This study was presented during ASRM2018. This is a systematic review and meta-analysis evaluating the potential clinical, obstetrical and perinatal benefits of the freeze-all policy ver the fresh embryo transfer

1. Clinical, obstetrical, and perinatal outcomes of freeze-all cycles:
systematic review and meta-analysis of randomized controlled trials
Human Reproduction Update - DOI: 10.1093/humupd/dmy033
Roque M.1; Haahr T.2, Geber S.1, Esteves SC.3,4; Humaidan P2,4
1ORIGEN, Center for Reproductive Medicine & Federal University of Minas Gerais (UFMG), Brazil
2Faculty of Health, Aarhus University, Denmark
3ANDROFERT–Andrology and Human Reproduction Clinic & University of Campinas (UNICAMP), Campinas, Brazil
4The Fertility Clinic Skive Regional Hospital, Skive, Denmark

2. Disclosure
• The authors declare no conflict with regards to the contents of this study
This presentation is available at:
www.slideshare.net/MatheusRoque1

3. INTRODUCTION
IMPLANTATION
Cha et al. 2012; Nat Med 18: 1754-67

4. NATURAL CYCLE IVF – STIMULATED CYCLE
Ovarian Stimulation vs. Endometrium
INTRODUCTION
Ubaldi et al. Fertil Steril 1997; 67:521-6; Devroey et al. Trends Endocrinol Metab 2004; 15:84-90; Horcajadas et al. Mol Hum Reprod 2005;11:195-205; Labarta et al. Hum Reprod 2011;26:1813-25

5. Ovarian Stimulation vs. Endometrium
INTRODUCTION
Cha et al. 2012; Nat Med 18: 1754-67

6. Cryopreservation 2: DELAYED FET:
Natural cycle or
with endometrial
priming
FREEZE-ALL STRATEGY
Shapiro et al. Fertil Steril 2008; 89:20-6; Shapiro et al. Fertil Steril 2011; 89:20-6; Shapiro et al. Fertil Steril 2011; 89:20-6
INTRODUCTION

7. OBJECTIVE
INTRODUCTION
Is Freeze-all advantageous for reproductive, obstetric,
and perinatal outcomes compared with Fresh ET ?

8. MATERIALS
&
METHODS

9. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis)
Study Protocol: PROSPERO CRD42018087454
Acessible at: http://www.crd.york.ac.ik/PROSPERO
Study question: Should elective frozen embryo transfer vs. fresh embryo transfer be used for
IVF/ICSI treatment?
Population: IVF/ ICSI patients
Intervention: Elective frozen embryo transfer (eFET)
Comparator: Fresh embryo transfer (ET)
Studies: Randomized controlled trials
Search: Pubmed/MEDLINE and EMBASE - until March 2018
Analysis: RevMan 5.3
Intention-to-treat
Risk Ratio (RR) and Mean Diference (MD)
Sensitivity Analysis for the outcomes with Funnel Plot asymmetry
MATERIALS
&
METHODS

10. Primary Outcome
Live birth rate per randomized patient
Primary Outcome - Sub-analysis
Live birth Rate – PCOS / Hyper-responder
Live birth Rate – Non-PCOS / Normo-responder
Live birth rate – Progesterone route (in luteal phase support in FET cycle)
Live birth rate – Cleavage stage
Live birth rate – Blastocyst stage
Live birth rate – Slow freezing
Live birth rate – Vitrification
Live birth rate – no-PGT-A
MATERIALS
&
METHODS

11. Secondary Outcomes
Cumulative live birth rate (12 months follow-up)
OHSS
Implantation rate
Miscarriage rate
Ectopic pregnancy
Preterm birth
Pregnancy induced hypertension
Preeclampsia
Birthweight (mean difference)
Congenital anomalies
MATERIALS
&
METHODS

12. RESULTS
Fig1. PRISMA Flowchart
11 Studies
5,379 women randomized

13. RESULTS
LIVE BIRTH RATE - 9 RCTs - 5,379 patients
Freeze-all - Overall Live Birth Rate
RR=1.12 (95% CI 1.01-1.24)

14. RESULTS
LIVE BIRTH RATE - NO-PGT - 8 RCTs - 5,200 patients
Freeze-all - Overall Live Birth Rate - No PGT
RR=1.07 (95% CI 0.99-1.17)

15. RESULTS
LIVE BIRTH RATE - Ovarian Response
Freeze-all PCOS/ Hyper Responder
RR=1.16 (95% CI 1.05-1.28)

16. RESULTS
LIVE BIRTH RATE - Ovarian Response
Freeze-all PCOS/ Hyper Responder
RR=1.16 (95% CI 1.05-1.28)
Freeze-all Normo Responder
RR=1.08 (95% CI 0.98-1.18)

17. RESULTS
CUMULATIVE LIVE BIRTH RATE
Freeze-all - Cumulative Live Birth
RR=1.04 (95% CI 0.97-1.11)

18. RESULTS
Ovarian Hyperstimulation Syndrome
Freeze-all and OHSS
RR=0.44 (95% CI 0.19-0.96)

19. RESULTS
Outcome
Absolute effect
Risk difference per
1000
Risk Ratio
(95% CI)
Total patients or other
denominator
(studies)
Quality of evidence
(GRADE)eFET versus Fresh
ET
(95%CI)
Ectopic pregnancy 3 fewer per 1000
(15 fewer to 19 more)
0.88
(0.45-1.71)
2765 patients
(4 studies)
⊕⊝⊝⊝
very low
Preterm birth 19 more per 1000
(10 fewer to 53 more)
1.13
(0.93-1.36)
2382 live births
(4 studies)
⊕⊕⊝⊝ low
Pregnancy induced
hypertension
0 fewer per 1000
(7 fewer to 17 more)
1.03
(0.48-2.18)
2398 clinical
pregnancies
(3 studies)
⊕⊕⊝⊝ low
Preeclampsia 18 more per 1000
(1 more to 47 more)
1.79
(1.03-3.09)
2388 patients
(3 studies)
⊕⊕⊕⊝ moderate
Birthweight (mean
difference)
127 grams higher
(3 lower to 257 higher)
n.s. 1489 patients
(4 studies)
⊕⊝⊝⊝
very low
Congenital anomalies 5 fewer per 1000
(22 fewer to 28 more)
0.88
(0.46-1.69)
2363 patients
(2 studies)
⊕⊝⊝⊝
very low
Higher in
Freeze-all
Obstetric and Perinatal Outcomes

20. When to do freeze-all?
‣For all?
‣Risk of OHSS?
‣Based on ovarian response?
‣P4 levels on the trigger day?
‣Implantation failure?
‣PGT (blastocyst)?
‣Slower developing blastocyst?
‣Endometriosis?
‣To improve obstetric / perinatal outcomes?
DISCUSSION

21. Endometrial advancement > 3 DAYS
NO PREGNANCY!
Mean number of retrieved oocytes
13.5-15.8
Ubaldi et al. Fertil Steril 1997; 67:521-6
FREEZE-ALL IS NOT FOR ALL
DISCUSSION

22. ‣COS -> endometrial gene expression profile
‣hCG+7 vs LH+7 – paired samples
‣>200 genes – different expression
OVARIAN STIMULATION AFFECTS ENDOMETRIAL RECEPTIVITY
Oocyte donors
13-18 oocytes retrieved
Estradiol Levels - 2200±300 pg/mL
Horcajadas et al. Mol Hum Reprod 2005;11:195-205
FREEZE-ALL IS NOT FOR ALL
DISCUSSION

23. ‣Oocyte donors
- P > 1.5 ng/mL (Study group)
- P < 1.5 ng/mL (Control group)
↑ HORMONAL LEVELS AFFECT ENDOMETRIAL RECEPTIVITY
Endometrium biopsy -> genic expression
140 genes ”up or down-regulated” – STUDY GROUP
Oocyte donors
20.5 -23.5 oocytes retrieved
Estradiol Levels – 2200 - 2600 pg/mL
Labarta et al. Hum Reprod 2011;26:1813-25
FREEZE-ALL IS NOT FOR ALL
DISCUSSION

24. Freeze-all to improve
obstetric/perinatal outcomes?
Outcome RR FAVOUR
Preterm delivery 0.90 (0.84-0.97) FET
Low birth weight 0.72 (0.67-0.77) FET
Small for gestational age 0.61 (0.56-0.67) FET
Hypertensive disorders 1.29 (1.07-1.56) FRESH
Large for gestational age 1.54 (1.48-1.61) FRESH
High birth weight 1.85 (1.46-2.33 FRESH
Maheshwari et al. Hum Reprod Update 2018; 24:35-58.
OUTCOME RR (95% CI) - FET vs Fresh FAVOURS
Preterm delivery 0.90 (0.84-0.97) FET
Low Birth weight 0.72 (0.67-0.77) FET
Small for gestational age 0.61 (0.56-0.67) FET
Hypertensive disorders 1.29 (1.07-1.56) FRESH
Large for gestational age 1.54 (1.48-1.61) FRESH
High birth weight 1.85 (1.46-2.33) FRESH
DISCUSSION

25. When to do freeze-all?
DISCUSSION

26. When to do freeze-all based on RCTs?
‣For all?
‣Risk of OHSS?
‣Based on ovarian response?
‣P4 levels on the trigger day?
‣Implantation failure?
‣PGT (blastocyst)?
‣Slower developing blastocyst?
‣Endometriosis?
‣To improve obstetric / perinatal outcomes?
DISCUSSION
?
?
?
?

27. CONCLUSIONS
No clinical data supporting the widespread use of freeze-all for all
Based on RCTs : Hyper response and PGT (blastocyst)
All other possible indications (RIF, ↑P4, AMA, endometriosis) still
need adequate studies
DISCUSSION

28. Thank you!
Matheus Roque
matheusroque@origen.com.brThor Haahr
Selmo Geber Peter Humaidan
Sandro Esteves
This presentation is available at:
www.slideshare.net/MatheusRoque1