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Topic:Assisted Reproductive Techniques

Assisted Reproductive Techniques (ART) in horses encompass a range of technologies designed to aid in the breeding process. These techniques include artificial insemination, embryo transfer, intracytoplasmic sperm injection (ICSI), and oocyte transfer. ART is employed to enhance reproductive efficiency, manage genetic diversity, and support breeding programs for both commercial and conservation purposes. Artificial insemination involves the collection and deposition of semen into the mare's reproductive tract, while embryo transfer entails the collection of a fertilized embryo from a donor mare and its implantation into a recipient mare. ICSI involves the direct injection of a single sperm into an oocyte to achieve fertilization. Oocyte transfer involves the transfer of an oocyte from one mare to another for fertilization and gestation. This page compiles peer-reviewed research studies and scholarly articles that examine the methodologies, advancements, and applications of assisted reproductive techniques in equine reproduction.
Investigating the impact of extracellular vesicle addition during IVM on the fertilization rate of equine oocytes following ICSI.
Reproductive biology    November 9, 2024   Volume 24, Issue 4 100967 doi: 10.1016/j.repbio.2024.100967
Gabryś J, Pietras N, Kowal-Mierzwa W, Karnas E, Andronowska A, Nowak A, Kochan J, Bugno-Poniewierska M.The efficacy of in vitro embryo production (IVEP) in equines is relatively limited compared to other species due to the lack of a reliable superovulation technique, limited availability of cumulus oocyte complexes (COCs), low in vitro oocyte maturation (IVM) and fertilization rates. Extracellular vesicles (EVs), which are nanoparticles involved in intercellular signaling in the ovarian environment, have shown potential as supplements to improve oocyte development during IVM. This study tested the hypothesis that EVs from small (< 20 mm) ovarian follicles could enhance fertilization rates in m...
IVF with frozen-thawed sperm after prolonged capacitation yields comparable results to ICSI in horses: A morphokinetics study.
Theriogenology    November 1, 2024   Volume 232 39-45 doi: 10.1016/j.theriogenology.2024.10.032
Martin-Pelaez S, Fuente A, Takahashi K, Perez IT, Orozco J, Okada CTC, Neto CR, Meyers S, Dini P.Intracytoplasmic sperm injection (ICSI) is the current clinical practice for the in vitro production of equine embryos. The use of conventional fertilization methods such as in vitro fertilization (IVF), has historically been associated with poor success in horses. However, recent improvements have led to better outcomes with IVF, though only when using fresh semen, which limits its use in clinical practice. IVF remains in its infancy in equine reproduction, and several unknowns remain about the technique. One significant gap in knowledge concerns the morphokinetics of IVF embryos and how they...
A new hormonal protocol supports early development of in vitro-produced embryos after transfer to anoestrus mares.
Reproduction in domestic animals = Zuchthygiene    October 14, 2024   Volume 59 Suppl 3 e14622 doi: 10.1111/rda.14622
Muñoz-García CC, Luis-Calero M, Fernández-Hernández P, Pizarro-Hernández A, Fernández-González R, Gutiérrez-Adán A, Sánchez-Calabuig MJ....The present study aimed to evaluate whether primed anoestrus mares are suitable recipients for embryos produced by intracytoplasmic sperm injection (ICSI). Anoestrus was confirmed in four mares and daily doses of oestradiol benzoate (6 mg in total) over 5 days were administered; after 3 days of rest, oral altrenogest was administered at 0.088 mg/kg and embryos (1 to 5 embryos per mare; 15 in total) were transferred 3.5 days after progesterone onset. Uterine lavage was conducted 48 h after transfer. The results revealed an 80% embryo recovery rate, and among the retrieved embryos, 6...
Prolonged incubation of frozen-thawed equine spermatozoa for in vitro fertilization: A preliminary study using low temperature and INRA96 medium.
Reproduction in domestic animals = Zuchthygiene    October 14, 2024   Volume 59 Suppl 3 e14593 doi: 10.1111/rda.14593
Luis-Calero M, Muñoz-García CC, Fernández-Hernández P, Macías-García B, González-Fernández L.A protocol for conventional in vitro fertilization (IVF) in horses using fresh semen has been described, using a prolonged incubation in FERT-TALP medium (22 h) at 38.2°C in the presence of penicillamine, hypotaurine and epinephrine (PHE). Our work aimed to develop a protocol that maintains quality parameters in frozen-thawed equine spermatozoa incubated for 22 h in the presence of PHE using different media (FERT-TALP and INRA96) and incubation temperatures (30 and 38.2°C). Twelve frozen ejaculates from four stallions were thawed and then incubated in either FERT-TALP or INRA96 with PHE...
Effect of refreezing extender on stallion sperm quality and embryo production after intracytoplasmic sperm injection.
Theriogenology    October 9, 2024   Volume 231 29-35 doi: 10.1016/j.theriogenology.2024.10.006
Brito LFC, Felix MR, Linardi RL, Martinez de Andino EV, Balamurugan NS, Hernández-Avilés C, Hinrichs K.Intracytoplasmic sperm injection (ICSI) is a valuable assisted reproduction technology in clinical practice, especially when semen availability is limited. Since the number of sperm required per ICSI cycle is much less than the number of sperm available in a standard straw of frozen semen, refreezing semen at lower sperm concentrations could yield multiple straws for ICSI use. However, there is little data on the effect of sperm refreezing on ICSI outcomes, especially on the effect of extender used for refreezing. The objective of the present study was to evaluate the effect of refreezing exte...
Effect of protein acetylation on capacitation of stallion sperm.
Journal of equine veterinary science    September 18, 2024   Volume 142 105195 doi: 10.1016/j.jevs.2024.105195
Aguiar LH, Pinto CRF.Sperm capacitation is considered the main factor limiting conventional in vitro fertilization (IVF) in horses. A recent scientific breakthrough in sperm processing for IVF in horses has resulted in embryos and foals being produced; however, various aspects of the IVF process remain to be fully elucidated. Lysine acetylation has been shown to play a role in sperm capacitation in several species and the objective of this study was to detect and evaluate this process in the horse. Ejaculates of two stallions were collected and incubated in different conditions with deacetylase inhibitors to induc...
Maturational competence of equine oocytes is associated with alterations in their ‘cumulome’.
Molecular human reproduction    September 17, 2024   Volume 30, Issue 9 doi: 10.1093/molehr/gaae033
No abstract available
Equine ART and antral follicle count: Can we deepen our understanding to improve outcomes?
Reproduction in domestic animals = Zuchthygiene    September 5, 2024   Volume 59 Suppl 2 e14625 doi: 10.1111/rda.14625
Le Breton A, Lewis N.Assisted reproductive technologies (ARTs) are performed worldwide in the equine industry to produce genetically valuable foals. Among them, ovum pick up (OPU) combined with intra-cytoplasmic sperm injection (ICSI) can now be more efficient than embryo transfer (ET) under optimal conditions. However, OPU is not a benign procedure for the mare and the process is costly. Improved efficiency is therefore in the interest of everyone, maximizing mare welfare and optimizing economics for the client. One of the key factors of success is the antral follicle count (AFC) at the time of OPU and subsequent...
Foal sex in Thoroughbred horses: related factors.
Animal reproduction    August 5, 2024   Volume 21, Issue 3 e20230073 doi: 10.1590/1984-3143-AR2023-0073
Flores JG, Bueno VC, Bastos HBA, Rechsteiner SMDEF.Reproductive biotechniques in the equine species have advanced in the last decade and horse breeders have started to question the possibilities of interfering in the determination of foal sex. The aim of the present study was to verify whether the variables mares and stallion's age, side of the ovary containing the preovulatory follicle, preovulatory follicle diameter, time between breeding and ovulation, and ovulation inducing hormones influence the sex of the foal. A total of 259 reproductive cycles of 160 mares and 22 Thoroughbred stallions were used. Statistical analysis was performed usin...
Use of excised ovaries for oocyte recovery by ultrasound guided follicular aspiration – Validation of an experimental model for research purposes in live mares ovum pick up.
Theriogenology    July 26, 2024   Volume 228 9-16 doi: 10.1016/j.theriogenology.2024.07.023
Sala-Ayala L, Pytel AT, Stychno K, Cuervo-Arango J.Ovum pick-up (OPU) by transvaginal ultrasound guided follicle aspiration in mares is a common assisted reproductive technique used for oocyte recovery and in vitro production of horse embryos. There has been relatively little research into the factors influencing oocyte recovery in OPU from live mares. The objective of this study was to compare oocyte recovery and morphology of ultrasound-guided follicle puncture and aspiration in live mares and in postmortem excised ovaries, in order to validate an experimental model for research purposes of the efficiency of OPU in mares. Data from OPU perfo...
A study on methods for preimplantation genetic testing (PGT) on in vivo- and in vitro-produced equine embryos, with emphasis on embryonic sex determination.
Theriogenology    July 11, 2024   Volume 227 41-48 doi: 10.1016/j.theriogenology.2024.07.009
Ramírez-Agámez L, Castaneda C, Hernández-Avilés C, Grahn RA, Raudsepp T, Love CC.Two methods for preimplantation genetic testing (PGT) have been described for equine embryos: trophoblast cell biopsy (TCB) or blastocoele fluid aspiration (BFA). While TCB is widely applied for both in vivo- and in vitro-produced embryos, BFA has been mostly utilized for in vivo-produced embryos. Alternative methods for PGT, including analysis of cell-free DNA (CFD) in the medium where in vitro-produced embryos are cultured, have been reported in humans but not for equine embryos. In Experiment 1, in vivo- (n = 10) and in vitro-produced (n = 13) equine embryos were subjected to BFA, cultu...
Preovulatory follicular fluid secretome added to in vitro maturation medium influences the metabolism of equine cumulus-oocyte complexes.
BMC veterinary research    June 25, 2024   Volume 20, Issue 1 272 doi: 10.1186/s12917-024-04129-1
Luis-Calero M, Ortiz-Rodríguez JM, Fernández-Hernández P, Muñoz-García CC, Pericuesta E, Gutiérrez-Adán A, Marinaro F, Embade N, Conde R....In vitro embryo production is a highly demanded reproductive technology in horses, which requires the recovery (in vivo or post-mortem) and in vitro maturation (IVM) of oocytes. Oocytes subjected to IVM exhibit poor developmental competence compared to their in vivo counterparts, being this related to a suboptimal composition of commercial maturation media. The objective of this work was to study the effect of different concentrations of secretome obtained from equine preovulatory follicular fluid (FF) on cumulus-oocyte complexes (COCs) during IVM. COCs retrieved in vivo by ovum pick up (OPU) ...
Advances in equine reproduction.
Equine veterinary journal    June 5, 2024   Volume 56, Issue 4 644-649 doi: 10.1111/evj.14102
Stout TAE, Crabtree JR, Cuervo-Arango J.No abstract available
Effect of exogenous sperm capacitation inducers on stallion sperm.
Theriogenology    May 29, 2024   Volume 226 29-38 doi: 10.1016/j.theriogenology.2024.05.042
Fuentes F, Contreras MJ, Arroyo-Salvo C, Cabrera P P, Silva M, Merino O, Arias ME, Felmer R.Although under appropriate laboratory conditions, sperm from different mammalian species can be capacitated in vitro, the optimal conditions for sperm capacitation in the stallion have been elusive. This study evaluated the effect of different capacitating inducers in Whitten and Tyrode media and assessed their impact on capacitation-related factors. Stallion sperm were incubated with different combinations of capacitating inducers at 38.5 °C in an air atmosphere. Sperm quality variables such as motility, mitochondrial membrane potential, and lipid peroxidation were assessed. Membrane fluidi...
Effect of bicarbonate and polyvinyl alcohol on in vitro capacitation and fertilization ability of cryopreserved equine spermatozoa.
Andrology    May 28, 2024   Volume 13, Issue 2 382-395 doi: 10.1111/andr.13667
Arroyo-Salvo C, Río S, Bogetti ME, Plaza J, Miragaya M, Yaneff A, Davio C, Fissore R, Gervasi MG, Gambini A, Perez-Martinez S.Factors contributing to the limited success of in vitro fertilization in horses remain to be studied. In this work, we elucidated the effect of different essential capacitation media components, bicarbonate, and bovine serum albumin or polyvinyl-alcohol, and the incubation microenvironment on sperm parameters associated with capacitation, acrosome reaction, and their ability to activate oocytes via heterologous intracytoplasmic spermatozoa injection in equine cryopreserved spermatozoa. Methods: Frozen-thawed spermatozoa underwent incubation at different time intervals in either Tyrode's albumi...
Effect of sperm treatment with lysolecithin on in vitro outcomes of equine intracytoplasmic sperm injection.
Journal of equine veterinary science    May 28, 2024   Volume 138 105095 doi: 10.1016/j.jevs.2024.105095
Aguila L, Cabrera P, Arias ME, Silva M, Felmer R.Intracytoplasmic sperm injection (ICSI) in horses is currently employed for clinical and commercial uses, but the protocol could be optimized to improve its efficiency. We have hypothesized that destabilization of plasma and acrosomal membranes prior to injection would positively impact the developmental potential of equine zygotes generated by ICSI. This study evaluated effects of the sperm treatment with lysolecithin on plasma and acrosomal membranes and on oocyte activation ability, initially following heterologous ICSI on bovine oocytes and subsequently employing equine oocytes. The effect...
The effect of uterine massage and number of embryo flushing attempts on embryo recovery in mares.
Theriogenology    May 15, 2024   Volume 224 94-101 doi: 10.1016/j.theriogenology.2024.05.017
Sala-Ayala L, Martínez-Boví R, Querol-Paajanen A, Cuervo-Arango J.The aims of this study were to determine the effect of the embryo flushing technique and the number of flushing attempts performed by operators of different experience on embryo recovery (ER). Ten non-lactating mares were inseminated with the same stallion in six cycles each (n = 60). Embryo flushing (EF) was performed 7-9 days after ovulation by three operators (OP; 20 EF cycles each): OP1 had performed >500 EF before the study, while OP2 and 3 had performed 0 EF. Each EF was performed with 2 flushing attempts (FA) using 1L of ringer's lactate "in-and-out" using two EF techniques: 1) ...
The ability of donkey sperm to induce oocyte activation and mule embryo development after ICSI.
Theriogenology    February 2, 2024   Volume 218 200-207 doi: 10.1016/j.theriogenology.2024.02.002
Arroyo-Salvo C, Cogollo Villarreal MY, Clérico G, Flores Bragulat AP, Niño Vargas A, Castañeira C, Briski O, Alonso C, Plaza J, Zeledon JM....Members of the Equus genus exhibit a fascinating capacity for hybridization, giving rise to healthy offspring. Mules, resulting from the mating of a mare with a jack, represent the most prevalent equid hybrid, serving diverse roles in our society. While in vitro embryo production, particularly through Intracytoplasmic Sperm Injection (ICSI), has rapidly gained significance in domestic horses, the in vitro production in other equids remains largely unexplored. Utilizing donkey sperm for fertilizing horse oocytes not only addresses this gap but also provides an opportunity to investigate donkey ...
Ethanol, Carnoy, and paraformaldehyde as fixative solutions for histological evaluation of preantral follicles in equine ovarian tissue.
Reproductive biology    October 25, 2023   Volume 23, Issue 4 100814 doi: 10.1016/j.repbio.2023.100814
Borges MA, Curcio BR, Gastal GDA, Gheno L, Junior ASV, Corcini CD, Nogueira CEW, Aguiar FLN, Gastal EL.The most adequate fixative solution for equine ovarian tissue is still to be determined as a tool to evaluate the improvement of methodological studies in assisted reproductive techniques and fertility preservation. This study aimed to evaluate a short-time ethanol 70% (ST-EtOH, 45 min) exposure as an alternative fixative compared with two classically fixatives [Carnoy's (CAR) solution and paraformaldehyde 4% (PFA)] at different fixation times (6 h, 12 h). The end points evaluated were morphology and classes of preantral follicles, follicular and stromal cell densities, and follicular and o...
Transcriptome Signature of Immature and In Vitro-Matured Equine Cumulus-Oocytes Complex.
International journal of molecular sciences    September 6, 2023   Volume 24, Issue 18 13718 doi: 10.3390/ijms241813718
de la Fuente A, Scoggin C, Bradecamp E, Martin-Pelaez S, van Heule M, Troedsson M, Daels P, Meyers S, Dini P.Maturation is a critical step in the development of an oocyte, and it is during this time that the oocyte advances to metaphase II (MII) of the meiotic cycle and acquires developmental competence to be fertilized and become an embryo. However, in vitro maturation (IVM) remains one of the limiting steps in the in vitro production of embryos (IVP), with a variable percentage of oocytes reaching the MII stage and unpredictable levels of developmental competence. Understanding the dynamics of oocyte maturation is essential for the optimization of IVM culture conditions and subsequent IVP outcomes....
Transcriptome analyses reveal transcriptional profiles of horse oocytes before and after in vitro maturation.
Reproduction in domestic animals = Zuchthygiene    August 31, 2023   doi: 10.1111/rda.14462
Song X, Jiang H, Lv P, Cui K, Liu Q, Yin S, Liu H, Li Z.Oocyte in vitro maturation is necessary for the study and application of animal-assisted reproduction technology in animal reproduction and breeding. The comprehensive transcriptional profile of equine oocyte maturated in vitro has not been fully mined yet, which makes many key transcriptional events still unidentified. Here, Smart-seq2 was performed to analyse the gene expression pattern and the underlying regulatory mechanism of horse germinal vesicle (GV) and in vitro metaphase II (MII) oocytes. The results showed that 6402 genes (2640 up-regulated and 3762 down-regulated in MII samples com...
Short-term preservation of canine sperm-binding ability and other metrics using the INRA-96 in comparison to Tris-egg yolk extender.
Reproduction in domestic animals = Zuchthygiene    August 6, 2023   Volume 58, Issue 9 1320-1329 doi: 10.1111/rda.14448
Cavalcanti TP, Pereira AG, Bezerra LGP, Moreira SSJ, da Silva AM, Matos YG, Jorge-Neto PN, Silva AR.The use of assisted reproductive techniques, such as chilled semen, contributes to the maintenance and genetic improvement of canine breeding. The INRA-96 extender is a commercially available, chemically defined medium that was initially developed for the preservation of equine semen and exhibits preservation potential in the canine species. This research aims to evaluate the INRA-96 extender as an alternative for the short-term preservation of canine semen in terms of sperm quality parameters such as motility and kinetic parameters, integrity and functionality of the plasma membrane in fresh ...
Embryo Pulsing: Repeated Expansion and Contraction of In Vivo and In Vitro Equine Blastocysts.
Journal of equine veterinary science    July 8, 2023   Volume 128 104891 doi: 10.1016/j.jevs.2023.104891
de la Fuente A, Omyla K, Cooper C, Daels P, Meyers S, Dini P.Morphokinetic evaluation of embryo development has allowed the discovery of events occurring during blastulation. Here, we describe equine embryo pulsing, determined as continued expansion and contraction of both in vivo and in vitro produced blastocysts. Using time-lapse imaging, we demonstrated that pulsing starts during early blastocyst development of in vitro-produced embryos in horses. The median time for a complete contraction was 0.22h (0.08h-2h; min-max) where embryos reduced their sizes around 12.0% (median; 2.3%-27.0%) and the median time for an expansion was 3.3h (0.75-9.0h) where e...
Comparative reproduction of the female horse, elephant and rhinoceros: implications for advancing Assisted Reproductive Technologies (ART).
Reproduction & fertility    July 1, 2023   Volume 4, Issue 3 doi: 10.1530/RAF-23-0020
Meuffels-Barkas J, Wilsher S, Allen WRT, Ververs C, Lueders I.Recent loss of rhinoceros subspecies has renewed interest in using more advanced assisted reproductive technologies (ART) in rhinoceroses and elephants. Currently, only semen collection, semen preservation and artificial insemination (AI) have been used repeatedly with success in these species. Although ovum pick-up (OPU) and intra-cytoplasmic sperm injection (ICSI) have been reported in rhinoceroses, the techniques are not yet optimised. In contrast, multiple ART applications are routinely used in the horse. Since elephant and rhinoceroses share some reproductive features with equids, we post...
In Vitro-Produced Equine Blastocysts Exhibit Greater Dispersal and Intermingling of Inner Cell Mass Cells than In Vivo Embryos.
International journal of molecular sciences    June 1, 2023   Volume 24, Issue 11 9619 doi: 10.3390/ijms24119619
Umair M, Scheeren VFDC, Beitsma MM, Colleoni S, Galli C, Lazzari G, de Ruijter-Villani M, Stout TAE, Claes A.In vitro production (IVP) of equine embryos is increasingly popular in clinical practice but suffers from higher incidences of early embryonic loss and monozygotic twin development than transfer of in vivo derived (IVD) embryos. Early embryo development is classically characterized by two cell fate decisions: (1) first, trophectoderm (TE) cells differentiate from inner cell mass (ICM); (2) second, the ICM segregates into epiblast (EPI) and primitive endoderm (PE). This study examined the influence of embryo type (IVD versus IVP), developmental stage or speed, and culture environment (in vitro ...
Lipid metabolites, interleukin-6 and oxidative stress markers in follicular fluid and their association with serum concentrations in mares.
Veterinary research communications    April 14, 2023   Volume 47, Issue 4 2221-2228 doi: 10.1007/s11259-023-10122-0
Hedia M, Leroy JLMR, Govaere J, Van Soom A, Smits K.The application of trans-vaginal ovum pick up (OPU) and intracytoplasmic sperm injection (ICSI) is well established for commercial in vitro embryo production in horses. These assisted reproductive techniques are especially applied during the non-breeding season of the mare. However, little is known about how the health of the oocyte donor may affect the biochemical composition of the follicular fluid (FF) in small and medium-sized follicles routinely aspirated during OPU. This study aimed to investigate associations between systemic and FF concentrations of interleukin-6 (IL-6), total choleste...
Horse Somatic Cell Nuclear Transfer Using Zona Pellucida-Enclosed and Zona-Free Oocytes.
Methods in molecular biology (Clifton, N.J.)    April 12, 2023   Volume 2647 269-281 doi: 10.1007/978-1-0716-3064-8_15
Salamone D, Maserati M.Horse cloning by somatic cell nuclear transfer (SCNT) is an attractive scientific and commercial endeavor. Moreover, SCNT allows generating genetically identical animals from elite, aged, castrated, or deceased equine donors. Several variations in the horse SCNT method have been described, which may be useful for specific applications. This chapter describes a detailed protocol for horse cloning, thus including SCNT protocols using zona pellucida (ZP)-enclosed or ZP-free oocytes for enucleation. These SCNT protocols are under routine use for commercial equine cloning.
Contributions to Mare Reproduction Research by the Ginther Team.
Journal of equine veterinary science    March 28, 2023   Volume 126 104295 doi: 10.1016/j.jevs.2023.104295
Ginther OJ.Examples of research discoveries and first reports on mare reproduction by the O.J. Ginther team are (1) determined daily circulating concentrations of four hormones during the estrous cycle, (2) showed that mares can be induced to ovulate and superovulate by hormone treatment during both ovulatory and anovulatory seasons, (3) demonstrated that prostaglandin F2α was the luteolysin in mares, (4) described the mare's elaborate hormonal and biochemical mechanism for selecting the ovulatory follicle from a pool of like follicles, (5) developed the method for diagnosing fetal sex by Day 60 using l...
Cloning horses by somatic cell nuclear transfer: Effects of oocyte source on development to foaling.
Theriogenology    March 23, 2023   Volume 203 99-108 doi: 10.1016/j.theriogenology.2023.03.018
Cortez JV, Hardwicke K, Cuervo-Arango J, Grupen CG.The cloning of horses is a commercial reality, yet the availability of oocytes for cloned embryo production remains a major limitation. Immature oocytes collected from abattoir-sourced ovaries or from live mares by ovum pick-up (OPU) have both been used to generate cloned foals. However, the reported cloning efficiencies are difficult to compare due to the different somatic cell nuclear transfer (SCNT) techniques and conditions used. The objective of this retrospective study was to compare the in vitro and in vivo development of equine SCNT embryos produced using oocytes recovered from abatt...
Vitrifying expanded equine embryos collapsed by blastocoel aspiration is less damaging than slow-freezing.
Theriogenology    March 2, 2023   Volume 202 28-35 doi: 10.1016/j.theriogenology.2023.02.028
Umair M, Beitsma M, de Ruijter-Villani M, Deelen C, Herrera C, Stout TAE, Claes A.The cryotolerance of equine blastocysts larger than 300 μm can be improved by aspirating blastocoele fluid prior to vitrification; however, it is not known whether blastocoele aspiration also enables successful slow-freezing. The aim of this study was therefore to determine whether slow-freezing of expanded equine embryos following blastocoele collapse was more or less damaging than vitrification. Grade 1 blastocysts recovered on day 7 or 8 after ovulation were measured (>300-550 μm, n = 14 and > 550 μm, n = 19) and blastocoele fluid was aspirated prior to slow-freezing in 10...