1. Embryo Transfer Technologies
and Luteal Phase Support to
Maximize Pregnancy Rates
Sandro Esteves
Androfert, Brazil

2. 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

3. 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)

4. 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

5. 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/mistakes
Patient-centeredness relates to physical burden and
invasiveness of techniques for ET and LPS

6. 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?

7. • 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?
?

8. 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

9. 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

10. 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

11. Are they beneficial as a routine?
Antibiotics pre-ET
Intrauterine hCG
Pre-cycle
hysteroscopy
Trial transfer
Endometrial
scratching
May be
beneficial;
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

12. 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

13. ET SOP at Androfert (cont.)
Two-step ET
Outer sheath soft catheter advanced to just past internal os
Embryo load into the catheter
Insertion of the loaded soft catheter into the uterine cavity
Placement mid-portion of the uterus
Two-step catheter withdrawal
Soft catheter removed first (pressure on the syringe plunger
maintained) while outer sheath withdrawn past internal os
Laboratory check
Rigid outer sheath removed and checked

14. 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

15. Effectiveness Safety Patient-
centeredness
Soft catheter ✔ ✔
US-guided ✔ ✔
Mid-uterine
embryo
placement
✔
ET SOP (DC
& DW)
✔

16. Luteal Phase Support

17. Luteal phase of stimulated cycles is abnormal
Supraphysiologic steroid
levels (by multifollicular
development) inhibits LH
secretion
Normal corpus luteum
function dependent on
pulsatile LH release from
pituitary
Low 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

18. 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)
LPS mandatory in all stimulated cycles
Level
1a
van der Linden et al, Cochrane Database Syst Rev 2011:CD009154

19. 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?

20. 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

21. LPS with Progesterone is critical
P alone enough for LPS
Progesterone is a natural hormone secreted by the
corpus luteum
In the presence of estrogen, P transforms a proliferative
into a secretory endometrium
Progesterone increases the receptivity of the
endometrium
Once an embryo is implanted,
progesterone acts to maintain
the pregnancy

22. Routes/Type Evidence Effect Conclusion
Vaginal P as
effective as
IM/oral?
13 RCT; 2
MA; >2,000
cycles
Similar CPR, LBR,
miscarriage True
Vaginal P safer
and more
patient-friendly?
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
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

23. Higher endometrial P levels with vaginal administration
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
ngP/mgprotein
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)

24. First-pass uterine effect of P gel
1 hour
3 hours
2 hours
4 hours
Time
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

25. Agents and routes of LPS
Summary
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

26. 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

27. Dose of vaginal P
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
Low dose
Crinone 8% (90 mg)
vs. high dose
200-800 mg/d;
capsules, tablets,
pressaries
Similar
outcome
Van der Linden et al Cochrane 2011

28. When to start LPS
Mochtar et al, 2009
RCT, N=385
LPS 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

29. 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

30. 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

31. Which dose and when to start and stop P
Summary
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

32. Effectiveness Safety Patient-
centeredness
P alone
✔ ✔
Vaginal P
gel
✔
✔
2-week
regimen
✔ ✔

33. Real-life practices reported worldwide
Vaisbuch et al. RBM 28: 330-5, 2014

34. LPS SOP at Androfert*
Progesterone gel (Crinone 8%)
90 mg daily
Start at day 2 post-OCP
Stop upon completion of 9-week
gestation
No serum determination of P or E2
Likely to bleed before progesterone
discontinuation if not pregnant
*hCG trigger

35. 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 supplementation
likely to have low
levels of estradiol
Roman E et al. Hum Reprod. 2000

36. How to individualize ET and
LPS according to TQM

37. Does one size fit all?
What to
do?
Normal
responder
High
responder
Poor
responder
Day 2
transfer
Day 3
transfer
Blastocys
t transfer
Freeze all
Type of LPS

38. 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%

39. 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
Each additional frozen ET leads to a higher
cumulative chance of achieving a live birth

40. Pregnancy by day of embryo freezing and
subsequent transfer in warming cycles
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
* * *p<.001

41. 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

42. What is the optimal means of preparing the
endometrium in FET cycles?
Meta-analysis from 20 comparative studies
Natural 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

43. 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…

44. 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
14h
20h
48h0 20 h
4h
GnRHa
Natural
Luteal
phase
defect
LH Surge

45. 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

46. Thank you