‘oil-in-water’ emulsion
Agents and routes of LPSSummary
Comparable cycle outcomes among P preparations (Vaginal, IM, Oral), fresh and FET
Vaginal P results in higher endometrial levels and is associated with fewer side effects than IM progesterone
Similar pregnancy outcome with vaginal gel and all other vaginal P preparations (capsules, pressaries, tablets, ring)
Patients prefer vaginal gel
Quality of LPS strategy can be measured…
What is the most effective, safe and patient-centered LPS protocol we should apply?
Agents and routes of administration
Which dose and when to start and stop LPS
Dose of vaginal P
No. studies
No. OR 95% CI
Live birth 2 14851.01
0.81-1.26
Clinical PR 12 49731.04
0.92-1.17
Miscarriage rate
8 23501.27
0.85-1.89
Multiple PR 4 905 0.95 0.57-1.58
Low doseCrinone 8% (90 mg)vs. high dose
200-800 mg/d;
capsules, tablets, pressaries
Similar outcome
Van der Linden et al Cochrane 2011
When to start LPS
Mochtar et al, 2009
RCT, N=385LPS started either at day of hCG, OPU or ET day
Similar outcome
Mochtar MH. Hum Reprod. 2006;21:905-8.
Outcome N (%) RR 95% CI
Clinical PR
OPU 36 (28.1)
hCG 30 (23.1) 0.82 0.54-1.24
ET 37 (29.1) 1.04 0.70-1.53
Live birth
OPU 27 (21.1)
hCG 26 (20.0) 0.94 0.58-1.52
ET 26 (20.5) 0.97 0.60-1.56
Agents
Early (pregnancy test) vs. late P cessation (6th-7th week)
Early vs. late P cessation
Early (pregnancy test or clinical pregnancy) vs. late P cessation (6th-7th week)
When to stop LPS
Liu et al. Reprod Biol Endocrinol. 2012; 10:107
Evidence Conclusion
2 RCT; 1 MA; >350 cycles
No difference LBR
6 RCT; 1 MA; >1,000 cycles
No difference miscarriage
8 RCT; 1 MA; >1,200 cycles No difference
OPR
Prolonged progesterone use for preventing recurrent miscarriage (≥3 events)
Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013
Treatment for these women may be warranted given the reduced rates of miscarriage and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby.
• 3 trials; 225 patients
Which dose and when to start and stop PSummary
Comparable cycle outcomes using low (90 mg/d) and high doses (>100 mg/d) vaginal P No difference when P is started at day of hCG, OCP or ET
Evidence supports early cessation of LPS, but for patients with a history of recurrent miscarriage
Effectiveness Safety Patient-centeredness
P alone✔ ✔
Vaginal P gel
✔✔
2-week regimen ✔ ✔
Real-life practices reported worldwide
Vaisbuch et al. RBM 28: 330-5, 2014
LPS SOP at Androfert*
Progesterone gel (Crinone 8%) 90 mg daily Start at day 2 post-OCPStop upon completion of 9-week gestation
No serum determination of P or E2Likely to bleed before progesterone discontinuation if not pregnant
*hCG trigger
Bleeding before P discontinuation
Consequence and not a cause of non-pregnant state
Reflects the lack of a viable pregnancy rather than inadequacy of luteal support Distribution of the onset of menses following
HCG (day 0) in non-pregnant women
n = 63
Women who bled before discontinuing P supplementationlikely to have low levels of estradiol
Roman E et al. Hum Reprod. 2000
How to individualize ET and LPS according to TQM
Does one size fit all?
What to do?
Normal responde
r
High responde
r Poor responde
r
Day 2 transfer
Day 3 transfer
Blastocyst
transfer
Freeze all
Type of LPS
Higher embryo freezing rate
62.7% vs 41%OR: 2.88; 2.35-3.51
Failure to transfer any embryos lower
3.4% vs 8.9%OR 0.35; 0.24-0.51
Day of ET
Higher LBR with blastocyst ET in fresh
cycles
Higher cumulative PR (fresh + frozen) with
D2/3 ET in fresh cycles
Glujovsky et al. Cochrane Database Syst Rev. 2012:11;7:CD002118.
31% vs 38.8%
46.3% vs 56.8%
Series1
Series1
0.404
Series1
0.48
ET #3 (FET) 49
ET #2 (FET)239
ET #1 (fresh)822
50.5%
+18.8%
+25.0%
Female Age ≤38
AN
DR
OFE
RT
332/822 63/239 17/49
Each additional frozen ET leads to a higher cumulative chance of achieving a live birth
Pregnancy by day of embryo freezing and subsequent transfer in warming cycles
D2/D3 D3/D4 D2/D5 D3/D5 D5/D5-60.0%
10.0%
20.0%
30.0%
40.0%
50.0%
LBR
Day embryo freezing/Day ET warming cycle
Androfert 2012-2013; N= 415 warming cycles; Age ≤38
* * *p<.001
One size ET does not fit all
eSET (fresh)
Avoid multiple PR
PGS/PGD (aCGH)
FET cycles
DET (fresh)
PGS/PGD (FISH)
D2 ET in poor responders
What is the optimal means of preparing the endometrium in FET cycles?
Meta-analysis from 20 comparative studiesNatural cycle, artificial cycle with and w/o GnRH agonist
Groenewoud ER et al. Hum Reprod Update. 2013;19:458-70
All of the current methods of endometrial preparation appear
to be equally effective in terms of ongoing pregnancy rate
Safety and patient-centeredness not addressed
GnRH-agonist vs hCG LH trigger
Fresh autologous cycles
Moderate/ severe OHSS
OR 0.10, 0.01-0.82
Live birth OR 0.440.29-0.68Youssef et al. Cochrane Database Syst Rev. 2011
Patients at risk of OHSS
Fresh ET Freeze all
GnRH-a trigger
Safety
Effectiv
eness
One size LPS also does not fit all…
Courtesy of Dr. Peter Humaidan
Modified LPS for fresh ET in GnRH-a trigger
No. follicles day OPU
1500 IU hCG at OPU & 1000 OPU+5 & standard LPS≤ 14
1500 IU hCG at OPU + standard LPS15-25
1000 IU hCG at OPU + standard LPS or Freeze all26-30
Freeze all>30
14h
14h20h
48h0 20 h
4h
GnRHaNatural
Luteal phase defect
LH Surge
How to individualize ET and LPS as per TQM Conclusions
• One size does not fit all
• Patient profile and treatment strategy aid in determining best day for ET and LPS
• Quality dimensions of infertility care (effectiveness, safety and patient-centeredness) offer an opportunity to individualize ET technique and LPS
Thank you