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