Time-Lapse Incubation for Embryo Culture - Morphokinetics and Environmental Stability

NCT02657811 | Unknown DMC

• 1 other identifier: 0169-15-SZMC
• Study Type: interventional
• Target: 372
• Locations: 1 country
• Sites: 1

Brief Summary

Embryo culture and selection has been a continuous challenge in evolution since the birth of In Vitro Fertilization (IVF). Traditionally, embryo quality and its presumed suitability for transfer were assessed based on morphologic features. However, the consensus as to the optimal time points for embryo assessment and as to 'preferable' characteristics have been challenging. Alongside this has been the challenge of achieving balance between multiple points of assessment, yet stabilizing the embryo environment for growth. In standard incubation, each new morphological assessment of embryos in culture theoretically creates an additional disruption to culture. Most recently, time-lapse incubators (TLI) have been introduced as a novel embryo culture system attempting to limit culture disturbances. These incubators have been integrated with digital imaging, allowing for a substantial limitation in embryo handling and environmental disturbances. They have also introduced new morphokinetic parameters to embryo assessment and to optimizing selection of embryos. Thus far, a limited number of studies have examined the clinical outcomes and value of time lapse monitoring systems versus the more ubiquitous incubators (e.g. multichamber) for reproductive outcomes. In particular, the isolated value of morphokinetics in embryo assessment and of this new stable culture environment in TLI are still in question. The objectives of this study are to prospectively assess and compare fertility outcomes when embryos are cultured in the TLI system versus more traditional bench incubators (BI). We will specifically assess the added value of the closed and isolated TLI compared to BI on reproductive outcomes, as well as the value of morphokinetic grading in IVF.

Conditions

Infertility; Genetic Diseases

Keywords

Time-Lapse Imaging; Embryo Culture Techniques; Fertilization in Vitro; Embryology; Assisted Reproductive Techniques; Infertility; Preimplantation diagnosis

Outcome Measures

Primary Outcomes (1)

• Ongoing pregnancy rate

  The number of women with a viable pregnancy (including gestational sac and fetal heart beat) at 12 weeks gestation divided by the number of women having an embryo transfer.

  12 weeks gestation

Secondary Outcomes (17)

• Embryo morphology - Number of pronuclei present following fertilization

  Day 1 post-fertilization

• Embryo morphology - Number of cells present

  Day 2 and Day 3 post-fertilization

• Embryo morphology - % fragmentation

  Day 2 and Day 3 post-fertilization

• Embryo morphology - Presence of multi nucleation

  Day 2 post-fertilization

• Embryo morphology - Symmetry

  Day 2 and Day 3 post-fertilization

Study Arms (3)

Bench Incubation

ACTIVE COMPARATOR

These embryos will be randomized to the bench incubator.

Device: Miri, Benchtop Multi-room incubator

Time Lapse Incubation

ACTIVE COMPARATOR

These embryos will be randomized to the Time Lapse Incubator.

Device: Miri TL, Time-Lapse incubator

Time Lapse Incubation - Modified

ACTIVE COMPARATOR

These embryos will be randomized to the bench incubator.

Device: Miri TL, Time-Lapse incubator

Interventions

Miri, Benchtop Multi-room incubator DEVICE

Bench Incubation - Morphologic Assessment These embryos will undergo multiple evaluations using light microscopy and traditional morphologic assessment.

Bench Incubation

Miri TL, Time-Lapse incubator DEVICE

Time Lapse Incubation - Morphologic/Morphokinetic Assessment These embryos will remain in the TLI and undergo both morphologic and morphokinetic evaluation and grading according to a hierarchical multivariable model. They will not be removed from incubation for the duration of culture.

Time Lapse Incubation

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patients requiring assisted reproductive technologies for one or more of the following reasons:
• Male factor infertility
• Unexplained infertility
• Mechanical factor infertility
• Ovulatory infertility
• Patients undergoing fertility treatment at Shaare Zedek Medical Centre alone.
• Patients attempting pregnancy with autologous gametes.
• Patients receiving embryo transfers according to the Israel Society of Obstetrics and Gynecology guideline on number of embryos for transfer during in vitro fertilization.
• Patients undergoing their first or second ICSI cycle (cumulative to all other institutions involved in prior treatment) since their previous pregnancy.
• BMI criteria: \>18 and \<30 kg/m2

You may not qualify if:

• An infertility diagnosis that includes the following:
• Severe male factor infertility requiring testicular aspiration, testicular biopsy for sperm retrieval, or less than 1000 sperm per ejaculate.
• Untreated hydrosalpinx
• Persistently thin endometrial lining or endometrial factor
• Severe Endometriosis
• Low ovarian reserve (≤8 antral follicle count (AFC) follicles measuring 2 to 10 mm in diameter on day 2-4 of menstrual cycle, or day 3 follicle stimulating hormone (FSH) ≥10 milli-International unit (mIU) /mL)
• High risk for Ovarian Hyperstimulation Syndrome (Estradiol level \>13 000 pmol/L or \>20 follicles ≥16 mm diameter during controlled ovarian hyper stimulation, ≥20 oocytes collected).
• Patients obtaining GnRH agonist for final follicular maturation
• Patients requiring preimplantation genetic diagnosis (PGD)
• Patients who require freezing of all oocytes or embryos
• More than 2 previous cycles of IVF since previous pregnancy
• Current smokers

Sponsors & Collaborators

• Shaare Zedek Medical Center: lead

Study Sites (1)

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

RECRUITING

Related Publications (26)

• Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.

  PMID: 21502182 BACKGROUND

• Kirkegaard K, Ahlstrom A, Ingerslev HJ, Hardarson T. Choosing the best embryo by time lapse versus standard morphology. Fertil Steril. 2015 Feb;103(2):323-32. doi: 10.1016/j.fertnstert.2014.11.003. Epub 2014 Dec 17.

  PMID: 25527231 BACKGROUND

• Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril. 2013 Jan;99(1):44-46. doi: 10.1016/j.fertnstert.2012.09.038. Epub 2012 Oct 22.

  PMID: 23095140 BACKGROUND

• Swain JE. Decisions for the IVF laboratory: comparative analysis of embryo culture incubators. Reprod Biomed Online. 2014 May;28(5):535-47. doi: 10.1016/j.rbmo.2014.01.004. Epub 2014 Jan 27.

  PMID: 24656561 BACKGROUND

• Fujiwara M, Takahashi K, Izuno M, Duan YR, Kazono M, Kimura F, Noda Y. Effect of micro-environment maintenance on embryo culture after in-vitro fertilization: comparison of top-load mini incubator and conventional front-load incubator. J Assist Reprod Genet. 2007 Jan;24(1):5-9. doi: 10.1007/s10815-006-9088-3. Epub 2006 Dec 13.

  PMID: 17160731 BACKGROUND

• Zhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010 Apr;20(4):510-5. doi: 10.1016/j.rbmo.2009.12.027. Epub 2009 Dec 28.

  PMID: 20129824 BACKGROUND

• Armstrong S, Arroll N, Cree LM, Jordan V, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2015 Feb 27;(2):CD011320. doi: 10.1002/14651858.CD011320.pub2.

  PMID: 25721906 BACKGROUND

• Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011 Oct;26(10):2658-71. doi: 10.1093/humrep/der256. Epub 2011 Aug 9.

  PMID: 21828117 BACKGROUND

• Lemmen JG, Agerholm I, Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes. Reprod Biomed Online. 2008 Sep;17(3):385-91. doi: 10.1016/s1472-6483(10)60222-2.

  PMID: 18765009 BACKGROUND

• Meseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 10.1016/j.fertnstert.2012.08.016. Epub 2012 Sep 10.

  PMID: 22975113 BACKGROUND

• Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Reijo Pera RA. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nat Biotechnol. 2010 Oct;28(10):1115-21. doi: 10.1038/nbt.1686. Epub 2010 Oct 3.

  PMID: 20890283 BACKGROUND

• Dal Canto M, Coticchio G, Mignini Renzini M, De Ponti E, Novara PV, Brambillasca F, Comi R, Fadini R. Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation. Reprod Biomed Online. 2012 Nov;25(5):474-80. doi: 10.1016/j.rbmo.2012.07.016. Epub 2012 Aug 2.

  PMID: 22995750 BACKGROUND

• Cruz M, Garrido N, Herrero J, Perez-Cano I, Munoz M, Meseguer M. Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality. Reprod Biomed Online. 2012 Oct;25(4):371-81. doi: 10.1016/j.rbmo.2012.06.017. Epub 2012 Jul 7.

  PMID: 22877944 BACKGROUND

• Hlinka D, Kalatova B, Uhrinova I, Dolinska S, Rutarova J, Rezacova J, Lazarovska S, Dudas M. Time-lapse cleavage rating predicts human embryo viability. Physiol Res. 2012;61(5):513-25. doi: 10.33549/physiolres.932287. Epub 2012 Aug 8.

  PMID: 22881225 BACKGROUND

• Rubio I, Kuhlmann R, Agerholm I, Kirk J, Herrero J, Escriba MJ, Bellver J, Meseguer M. Limited implantation success of direct-cleaved human zygotes: a time-lapse study. Fertil Steril. 2012 Dec;98(6):1458-63. doi: 10.1016/j.fertnstert.2012.07.1135. Epub 2012 Aug 25.

  PMID: 22925687 BACKGROUND

• Azzarello A, Hoest T, Mikkelsen AL. The impact of pronuclei morphology and dynamicity on live birth outcome after time-lapse culture. Hum Reprod. 2012 Sep;27(9):2649-57. doi: 10.1093/humrep/des210. Epub 2012 Jun 26.

  PMID: 22740496 BACKGROUND

• Aguilar J, Motato Y, Escriba MJ, Ojeda M, Munoz E, Meseguer M. The human first cell cycle: impact on implantation. Reprod Biomed Online. 2014 Apr;28(4):475-84. doi: 10.1016/j.rbmo.2013.11.014. Epub 2013 Dec 11.

  PMID: 24581982 BACKGROUND

• Hashimoto S, Kato N, Saeki K, Morimoto Y. Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging. Fertil Steril. 2012 Feb;97(2):332-7. doi: 10.1016/j.fertnstert.2011.11.042. Epub 2012 Jan 2.

  PMID: 22217963 BACKGROUND

• Conaghan J, Chen AA, Willman SP, Ivani K, Chenette PE, Boostanfar R, Baker VL, Adamson GD, Abusief ME, Gvakharia M, Loewke KE, Shen S. Improving embryo selection using a computer-automated time-lapse image analysis test plus day 3 morphology: results from a prospective multicenter trial. Fertil Steril. 2013 Aug;100(2):412-9.e5. doi: 10.1016/j.fertnstert.2013.04.021. Epub 2013 May 28.

  PMID: 23721712 BACKGROUND

• VerMilyea MD, Tan L, Anthony JT, Conaghan J, Ivani K, Gvakharia M, Boostanfar R, Baker VL, Suraj V, Chen AA, Mainigi M, Coutifaris C, Shen S. Computer-automated time-lapse analysis results correlate with embryo implantation and clinical pregnancy: a blinded, multi-centre study. Reprod Biomed Online. 2014 Dec;29(6):729-36. doi: 10.1016/j.rbmo.2014.09.005. Epub 2014 Sep 21.

  PMID: 25444507 BACKGROUND

• Rubio I, Galan A, Larreategui Z, Ayerdi F, Bellver J, Herrero J, Meseguer M. Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertil Steril. 2014 Nov;102(5):1287-1294.e5. doi: 10.1016/j.fertnstert.2014.07.738. Epub 2014 Sep 11.

  PMID: 25217875 BACKGROUND

• Yang Z, Zhang J, Salem SA, Liu X, Kuang Y, Salem RD, Liu J. Selection of competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing for patients undergoing preimplantation genetic screening: a prospective study with sibling oocytes. BMC Med Genomics. 2014 Jun 22;7:38. doi: 10.1186/1755-8794-7-38.

  PMID: 24954518 BACKGROUND

• Morbeck DE, Krisher RL, Herrick JR, Baumann NA, Matern D, Moyer T. Composition of commercial media used for human embryo culture. Fertil Steril. 2014 Sep;102(3):759-766.e9. doi: 10.1016/j.fertnstert.2014.05.043. Epub 2014 Jul 4.

  PMID: 24998366 BACKGROUND

• Basile N, Morbeck D, Garcia-Velasco J, Bronet F, Meseguer M. Type of culture media does not affect embryo kinetics: a time-lapse analysis of sibling oocytes. Hum Reprod. 2013 Mar;28(3):634-41. doi: 10.1093/humrep/des462. Epub 2013 Jan 12.

  PMID: 23315059 BACKGROUND

• Ciray HN, Aksoy T, Goktas C, Ozturk B, Bahceci M. Time-lapse evaluation of human embryo development in single versus sequential culture media--a sibling oocyte study. J Assist Reprod Genet. 2012 Sep;29(9):891-900. doi: 10.1007/s10815-012-9818-7. Epub 2012 Jun 20.

  PMID: 22714134 BACKGROUND

• Goodman LR, Goldberg J, Falcone T, Austin C, Desai N. Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trial. Fertil Steril. 2016 Feb;105(2):275-85.e10. doi: 10.1016/j.fertnstert.2015.10.013. Epub 2015 Oct 29.

  PMID: 26522611 BACKGROUND

Related Links

• Practice Guideline #201- Number of embryos for transfer during in vitro fertilization. Israel Society of Obstetrics and Gynecology. 2010 May 23;:1-1

MeSH Terms

Conditions

Infertility; Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Ruth Ronn, M.D. C.M.

  Shaare Zedek Medical Center

  PRINCIPAL INVESTIGATOR

• Talia Eldar-Geva, M.D. Ph.D.

  Shaare Zedek Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ruth Ronn, M.D. C.M.

CONTACT

972-2-655-5111; RuthRonn@szmc.org.il

Talia Eldar-Geva, M.D. Ph.D.

CONTACT

972-2-655-5111; gevat@szmc.org.il

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. Ruth Ronn

Study Record Dates

• First Submitted: January 5, 2016
• First Posted: January 18, 2016
• Study Start: October 1, 2016
• Primary Completion: December 1, 2017
• Study Completion: August 1, 2018
• Last Updated: February 23, 2017

Record last verified: 2017-02

Locations

IL (1)