CLEAVAGE OR BLASTOCYST EMBRYO TRANSFER

1. CLEAVAGE OR
BLASTOCYST
EMBRYO
TRANSFER
Is the Debate Over?
Dr Kaberi Banerjee

2. Pros & Cons

3. < 4 E M B RYO S
C L E AVAG E B E T T E R
C L E AVAG E B E T T E R
I N YO U N G E R
B L A S TO C Y S T N OT
S I G N I F I CA N T LY
B E T T E R
ASSISTED REPRODUCTION TECHNOLOGIES
Ongoing and cumulative pregnancy rate after cleavage-stage
versus blastocyst-stage embryo transfer using vitrification
for cryopreservation: Impact of age on the results
S. Fernández-Shaw & R. Cercas & C. Braña & C. Villas & I. Pons
Received: 8 August 2014 /Accepted: 4 November 2014 /Published online: 18 November 2014
# Springer Science+Business Media New York 2014
Abstract
Purpose To determine if blastocyst transfer increases the on-
going and cumulative pregnancy rates, compared with day 3
embryo transfer, in women of all ages when at least 4 zygotes
are obtained.
Methods Prospective study including patients undergoing a
first IVF/ICSI treatment and assigned to cleavage stage (n=
46) or blastocyst (n=58) embryo transfer. Supernumerary em-
bryos were vitrified and patients failing to achieve an ongoing
pregnancy after fresh embryo transfer would go through cryo-
preserved cycles. The main outcome measure was the ongoing
pregnancy rate after the fresh IVF/ICSI transfer and the cumu-
lative ongoing pregnancy rate. Results were also analyzed
according to age (under 35 and 35 or older).
Results A majority of patients (96.6 %) had a blastocyst
transfer when at least 4 zygotes were obtained. The ongoing
pregnancy rate was significantly higher in the day-5 group
compared with the day-3 group (43.1 % vs. 24 %, p=0.041).
The cumulative ongoing pregnancy rate was higher (but not
significantly) with blastocyst than with cleavage stage embry-
os (56.8 % vs. 43.4 %, p=0.174). When analysed by age,
Keywords Blastocyst .Ongoingpregnancyrate .Cumulative
pregnancy rate . Age . Vitrification
Introduction
The rationale for blastocyst culture is to improve both uterine
and embryonic synchronicity and enable self selection of
viable embryos thus resulting in higher implantation rate [1].
The meta-analysis by Papanikolaou et al., in 2008 [2],
analysing eight randomized controlled trials (RCTs) conclud-
ed that the clinical pregnancy rate and live birth rate after fresh
IVF were significantly higher after blastocyst-stage embryo
transfer as compared to cleavage-stage embryo transfer when
equal number of embryos were transferred in the two groups
compared. Subsequently 12 RCTs summarized in the
Cochrane review [1] demonstrated that live birth rates can
be optimized by performing fresh blastocyst transfer com-
pared to cleavage stage embryo transfers, but no differences
were observed in the analysis of 23 RCTs in either clinical
J Assist Reprod Genet (2015) 32:177–184
DOI 10.1007/s10815-014-0387-9
pregnancy rate after the fresh IVF/ICSI transfer and the cumu-
lative ongoing pregnancy rate. Results were also analyzed
according to age (under 35 and 35 or older).
Results A majority of patients (96.6 %) had a blastocyst
transfer when at least 4 zygotes were obtained. The ongoing
pregnancy rate was significantly higher in the day-5 group
compared with the day-3 group (43.1 % vs. 24 %, p=0.041).
The cumulative ongoing pregnancy rate was higher (but not
significantly) with blastocyst than with cleavage stage embry-
os (56.8 % vs. 43.4 %, p=0.174). When analysed by age,
patients 35 or older showed significantly higher ongoing
pregnancy rate (48.4 % vs. 19.3 %, p=0.016) and cumulative
ongoing pregnancy rate (58 % vs. 25.8 %, p=0.01) in the day-
5 group compared to the day-3 group, while no such differ-
ences were observed in women under 35.
Conclusions Blastocyst transfer can be suggested whenever
there are at least 4 zygotes. While there are no differences in
women under 35, the benefit of this option over cleavage stage
transfer could be significant in women 35 or older.
ana
ed
IVF
tran
equ
com
Co
be
par
we
pre
tria
gro
The
cre
sig
rate
per
pre
stu
cle
age
Capsule The transfer of blastocysts significantly improve the clinical and
ongoing pregnancy rate as well as thecumulative pregnancy rate in
women 35 years or older.

4. COMMENTARY
Should we be promoting embryo transfer at
blastocyst stage?
Abha Maheshwari a,
*, Mark Hamilton a
, Siladitya Bhattacharya b
a
Aberdeen Fertility Centre, NHS Grampian, Foresterhill, Aberdeen AB25 2ZL, UK; b
University of Aberdeen, Polwarth
Building, Foresterhill, Aberdeen, UK
* Corresponding author. E-mail address: abha.maheshwari@abdn.ac.uk (A Maheshwari).
Abstract Improved laboratory standards and better culture media have made extended culture to blastocyst stage a reality to iden-
tify embryos with maximum implantation potential. The strategy of extended culture has become more popular across the world at
a time when regulatory bodies have emphasized the need to increase the uptake of elective single embryo transfer, minimize com-
plications associated with multiple births and aim for a healthy singleton live-birth as the preferred outcome in IVF. New data on
perinatal outcomes suggest that pregnancies after embryo transfer at blastocyst stage are associated with a higher risk of preterm
delivery, large for gestational age babies, monozygotic twins and altered sex ratio compared with those following embryo transfers
at cleavage stage. In addition, concerns have been raised of increased congenital anomalies and epigenetic modifications with embryo
transfer at blastocyst stage. Twenty-four years on from the first embryo transfer at blastocyst stage, we examine the reasons for
extended embryo culture, evaluate the risks and benefits of this strategy and suggest the need to reconsider this policy in the in-
terests of fetal safety.
© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: blasocyst, embryo transfer, preterm delivery, IVF
Introduction
Advances in our knowledge of in-vitro culture conditions have
led to the development of stage-specific or sequential media
(Gardner et al., 1998), making it possible to conduct rou-
tinely extended culture of embryos to the blastocyst stage.
The first reports of pregnancy and live birth from an embryo
transferred at blastocyst stage (day 5–6 after egg collec-
tion) were published in 1985 (Cohen et al., 1985) and 1991
(Bolton et al., 1991), respectively. Since then, a constant in-
crease in proportion of embryo transfers at blastocyst stage
has been reported (from 1% in 2000 to 34% in 2012 in UK
(http://www.hfea.gov.uk/104.html).
In this paper, we examine the reasons for extended embryo
culture, evaluate the risks and benefits of this strategy and
consider whether a policy of embryo transfer at blastocyst
stage is still justified.
Reasons for choosing extended culture
Extended culture has been considered to be a better option
than cleavage stage embryo transfer for a number of reasons.
Physiological synchronization
Transfer of the embryo to the uterine cavity after 5 days of
insemination or injection is thought to provide better embryo–
endometrium synchrony, and therefore higher chances of im-
plantation as it mimics more closely the sequence of events
in natural conception. Unlike the situation in a natural
cycle, however, ovarian stimulation during IVF leads to
supraphysiological levels of oestrogen and progesterone, which
enhances the endometrial development, i.e. the endome-
trial milieu at day 3 after egg collection (in a stimulated
Reproductive BioMedicine Online (2016) 32, 142–146
www.sciencedirect.com
www.rbmonline.com
stage. It could be argued that the type of culture media used
in extended culture could be responsible for large for gesta-
tional age babies; however, a recent study seems to refute
this (De Vos et al., 2015).
Congenital anomalies
A recent meta-analysis (Dar et al., 2014) reported that the
odds of congenital anomalies were significantly higher for
babies born after embryo transfer at blastocyst stage com-
pared with those born after embryo transfer at cleavage stage
(1.29, 95% CI 1.03 to 1.62).
culture?
Despite the concerns highlighted above (Figure 1), exte
ing culture to blastocyst stage seems to be the preferred st
egy among many IVF clinics, and its popularity has gro
exponentially in recent years. The key drivers for this
proach are the importance clinics, commissioners and
tients attach to the realization of short-term goals (hig
pregnancy rates per embryo transfer episode) and their
sition in national league tables based on success rates. T
is mainly due to the fact that single embryo transfer at b
tocyst stage leads to a significantly higher pregnancy rate
embryo transfer compared with those at cleavage stage.
Factors favouring
blastocyst stage
embryo transfer
Factors favouring
cleavage stage
embryo transfer
Figure 1 Balance between blastocyst and cleavage stage embryo transfer.

5. ASSISTED REPRODUCTION TECHNOLOGIES
No advantage of fresh blastocyst versus cleavage stage embryo transfer
in women under the age of 39: a randomized controlled study
Paolo Emanuele Levi-Setti1,2
& Federico Cirillo1
& Antonella Smeraldi1
&
Emanuela Morenghi3
& Giulia E. G. Mulazzani4
& Elena Albani1
Received: 17 August 2017 /Accepted: 14 November 2017 /Published online: 22 November 2017
# Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract
Purpose Is there a difference in implantation and pregnancy rates between embryos transferred electively at cleavage or blasto-
cyst stage in infertile women ≤ 38 years with at least four zygotes on day 1 post retrieval?
Methods A randomized clinical trial was conducted in a single tertiary care hospital with a sample size of 194 patients in each
arm for a total population of 388 women. Patients less than 39 years of age with more than three fertilized oocytes and less than
four previous assisted reproductive technology (ART) attempts were inclusion criteria.
Results The two groups were similar for age, years of infertility, indication to treatment, basal antimüllerian hormone and FSH,
number of previous ART cycles, primary or secondary infertility, type of induction protocol, days of stimulation, total gonad-
otrophin dose, and estradiol (E2) and progesterone (P) levels at trigger. No statistically significant differences were found in terms
of number of retrieved oocytes, inseminated oocytes, fertilization rate, canceled transfers (7.73% in blastocyst and 3.61% in
cleavage stage group), and cycles with frozen embryos and/or oocytes. Although a higher number of fertilized oocytes were in the
blastocyst stage group (6.18 ± 1.46 vs 5.89 ± 1.54, p = 0.052), a statistically greater number of embryos/randomized cycle were
Journal of Assisted Reproduction and Genetics (2018) 35:457–465
https://doi.org/10.1007/s10815-017-1092-2

6. • Low quality evidence that Blastocyst
transfer may be associated with
higher live birth rates than Cleavage
stage.
• No evidence of a difference between
the groups in Cumulative Pregnancy
rates
• Further RCTs are needed
Cochrane
Library
Cochrane Database of Systematic Reviews
Cleavage stage versus blastocyst stage embryo transfer in assisted
reproductive technology (Review)
Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D

7. • Burden of additional transfer of
Cleavage Stage Embryos
• Cost of more embryos to freeze in
Cleavage Stage
• Burden of additional oocyte pick up if
no embryo formed or to freeze in
Blastocyst Transfer
• Cost of extended culture and
vitrification of Blastocyst
Cleavage-stage or blastocyst
transfer: what are the benefits
and harms?
Demi!
an Glujovsky, M.D., M.Sc.a
and Cynthia Farquhar, M.D., M.P.H.b
a
Department of Reproductive Medicine, Center of Studies of Genetics and Reproduction (CEGYR), Buenos Aire
and b
Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University
Auckland, New Zealand
ET is a critical step in an assisted reproduction cycle. Over the past decade there has been an increasing trend
cleavage-stage to blastocyst transfer. There has also been a trend to single ET and reporting the success of an
as a cumulative live-birth rate after using both fresh and frozen embryos. There is low evidence that fresh b
ciated with improved live-birth rates compared with fresh cleavage-stage embryos. However, in the few stud
pregnancy rates after fresh and frozen transfers, no significant difference was found. Cleavage-stage transfe
numbers of embryos available for freezing, and blastocyst transfer is associated with increased number of
transfer. Further well-designed studies are warranted to evaluate the outcomes for blastocyst transfer inclu
rate after fresh and frozen transfers, time to live birth, costs of the different transfer strategies, and perinatal
natal morbidity. (Fertil Steril! 2016;106:244–50. "2016 by American Society for Reproductive Medicine.)
Key Words: Embryo transfer, cleavage, blastocyst
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.f
10584-cleavage-stage-or-blastocyst-transfer-what-are-the-benefits-and-harms
A
s many as one in six couples
will experience difficulty
conceiving and may seek assis-
ted reproduction to achieve a preg-
nancy. One of the most important
steps during an assisted reproduction
cycle is the transfer of the embryo
from the laboratory to the uterus. Tradi-
tionally, cleavage-stage embryos were
transferred on day 3, but over the past
decade there has been a move to trans-
ferring blastocysts on day 5 or 6. Trans-
fer at this stage is considered to be a
In Australia they have risen from less
than 30% of cycles in the 2004–7 to
over 60% of assisted reproductive tech-
nology (ART) cycles in 2013 (1, 2).
Similar increases have been reported in
the United States and the United
Kingdom, with approximately more
than one third of ART cycles in 2012
being blastocyst transfers (3, 4).
At the same time that blastocyst
transfer was increasingly used, there
were a number of other developments
occurring in the fertility laboratory.
move to p
screening of e
blastocyst dev
these new dev
of these shou
focus of this
whether blast
effective than
Direct co
two stages o
appear to supp
transfers in c
who undergo
Fertil Steril 2016

8. Extended embryo culture to the
blastocyst stage has the potential to
compromise obstetric and perinatal
outcomes as increased rate of
placenta praevia and preterm
delivery in fresh cycles.
Human Reproduction, Vol.35, No.4, pp. 805–815, 2020
Advance Access Publication on April 15, 2020 doi:10.1093/humrep/deaa032
ORIGINAL ARTICLE Fertility control
Obstetric and perinatal risks in 4601
singletons and 884 twins conceived
after fresh blastocyst transfers: a
Nordic study from the CoNARTaS
group
A.L. Spangmose1,*, E. Ginström Ernstad2
, S. Malchau2
, J. Forman3
,
A. Tiitinen4
, M. Gissler5
, S. Opdahl6
, L.B. Romundstad6,7
, C. Bergh2
,
U.B. Wennerholm2
, A.A. Henningsen1
, and A. Pinborg1
1
Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark 2
Department of Obstetrics and Gynecology,
Institute of Clinical Science, Sahlgrenska Academy, Gothenburg University, Sahlgrenska University Hospital, Gothenburg, Sweden 3
Section of
Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark 4
Department of Obstetrics and Gynecology,
Helsinki University Hospital and University of Helsinki, Helsinki, Finland 5
Information Services Department, Finnish Institute for Health and
Welfare (THL), Helsinki, Finland and Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
6
Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology,
Trondheim, Norway 7
Spiren Fertility Clinic, Trondheim, Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
*Correspondence address. Fertility Clinic, Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Rigshospitalet,
Denmark. Tel: +45 30 59 38 15; E-mail: anne.laerke.spangmose.pedersen@regionh.dk
Submitted on October 21, 2019; resubmitted on December 13, 2019; editorial decision on February 9, 2020
STUDY QUESTION: Are obstetric and perinatal outcomes in pregnancies after fresh blastocyst transfer (BT) comparable with those born
after fresh cleavage stage transfer (CT) and spontaneous conception (SC)?
SUMMARY ANSWER Fresh BT is associated with a higher risk of placental and perinatal complications.
Downloaded
from
https://academic.oup.com/humrep/article/35/4/805/5820

9. • Good for good prognosis
• Not always for recurrant
implantation failure and those
with fewer embryos
• Pregnancy rate/started cycle may
be low
• CancelledTransfers Increase
• Can we predict blastulation rate?
• Excellent Laboratory and Skill set
• Excellent Cryopreservation Unit
• May have fewer/no embryos to
transfer
Blastocyst culture and transfer in
clinically assisted reproduction:
a committee opinion
Practice Committee of the American Society for Reproductive Medicine and Practice Committee of the
Society for Assisted Reproductive Technology
American Society for Reproductive Medicine, Birmingham, Alabama
The purposes of this Practice Committee Opinion, which replaces the 2013 ASRM Practice Committee Opinion of the same name (Fertil
Steril 2013; 99:667–72), are to review the literature regarding the clinical application of blastocyst transfer and identify the potential risks
and laboratory issues related to the use of this technology. This document does not apply to patients undergoing blastocyst culture and
transfer for preimplantation genetic testing. (Fertil Steril! 2018;110:1246–52. "2018 by American Society for Reproductive Medicine.)
Earn online CME credit related to this document at www.asrm.org/elearn
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/38842-26977
INTRODUCTION
Extending the duration of embryo cul-
ture to the blastocyst stage for assisted
reproduction offers several theoretical
advantages over the transfer of
ports blastocyst development equiva-
lently to that of sequential media
(14–16).
Commercially available media pro-
vide the means for any in vitro fertiliza-
these reasons, blastocyst transfer
should translate into higher implanta-
tion and, more importantly, live-birth
rates.
The results of a randomized trial in
Fertil Steril,2018

10. STUDY PROTOCOL Open Access
Non-inferiority of cleavage-stage versus
blastocyst-stage embryo transfer in poor
prognosis IVF patients (PRECiSE trial): study
protocol for a randomized controlled trial
Werner M. Neuhausser1,2,3,4,5*
, Denis A. Vaughan1,2,3
, Denny Sakkas3
, Michele R. Hacker1,2
, Tom Toth1,2,3
and
Alan Penzias1,2,3
Abstract
Background: With improvements in in vitro culture techniques there has been a steady shift in practice to transfer
embryos at the blastocyst stage (post fertilization day (p.f.d.) 5–7), when embryos reach the endometrial cavity
during natural conception. For patients with > 5 zygotes on day 1 of embryo development, fresh blastocyst embryo
transfer (ET) increases live birth rates when compared to cleavage stage (p.f.d. 3) transfer. In poorer prognosis
patients (≤ 5 zygotes) cleavage stage ET is commonly performed to reduce the risk of cycle cancellation if no
embryo survives to the blastocyst stage. However, there is a dearth of randomized controlled trial (RCT) data
demonstrating improved live birth rates per cycle for cleavage vs blastocyst stage ET in this subgroup of patients.
The hypothesis of the PRECiSE (PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer) trial is that
blastocyst ET is not inferior to cleavage stage ET with regard to live birth rates per retrieval in poorer prognosis
Neuhausser et al. Reproductive Health (2020) 17:16
https://doi.org/10.1186/s12978-020-0870-y

11. Blastocyst vs Cleavge
The Debate is
Ongoing!
ThankYou!