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

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sandroesteves