Human Reproduction, pp.

1–5, 2023
https://doi.org/10.1093/humrep/deac269

PEER PERSPECTIVES

Better late than never: the clinical

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value of Day 7 blastocysts
Juan J. Fraire-Zamora 1, Munevver Serdarogullari 2,
Kashish Sharma 3, Omar Farhan Ammar 4, Mina Mincheva 5
,
Nick Macklon6, Aı̈da Pujol7, Antonio Capalbo 8,
Marcos Meseguer9,10, and George Liperis 11*
1
Clınica EUGIN, Barcelona, Spain 2Department of Histology and Embryology, Faculty of Medicine, Cyprus International
University, Northern Cyprus via Mersin 10, Turkey 3ART Fertility Clinics LLC, Abu Dhabi, United Arab Emirates 4Nuffield Department of
Women’s & Reproductive Health, University of Oxford, Oxford, UK 5Biomathematics Research Centre, University of Canterbury,
Christchurch, New Zealand 6London Women’s Clinic, London, UK 7Centro de Infertilidad y Reproducción Humana (CIRH)—Eugin
Group, Barcelona, Spain 8JUNO Genetics, Reproductive Genetics, Rome, Italy 9IVF Laboratory, IVI Valencia, Valencia, Spain 10Health
Research Institute la Fe, Valencia, Spain 11Westmead Fertility Centre, Institute of Reproductive Medicine, University of Sydney,
Westmead, NSW, Australia

*Correspondence address. Westmead Fertility Centre, Institute of Reproductive Medicine, University of Sydney, Corner of Hawkesbury
and Darcy Roads, Westmead Hospital, Westmead NSW 2145, Australia. E-mail: georgeliperis@gmail.com https://orcid.org/0000-
0001-9588-3392

The advancement of in vitro culture media has improved the efficacy of

..
..
ARTs in the treatment of infertility (Chronopoulou and Harper, 2015). ..
..
Despite this progress, embryos may demonstrate delayed develop- ..
ment and reach the blastocyst stage on Day 7. The prevalence of ..
..
these slow embryos has been reported as 5% and even though they ..
are considered to be less competent and reveal a lower euploidy rate ..
..
than faster growing embryos, they are still capable of achieving high im- ..
plantation and clinical pregnancy rates (Hammond et al., 2018). These ..
..
slow-developing embryos could have clinical value in patients with re- ..
duced chance to achieve a live birth (LB) with their own oocytes. This
..
..
clinical value has been demonstrated by the increased number of ..
..
patients that obtain at least one transferable embryo following preim- ..
plantation genetic testing for aneuploidy (PGT-A) with the extension ..
..
of culture to Day 7 (Capalbo et al., 2014; Cimadomo et al., 2018; ..
Tiegs et al., 2019). Studies thus far exploring the extension of culture ..
..
to Day 7 lack uniformity in defining the Day 7 embryo, as well as pro- ..
viding context toward the parameters for proceeding with extended ..
..
culture, culture conditions, local regulations and clinical setting.
The October edition of the ESHRE Journal Club (#ESHREjc) dis-
cussed an observational study by Cimadomo et al. (2022b), in which
1966 blastocysts obtained from 681 patients were cultured to the full
expanded blastocyst stage up to Day 7 and before undergoing embryo
biopsy and PGT-A. The study defined Day 7 based on hours post in-
semination (h.p.i.) and assessed embryo quality using Gardner’s crite-
ria, confirming with artificial intelligence (AI)-powered software.
Euploidy, miscarriage and live birth rates (LBRs) were also assessed
per vitrified-warmed euploid single blastocyst transfer for different
groups based on the time of biopsy (from <120 h.p.i. and at 12 h
intervals up to >168 h.p.i.). The #ESHREjc discussion focused on the
definition, utilization and safety of Day 7 embryos and their grading/
ranking using AI software. The Twitter event hosted 27 participants
along with experts Nick Macklon, Aı̈da Pujol, Antonio Capalbo,
Marcos Meseguer and author Danilo Cimadomo. The discussion
resulted in 882 tweets and 1.3 M impressions generated over a 24-h
period. Figure 1 summarizes the key points discussed.
Definition and utilization of Day
7 blastocysts
Cimadomo et al., reported the use of ICSI, continuous culture with
Day 5 media refresh, trophectoderm (TE) biopsy without assisted
hatching and PGT-A for all cases. These lab procedures allowed them
to define Day 7 embryos as those reaching the blastocyst full expan-
sion stage at a specific time-lapse imaging observational timing
reported in h.p.i. Since there is not yet an internationally standardized
.. definition for a Day 7 blastocyst, the Journal Club participants agreed
.. with the authors on their definition and the use of the time point
..
.. 144 h.p.i. to characterize Day 6 embryos as the threshold to which
..
.. Day 7 embryos can be defined. However, participants also acknowl-
.. edged that clinical and laboratory disparities could result to a few hour
..
.. differences in different clinical settings.
.. The study was conducted in Italy, where Law 40/2004 imposes the
..
.. clinical use of all viable embryos produced. The Journal Club discussion
.. continued with a question on whether there is any value behind ex-
..
.. tended culture over performing another cycle in countries where there
.. are no stringent policies around the use of all viable embryos. Journal
..
. club participants agreed that, even though we cannot generalize for all

C The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email:
V
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2 Fraire-Zamora et al.

Better late than never. The clinical value of Day 7 blastocysts

Is miscarriage associated Application of time lapse
Definition and utilisation of Safety of extended culture to
with slow-developing and AI for Day 7 blastocyst
Day 7 blastocysts Day 7 blastocysts

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• Currently there is no internationally
standardised definition of Day 7
blastocysts.
• In Cimadomo et al, Day 7 embryos
are defined: a) as those reaching
fully expanded blastocyst at a
specific time-lapse imaging time
point, reported as h.p.i. b) Day 6
embryos (144 h.p.i.) are used as a
threshold for Day 7 embryo
definition.
•
blastocysts? ranking
• What are the factors that may • Available data suggest that external • TLM systems can help describe
contribute to higher aneuploidy among environment and in vitro conditions can blastocyst expansion dynamics.
Day 7 blastocysts in Cimadomo et al? have profound effects.
• Morphokinetic features and
Æ higher prevalence of slower Æ culture conditions can impact embryological events which have
development, poorer morphological epigenome, gene expression and been used so far in AI algorithms
quality, more frequent spontaneous embryo metabolism with consequent to predict embryo competency
collapses (1) effects on monozygotic twinning, foetal and clinical outcomes:
growth and birth weight
• What is the clinical value of high Æ time of blastulation (3)
miscarriage rate (40%) observed in Æ incubator environment may impact
Cimadomo et al when biopsy was embryo metabolism with implications to Æ blastocyst collapse (marker for low
performed past 144 h.p.i? extended embryo culture implantation potential (4)
-

The value of Day 7 blastocyst over

performing a new cycle was
suggested: a) for poor prognosis
patients (AMA, <3 embryos), where
cLBR will increase per ITT b)
patients who cannot consider
oocyte donation c) to reduce
psychological distress resulting
from each failed cycle
• Day 7 blastocysts should be
transferred in FET on a
synchronous endometrium
Æ the study was retrospective and the Æ number and timeframes of changing
sample size of patients having transfer medium in extended culture may thus
of embryos >144 h.p.i. was small have added importance and requires
validation
Æ retrospective associations do not
provide evidence of causation or • Safety data on offspring health is still
estimation of the clinical impact limited
Æ there may be selection bias toward • perinatal outcomes in offspring born
poor prognosis patients receiving slow- from day 7 blastocyst transfer are
developing embryos comparable to those from day 5 and
day 6 blastocyst transfers (2)
Legend:
h.p.i.: time post insemination
AMA: advanced maternal age
cLBR: cumulative live birth rate
ITT: intention to treat
FET: frozen embryo transfer
AI: artificial intelligence
TLM: time lapse monitoring

Ref: 1. Bamford et al. 2022, PMID: 35613016; 2. Hiraoka et al. 2009, PMID: 20485579;
3. Bori et al. 2022, PMID: 35435210; 4. Sciorio et al. 2020, PMID: 31928572

Figure 1. Graphical summary of the #ESHREjc discussion.

..
patients, poor prognosis patients such as advanced maternal age and ..
..
those with less than three embryos would benefit more in terms of
..
cumulative live birth rate (cLBR) increase per intention to treat. ..
Furthermore, patients that cannot consider donor cycles and those ..
..
that experience financial difficulties could also benefit from the ex- ..
tended culture. The emotional impact of each failed cycle should also ..
..
be considered as IVF failure can result in subsequent psychological dis- ..
tress (Pasch et al., 2012). Furthermore, it was highlighted that patient
..
..
preference to optimize the chances of one cycle instead of undergoing ..
additional cycles should also be considered.
..
..
With regard to the optimal window to transfer slow developing ..
embryos, Journal Club experts, explained that slower blastocysts
..
..
may breach the epithelium beyond the ‘window of selectivity’ ..
..
which means that the first maternal check point for quality would
fail (Teklenburg et al., 2010). Transferring slow-developing em-
bryos in a fresh cycle could therefore lead to higher miscarriage
rate of endometrial origin. Journal club participants agreed that
slow-developing blastocysts should not be transferred fresh, but
after vitrification and frozen embryo transfer (FET) on a synchro-
nous endometrium. Even further, Journal Club experts pointed out
that despite slow-developing blastocysts taking longer to reach the
stage of initiating implantation, the number of days of exposure to
progesterone does not need to be adjusted in subsequent FET
cycles. Therefore, Day 7 blastocysts should be considered as Day
5 embryos in regard to the planning of the FET cycle in order to
optimize synchronization with the window of implantation of the
endometrium.
Is miscarriage associated with
slow-developing blastocysts?
Since Cimadomo et al., claimed that euploidy is imputable to quality
and age, but not to a slower development, another question focused
on the factors that could be contributing to the higher rate of aneu-
ploidy seen in Day 7 blastocysts in this study. Journal Club experts
explained that, to the best of our knowledge, meiotic aneuploidies are
just mildly associated with a developmental arrest in the preimplanta-
tion period and certainly do not prevent blastulation. Nonetheless,
aneuploidies have been associated with a higher prevalence of mild
defects such as slower development, poorer morphological quality and
more frequent spontaneous collapses (Bamford et al., 2022). In the fu-
.. ture, it would be interesting to investigate whether, which and to what
.. extent certain hallmarks of embryo development might be impaired by
..
.. chromosomal aneuploidies.
.. Cimadomo et al., reported that miscarriage was not statistically as-
..
... sociated with slow development after adjusting for euploidy in their
.. study. However, miscarriage rate was as high as 40% when biopsy was
.. performed beyond 144 h.p.i. (compared to 13% in the control at
..
.. <120 h.p.i.). In terms of the clinical value of these findings, Journal
.. Club participants and experts agreed that these correlations need to
..
.. be taken with caution because of the retrospective observational origin
.. of the study. It was highlighted that the sample size beyond 144 h.p.i.
..
.. is small for robust conclusions, simply because few patients had trans-
.. fers of euploid blastocysts in this group. In clinical practice and work-
..
. flow, slow-developing blastocysts are considered the last option and
#ESHREjc October 2022 3

..
are therefore transferred in those women with no other available eu- .. study that examined perinatal outcomes from Day 7 vitrified-warmed
ploid embryos. This practice can introduce a selection bias toward .. blastocyst transfer cycles (Huang et al., 2020). The study by Huang
..
poor prognosis patients receiving slow-developing embryos for trans- .. et al., showed a higher risk of very large for gestational age of Day 7
fer, who perhaps failed to get pregnant with faster and better quality ... blastocysts when compared with Day 3 cleavage-stage embryos, while
euploid blastocysts. Furthermore, euploid blastocysts beyond 144 h.p.i. .. blastocysts with diverse growth rates demonstrated similar develop-
..
only account for a minority of embryos. A larger dataset will thus be .. mental viability regardless of the day of vitrification. Having in mind the

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required to corroborate these data. Overall, participants and experts .. complexity in terms of the number of confounding variables with
..
agreed that retrospective associations do not provide evidence of cau- .. known effects on obstetric outcomes such as the type of embryo
sation or estimation of the clinical gain. To understand if and to what .. (fresh vs frozen), stimulation protocol, fertilization method (IVF vs
..
extent extended culture could impact embryo selection in clinical prac- .. ICSI), cause of infertility, maternal and paternal age, co-morbidities, ad-
tice, randomized control trials (RCTs) would need to be conducted .. jacent treatments, and type of pregnancy (single vs twin/multiple), ex-
..
where slow developing euploid embryos are not de-prioritized for .. ecution of an RCT becomes a mountainous task (Kondapalli and
transfer.
.. Perales-Puchalt, 2013).
..
.. Regarding the plausible biological factors undermining delayed attain-
.. ment of blastocyst stage in good quality embryos, several factors have
..
.. been attributed (Hammond et al., 2018). An investigation of the differ-
Safety of Day 7 blastocysts .. ent embryological events such as the first cleavage, genome activation
..
In certain countries, including Italy, extended embryo culture is used, .. and morula formation in blastocysts with slow development will shed
as the law mandates the use of all viable embryos for clinical purposes.
..
.. light on factors affecting the speed of development. Potential issues
While many other clinics are not subject to laws or regulations like .. with maternal to zygotic transition could for example lead to a delayed
those in Italy, they continue to culture embryos beyond Day 5, partic-
..
.. formation of inner cell mass (ICM) and TE. Journal club participants in-
ularly for couples with poor prognosis cycles and those who are un- .. dicated that there could be some embryos more sensitive to culture
able to consider donor cycles. With this approach, LBR per embryo
..
.. conditions that delay their development when the environment is sub-
transfer (ET) might decrease because the embryos are less competent, .. par or maybe there is a correction machinery in vivo that we still don’t
..
but more patients would have embryos available for ET and therefore .. know. Omics will also be useful to attain information regarding this
an increase in the cLBR might be expected. From experience in cen- .. ‘black box’ of embryo development. ESHREjc participants agreed that
..
ters that utilize extended culture, it was noted that not all patients .. this is just the beginning of threading the needle of slow-developing
have extended culture and it often involves only a limited extension of .. blastocysts.
..
the time of culture. Therefore, not much disruption of the laboratory ..
workflow is anticipated from a cost-benefit perspective when employ- ..
..
ing extended culture. .. How can time lapse and AI help
However, data and knowledge are both lacking regarding the safety ..
.. select the best ranking embryo
of extended culture systems. In the early stages of embryonic develop- ..
..
ment, the external environment and in vitro culture conditions can .. for transfer amongst a cohort
have profound effects (Behr and Wang, 2004; Duranthon and ..
Chavatte-Palmer, 2018). Culture conditions can have an impact on the
.. of Day 7 blastocysts?
..
epigenome, gene expression and embryo metabolism. These effects .. The factors affecting blastocyst expansion dynamics are not fully eluci-
for instance can have a variety of effects such as increasing chances of
.. dated. Time lapse (TL) monitoring systems are well suited to describe
..
monozygotic twinning and influencing fetal growth and birth weight .. these dynamic features of blastocyst expansion. Since the first report
(Cassuto et al., 2003; Behr and Wang, 2004; Nelissen et al., 2013;
.. of a successful pregnancy following blastocyst selection by TL monitor-
..
Spangmose et al., 2020). The incubator environment has also been .. ing (Pribenszky et al., 2010), several studies have provided useful data
shown to impact embryo metabolism with implications for embryos in
.. in terms of blastocyst features useful for selection algorithms (Marcos
..
prolonged culture and for the potential importance of changing the cul- .. et al., 2015; Huang et al., 2016). For instance, it has been shown that
..
ture medium (Kermack et al., 2022). The number and timeframes of .. expansion may be relatively restricted in embryos blastulating at rela-
changing the culture medium in extended culture can therefore be of .. tively later times (Huang et al., 2016). The feature of time of blastula-
..
added importance and requires validation. Concerning obstetric and .. tion has since been integrated by AI to rank embryos, with embryos
perinatal risks on children conceived after fresh blastocyst transfer, a .. blastulating late having a lower score and diminished clinical outcomes
..
Danish study found an increased risk of placental and perinatal compli- .. (Bori et al., 2022).
cations when compared to children born after fresh cleavage-stage .. One of the features monitored by TL systems, blastocyst collapse,
..
ETs or spontaneous conception (Spangmose et al., 2020). If part of .. has also been identified as an embryo marker of low implantation po-
this effect could be due to the extended culture, it might be assumed .. tential (Sciorio et al., 2020). In particular, it was shown that human
..
that culturing to Day 7 could worsen these effects. .. blastocysts that collapse spontaneously during development are less
So far there has been limited evidence for safety for extended em- .. likely to implant and generate a clinical pregnancy compared with em-
..
bryo culture. Day 7 blastocysts have been shown to result in healthy .. bryos that do not. This was also observed in a recent study, where
LBs with comparable perinatal outcomes to the ones obtained by .. collapsing blastocysts were reported less euploid even when adjusting
..
transferring Days 5 and 6 blastocysts (Hiraoka et al., 2009). Similar .. for morphological quality (Cimadomo et al., 2022a). As Journal Club
perinatal outcomes were also reported in a more recent retrospective
.. experts pointed out, blastocyst collapse is one of those features that
4 Fraire-Zamora et al.

..
should be implemented by all TL users, as morphology assessment .. two centers involving 956 screened blastocysts. Hum Reprod 2014;
.. 29:1173–1181.
alone may limit implantation potential for embryos exhibiting a strong ..
collapse. It is therefore reasonable to consider that expansion and .. Cassuto G, Chavrier M, Menezo Y. Culture conditions and not pro-
.. longed culture time are responsible for monozygotic twinning in
spontaneous collapse dynamics are indicative of reproductive fitness. ..
The question, however, remains on what the clinical gain is from iden- .. human in vitro fertilization. Fertil Steril 2003;80:462–463.
.. Chronopoulou E, Harper JC. IVF culture media: past, present and fu-
tifying these features. Prospective trials would be valuable to investi- ..

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gate if any of these features result in improvement of cycle outcomes.
.. ture. Hum Reprod Update 2015;21:39–55.
..
.. Cimadomo D, Capalbo A, Levi-Setti PE, Soscia D, Orlando G,
.. Albani E, Parini V, Stoppa M, Dovere L, Tacconi L et al.
..
.. Associations of blastocyst features, trophectoderm biopsy and
Concluding remarks .. other laboratory practice with post-warming behavior and implan-
..
Even though Day 7 embryos are less competent than faster-growing .. tation. Hum Reprod 2018;33:1992–2001.
ones, Cimadomo et al., demonstrated that ending embryo culture on
.. Cimadomo D, Marconetto A, Trio S, Chiappetta V, Innocenti F,
..
Day 6 would result in a 4.4% relative reduction in LBR. Since safety .. Albricci L, Erlich I, Ben-Meir A, Har-Vardi I, Kantor B et al. Human
..
studies for extended culture systems are generally lacking, the choice .. blastocyst spontaneous collapse is associated with worse morpho-
of extending culture to Day 7 should be evaluated individually for each .. logical quality and higher degeneration and aneuploidy rates: a
..
couple based on their financial and emotional status along with their .. comprehensive analysis standardized through artificial intelligence.
prognosis and reproductive history in mind. Future advances in AI can .. Hum Reprod 2022a;37:2291–2306.
..
potentially identify slow-developing embryos with the ability to reach .. Cimadomo D, Soscia D, Casciani V, Innocenti F, Trio S, Chiappetta
the full expansion stage. .. V, Albricci L, Maggiulli R, Erlich I, Ben-Meir A et al. How slow is
..
.. too slow? A comprehensive portrait of Day 7 blastocysts and their
..
Data availability ..
..
clinical value standardized through artificial intelligence. Hum
Reprod 2022b;37:1134–1147.
No datasets were generated or analyzed in the current manuscript. ..
.. Duranthon V, Chavatte-Palmer P. Long term effects of ART: what
.. do animals tell us? Mol Reprod Dev 2018;85:348–368.
..
Acknowledgements ..
..
Hammond ER, Cree LM, Morbeck DE. Should extended blastocyst
.. culture include day 7? Hum Reprod 2018;33:991–997.
The authors would like to thank Danilo Cimadomo and all the partici- .. Hiraoka K, Hiraoka K, Miyazaki M, Fukunaga E, Horiuchi T, Kusuda
pants of ESHRE journal club on Twitter for their contribution in the .. T, Okano S, Kinutani M, Kinutani K. Perinatal outcomes following
discussion. ..
.. transfer of human blastocysts vitrified at day 5, 6 and 7. J Exp Clin
.. Assist Reprod 2009;6:4.
..
Funding ..
..
Huang J, Yang X, Wu J, Kuang Y, Wang Y. Impact of day 7 blastocyst

This research did not receive any specific grant from funding agencies .. transfer on obstetric and perinatal outcome of singletons born af-
.. ter vitrified-warmed embryo transfer. Front Physiol 2020;11:74.
in the public, commercial or not-for-profit sectors. ..
.. Huang TT, Chinn K, Kosasa T, Ahn HJ, Kessel B. Morphokinetics of
.. human blastocyst expansion in vitro. Reprod Biomed Online 2016;
..
Conflict of interest .. 33:659–667.
.. Kermack AJ, Fesenko I, Christensen DR, Parry KL, Lowen P,
All authors declare no conflict of interest. ..
.. Wellstead SJ, Harris SF, Calder PC, Macklon NS, Houghton FD.
.. Incubator type affects human blastocyst formation and embryo
..
.. metabolism: a randomized controlled trial. Hum Reprod 2022;37:
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