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| Name | Class |
|---|---|
| Main Line Fertility Center | OTHER |
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We propose to perform a clinical randomized trial to evaluate the effect of blastocyst biopsy and whole chromosome analysis by Next Generation Sequencing (NGS) in comparison to standard Assisted Reproductive Technologies (ART) methods on on implantation rates, miscarriage rates, and pregnancy rates.
This will be three studies into one: a) a comparison of treatment (NGS) and no treatment, b) a non-selection study based on the control group for which we will replace without knowing the ploidy of the embryos, but we will know it later, c) a retrospective study about the use of Mitochondrial DNA as a selection tool.
Patients following the inclusion criteria will be randomized into two groups:
(*) Hatching blastocysts as described by Gardner and Schoolcraft (1999)
The Primary efficacy endpoint of comparing the study group with the control will be ongoing implantation rate (# fetus reaching 2nd trimester / # embryos replaced).
All biopsied embryos from the test and control group will have their mitochondrial DNA analyzed, but that information will not be used for purposes of choosing embryos for replacement. Retrospectively but blindly (see blinding of results section), the information will be used at the end of the study to determine which embryos have a higher chance of implanting. If at that point the participating patients have remaining embryos frozen, they will be able to use that information for purposes of embryo selection.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control - Standard ART treatment | No Intervention | ||
| Test - PGS | Experimental | All embryos will be hatched on day 3. Patients will have hatching blastocysts (*) biopsied on day 5,/6. Embryos will be vitrified. Patients will have a single hatching euploid blastocyst (*) replaced on a thawed cycle. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Next Generation Sequencing after Blastocyst biopsy | Genetic | PGD using blastocyst biopsy and testing of the biopsy by NGS |
|
| Measure | Description | Time Frame |
|---|---|---|
| improvement in ongoing implantation rates | We foresee a significant increase in ongoing implantation rates in the Test group compared to the Control group based on several studies showing about a 50% improvement of implantation rates after Preimplantation Genetic Diagnosis (PGD) with blastocyst biopsy and comprehensive chromosome analysis techniques The center participating in the study has an average 41.5% implantation rate of blastocysts in patients 35-39 years of age without PGD. Assuming that NGS will increase the detection power of chromosome abnormalities, we expect a higher implantation rate in the test group. Furthermore, we expect a 6% miscarriage rate in the Test group, based on extensive data from array comparative genomic hybridization (aCGH) results (Hodes-Wertz et al. 2012), while about 21% in the Control group based on Society for Assisted Reproductive Technologies (SART) data (ages 35-40, SART 2011). | When a fetal heartbeat is detected for each patient. (8 weeks after implantation). |
| Measure | Description | Time Frame |
|---|---|---|
| Determine specificity and sensitivity rates | The pregnancy outcome of Controls patients with euploid embryos replaced will be compared to that of control patients with aneuploid embryos replaced. This will give us the specificity of the test (false positive rate) by obtaining the ongoing pregnancy rate of cycles with aneuploid embryos replaced, and the sensitivity of the test (false negative rate) by obtaining the miscarriage rate and ongoing pregnancy rate of cycles with euploid embryos replaced. |
| Measure | Description | Time Frame |
|---|---|---|
| Correlation of Mitochondrial DNA and implantation | The third aim of this study is to determine retrospectively if mt DNA content is linked to implantation potential and if that is measurable by NGS. NGS provides the additional advantage that it can measure mitochondrial DNA, which it's content, seems to be inversely correlated with implantation (Fragouli et al 2013, ASRM). | When a fetal heartbeat is detected (8 weeks after implantation) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Santiago Munne, PhD | Reprogenetics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Reprogenetics | Recruiting | Livingston | New Jersey | 07039 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17141767 | Background | Cohen J, Wells D, Munne S. Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates. Fertil Steril. 2007 Mar;87(3):496-503. doi: 10.1016/j.fertnstert.2006.07.1516. Epub 2006 Dec 4. | |
| 19773223 | Background | De Vos A, Staessen C, De Rycke M, Verpoest W, Haentjens P, Devroey P, Liebaers I, Van de Velde H. Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers. Hum Reprod. 2009 Dec;24(12):2988-96. doi: 10.1093/humrep/dep251. Epub 2009 Sep 21. |
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| ID | Term |
|---|---|
| D007246 | Infertility |
| D000022 | Abortion, Spontaneous |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| During a pregnancy term |
| 20971462 | Background | Gutierrez-Mateo C, Colls P, Sanchez-Garcia J, Escudero T, Prates R, Ketterson K, Wells D, Munne S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011 Mar 1;95(3):953-8. doi: 10.1016/j.fertnstert.2010.09.010. Epub 2010 Oct 25. |
| 19409550 | Background | Munne S, Wells D, Cohen J. Technology requirements for preimplantation genetic diagnosis to improve assisted reproduction outcomes. Fertil Steril. 2010 Jul;94(2):408-30. doi: 10.1016/j.fertnstert.2009.02.091. Epub 2009 May 5. |
| 19939370 | Background | Schoolcraft WB, Fragouli E, Stevens J, Munne S, Katz-Jaffe MG, Wells D. Clinical application of comprehensive chromosomal screening at the blastocyst stage. Fertil Steril. 2010 Oct;94(5):1700-6. doi: 10.1016/j.fertnstert.2009.10.015. Epub 2009 Nov 25. |
| 22503277 | Background | Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, Munne S. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. 2012 Jun;24(6):614-20. doi: 10.1016/j.rbmo.2012.02.009. Epub 2012 Feb 25. |
| 3384119 | Background | Cohen J, DeVane GW, Elsner CW, Kort HI, Massey JB, Norbury SE. Cryopreserved zygotes and embryos and endocrinologic factors in the replacement cycle. Fertil Steril. 1988 Jul;50(1):61-7. doi: 10.1016/s0015-0282(16)60009-2. |
| 23548942 | Background | Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT Jr. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013 Jul;100(1):100-7.e1. doi: 10.1016/j.fertnstert.2013.02.056. Epub 2013 Mar 30. |
| Background | Fragouli E, Spath K, Alfarawati S, Wells D (2013) Quantification of mitochondrial DNA predicts the implantation potential of chromosomally normal embryos. Fertil Steril, in press (ASRM abstract) |
| Background | Gardner DK and Schoolcraft WB. In vitro culture of human blastocysts. In: Jansen R, Mortimer D. eds. Towards Reproductive Certainty: Fertility and Genetics Beyond 1999. Carnforth, Parthenon Publishin, 1999, 378-88 |
| 22683012 | Background | Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, Munne S. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril. 2012 Sep;98(3):675-80. doi: 10.1016/j.fertnstert.2012.05.025. Epub 2012 Jun 7. |
| Background | SART (2011): https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0 |
| 22305103 | Background | Scott RT Jr, Ferry K, Su J, Tao X, Scott K, Treff NR. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study. Fertil Steril. 2012 Apr;97(4):870-5. doi: 10.1016/j.fertnstert.2012.01.104. Epub 2012 Feb 2. |
| 20188357 | Background | Treff NR, Su J, Tao X, Levy B, Scott RT Jr. Accurate single cell 24 chromosome aneuploidy screening using whole genome amplification and single nucleotide polymorphism microarrays. Fertil Steril. 2010 Nov;94(6):2017-21. doi: 10.1016/j.fertnstert.2010.01.052. Epub 2010 Feb 26. |
| Background | Treff NR, Ferry KM, Zhao T, Su J, Forman EJ, Scott RT (2011) Cleavage stage embryo biopsy significantly impairs embryonic reproductive potential while blasto- cyst biopsy does not: a novel paired analysis of cotransferred biopsied and non-biopsied sibling embryos. Fertil Steril, 96: Supplement, S2 |
| Background | Wells W, Kaur K, Fragouli E, Munné S (2013) Next generation sequencing. Reprod Biomed Online 26: Suppl 1, 55. |
| 22551456 | Background | Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES, Salem RD. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012 May 2;5(1):24. doi: 10.1186/1755-8166-5-24. |
| 32898291 | Derived | Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev. 2020 Sep 8;9(9):CD005291. doi: 10.1002/14651858.CD005291.pub3. |