Embryo quality

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Embryo quality is the ability of an embryo to perform successfully in terms of conferring a high pregnancy rate and/or resulting in a healthy person. Embryo profiling is the estimation of embryo quality by qualification and/or quantification of various parameters. Estimations of embryo quality guides the choice in embryo selection in in vitro fertilization.

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In general, embryo profiling for prediction of pregnancy rates focuses mainly on visual profiles and short-term biomarkers including expression of RNA and proteins, preferably in the surroundings of embryos to avoid any damage to them. On the other hand, embryo profiling for health prediction puts more focus on the genome, and where there is a risk of a genetic disorder it more often involves cell sampling from the embryo for preimplantation genetic diagnosis.

Prediction of pregnancy rates

Microscopy

Embryo quality is mainly evaluated by microscopy at certain time points using a morphological scoring system. This has shown to significantly improve pregnancy rates. [1] Assessment of morphological features as a reliable non-invasive method that provides valuable information in prediction of IVF/intra cytoplasmic sperm injection (ICSI) outcome has been frequently used as a scoring system of the embryo quality. The parameters for evaluation at day 2-3:

Number of cells and division rhythm: The optimal number of cells is 4 at day 2 and 8 at day 3 (A quality). In day 3 9-10 cells is B, >=10 is C (suboptimal) and <=4 is D (barely implant). A normal division rate is to double cell number each 24 hours. A higher rate implies chromosomal abnormalities and a lower rate entails possible embryo arrest (it is dying).

Fragmentation: happens due to cell apoptosis and can be quantified by the % of the embryo total volume eccupied by fragments. Fragments are cytoplasm fractions without nuclei.

Cells symmetry and size: it is normal that all blastomeres had same or similar size in embryos with 2, 4 or 8 cells, while for the rest of embryos, a certain variety in cells size is normal. When the number of cells is impaired, if all of them have the same size, it is considered asymmetrical. Those embryos with one big size blasomere is considered abnormal and is associated with high rate of polyploidy.

Multinucleation: multinucleated blastomeres on day 2 and day 3 is associated to a lower implantation rate. These embryos often are mosaics or with aneuploidy. It is more related to abnormalities on day 2 than on day 3.

Cytoplasm aspect: the presence of vesicles on day 3 is considered a sign of embryo genome activation and, therefore, of good prognosis. The presence of vacuoles is a sign of bad prognosis. [2]

Time-lapse microscopy is an expansion of microscopy wherein the morphology of embryos is studied over time. As of 2014, time-lapse microscopy for embryo quality assessment is emerging from the experimental stage to something with enough evidence for broader clinical use. [3] [4] Studies using the EmbryoScope (tm) time-lapse incubator have used several indicators for embryo quality, such as direct cleavage from 1 to 3 cells, [5] as well as the initiation of compaction and start of blastulation. [6] [7] [8] Also, two-pronuclear zygotes (2PN) transitioning through 1PN or 3PN states tend to develop into poorer-quality embryos than those that constantly remain 2PN. [9]

Molecular analysis

Molecular analysis can be performed by taking one of the cells from an embryo. The analysis can vary in extent from a single target biomarker to entire genomes, transcriptomes, proteomes and metabolomes. The results may be used to score embryos by comparing the patterns with ones that have previously been found among embryos in successful versus unsuccessful pregnancies: [10]

Transcriptome profiling

In transcriptome evaluation, gene expression profiling studies of human embryos are limited due to legal and ethical issues. [10]

Gene expression profiling of cumulus cells surrounding the oocyte and early embryo, or on granulosa cells, provides an alternative that does not involve sampling from the embryo itself. [10] Profiling of cumulus cells can give valuable information regarding the efficiency of an ovarian hyperstimulation protocol, and may indirectly predict oocyte aneuploidy, embryo development and pregnancy outcomes, without having to perform any invasive procedure directly in the embryo. [10]

In addition, microRNA (miRNA) and cell-free DNA (cfDNA) can be sampled from the vicinity of embryos, functioning as transcriptome-level-markers of embryo quality. [11]

Proteome profiling

Proteome profiling of embryos can indirectly be evaluated by sampling of proteins found in the vicinity of embryos, thereby providing a non-invasive method of embryo profiling. [10] Examples of protein markers evaluated in such profiling include CXCL13 and granulocyte-macrophage colony-stimulating factor, where lower protein amounts are associated with higher implantation rates. [10] The presence of soluble HLA-G might be considered as another parameter if a choice has to be made between embryos of equal visible quality. [1]

Another level of opportunity can be achieved by having the evaluation of the embryo profile tailored to the maternal status in regard to, for example health or immune status, potentially further detailed by similar profiling of the maternal genome, transcriptome, proteome and metabolome. Two examples of proteins that may be included in maternal profiling are endometrium-derived stathmin and annexin A2, whose down- and up-regulation, respectively, are associated with higher rates of successful implantation. [10]

Genome profiling

A systematic review and meta-analysis of existing randomized controlled trials came to the result that there is no evidence of a beneficial effect of PGP as measured by live birth rate. [12] On the contrary, for women of advanced maternal age, PGP significantly lowers the live birth rate. [12] Technical drawbacks, such as the invasiveness of the biopsy, and chromosomal mosaicism are the major underlying factors for inefficacy of PGP. [12]

A major drawback of genomic profiling for embryo quality is that the results generally rely on the assessment of a single cell, PGP has inherent limitations as the tested cell may not be representative of the embryo because of mosaicism. [12]

When used for women of advanced maternal age and for patients with repetitive IVF failure, PGP is mainly carried out as a screening for detection of chromosomal abnormalities such as aneuploidy, reciprocal and Robertsonian translocations, and few cases for other abnormalities such as chromosomal inversions or deletions. The principle behind it is that, since it is known that numerical chromosomal abnormalities explain most of the cases of pregnancy loss, and a large proportion of the human embryos are aneuploid, the selective replacement of euploid embryos should increase the chances of a successful IVF treatment. Comprehensive chromosome analysis methods include array-comparative genomic hybridization (aCGH), quantitative PCR and SNP arrays. [10] Combined with single blastomere biopsy on day-3 embryos, aCGH is very robust with 2.9% of tested embryos with no results, and associated with low error rates (1.9%). [10] There is no evidence that testing the embryo for abnormal number of chromosomes increases the number of live births. [13]

In addition to screening for specific abnormalities, techniques are in development that can avail for up to full genome sequencing, from which genetic profiling can score the DNA patterns by comparing with ones that have previously been found among embryos in successful or unsuccessful pregnancies. [10]

Health prediction

The main method currently used to predict the health of a resultant person of an embryo is preimplantation genetic diagnosis (also called preimplantation genetic screening, preimplantation genetic profiling or PGP), in order to determine whether the resultant person will inherit a specific disease or not. On the other hand, a systematic review and meta-analysis of existing randomized controlled trials came to the result that there is no evidence of a beneficial effect of PGP as measured by live birth rate. [12] On the contrary, for women of advanced maternal age, PGP significantly lowers the live birth rate. [12] Technical drawbacks, such as the invasiveness of the biopsy, and chromosomal mosaicism are the major underlying factors for inefficacy of PGP. [12]

Related Research Articles

<span class="mw-page-title-main">In vitro fertilisation</span> Assisted reproductive technology procedure

In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro. The process involves monitoring and stimulating a woman's ovulatory process, removing an ovum or ova from their ovaries and letting a man's sperm fertilise them in a culture medium in a laboratory. After the fertilised egg (zygote) undergoes embryo culture for 2–6 days, it is transferred by catheter into the uterus, with the intention of establishing a successful pregnancy.

<span class="mw-page-title-main">Intracytoplasmic sperm injection</span> In vitro fertilization procedure

Intracytoplasmic sperm injection is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of embryos that may be transferred to a maternal uterus. With this method, the acrosome reaction is skipped.

<span class="mw-page-title-main">Blastocyst</span> Structure formed around day 5 of mammalian embryonic development

The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the embryoblast which subsequently forms the embryo, and an outer layer of trophoblast cells called the trophectoderm. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. In the late blastocyst, the trophectoderm is known as the trophoblast. The trophoblast gives rise to the chorion and amnion, the two fetal membranes that surround the embryo. The placenta derives from the embryonic chorion and the underlying uterine tissue of the mother.

<span class="mw-page-title-main">Nondisjunction</span> Failure to separate properly during cell division

Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).

<span class="mw-page-title-main">Preimplantation genetic diagnosis</span> Genetic profiling of embryos prior to implantation

Preimplantation genetic diagnosis is the genetic profiling of embryos prior to implantation, and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. When used to screen for a specific genetic disease, its main advantage is that it avoids selective abortion, as the method makes it highly likely that the baby will be free of the disease under consideration. PGD thus is an adjunct to assisted reproductive technology, and requires in vitro fertilization (IVF) to obtain oocytes or embryos for evaluation. Embryos are generally obtained through blastomere or blastocyst biopsy. The latter technique has proved to be less deleterious for the embryo, therefore it is advisable to perform the biopsy around day 5 or 6 of development.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

Recurrent miscarriage or recurrent pregnancy loss (RPL) is the spontaneous loss of 2-3 pregnancies that is estimated to affect up to 5% of women. The exact number of pregnancy losses and gestational weeks used to define RPL differs among medical societies. In the majority of cases, the exact cause of pregnancy loss is unexplained despite genetic testing and a thorough evaluation. When a cause for RPL is identified, almost half are attributed to a chromosomal abnormality. RPL has been associated with several risk factors including parental and genetic factors, congenital and acquired anatomical conditions, lifestyle factors, endocrine disorders, thrombophila, immunological factors, and infections. The American Society of Reproductive Medicine recommends a thorough evaluation after 2 consecutive pregnancy losses, however, this can differ from recommendations by other medical societies. RPL evaluation be evaluated by numerous tests and imaging studies depending on the risk factors. These range from cytogenetic studies, blood tests for clotting disorders, hormone levels, diabetes screening, thyroid function tests, sperm analysis, antibody testing, and imaging studies. Treatment is typically tailored to the relevant risk factors and test findings. RPL can have a significant impact on the psychological well-being of couples and has been associated with higher levels of depression, anxiety, and stress. Therefore, it is recommended that appropriate screening and management be considered by medical providers.  

<span class="mw-page-title-main">Assisted reproductive technology</span> Methods to achieve pregnancy by artificial or partially artificial means

Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes or embryos, and/or the use of fertility medication. When used to address infertility, ART may also be referred to as fertility treatment. ART mainly belongs to the field of reproductive endocrinology and infertility. Some forms of ART may be used with regard to fertile couples for genetic purpose. ART may also be used in surrogacy arrangements, although not all surrogacy arrangements involve ART. The existence of sterility will not always require ART to be the first option to consider, as there are occasions when its cause is a mild disorder that can be solved with more conventional treatments or with behaviors based on promoting health and reproductive habits.

<span class="mw-page-title-main">Embryo transfer</span> Method of assisted reproduction

Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique - which is often used in connection with in vitro fertilization (IVF) - may be used in humans or in other animals, in which situations and goals may vary.

<span class="mw-page-title-main">Polar body</span> Byproduct of oogenesis

A polar body is a small haploid cell that is formed at the same time as an egg cell during oogenesis, but generally does not have the ability to be fertilized. It is named from its polar position in the egg.

<span class="mw-page-title-main">Implantation (embryology)</span> First stage of pregnancy

Implantation, also known as nidation, is the stage in the embryonic development of mammals in which the blastocyst hatches, attaches, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.

The genetics and abortion issue is an extension of the abortion debate and the disability rights movement. Since the advent of forms of prenatal diagnosis, such as amniocentesis and ultrasound, it has become possible to detect the presence of congenital disorders in the fetus before birth. Specifically, disability-selective abortion is the abortion of fetuses that are found to have non-fatal mental or physical defects detected through prenatal testing. Many prenatal tests are now considered routine, such as testing for Down syndrome. Women who are discovered to be carrying fetuses with disabilities are often faced with the decision of whether to abort or to prepare to parent a child with disabilities.

Embryo culture is a component of in vitro fertilisation where in resultant embryos are allowed to grow for some time in an artificial medium.

Oocyte selection is a procedure that is performed prior to in vitro fertilization, in order to use oocytes with maximal chances of resulting in pregnancy. In contrast, embryo selection takes place after fertilization.

Menstruation is the shedding of the uterine lining (endometrium). It occurs on a regular basis in uninseminated sexually reproductive-age females of certain mammal species.

Polar body biopsy is the sampling of a polar body of an oocyte. It was first applied clinically in humans in 1987 after extensive animal studies. A polar body is a small haploid cell that is formed concomitantly as an egg cell during oogenesis, but which generally does not have the ability to be fertilized.

Morphokinetics (‘morpho’’ form/shape and ‘kinetics’ movement) refers to time specific morphological changes during embryo development providing dynamic information on a fertilized egg. The detailed information eases morphological selection of embryos with high implantation potential to be used in In-Vitro Fertilisation treatment.

Repeated implantation failure (RIF) is the repeated failure of the embryo to implant onto the side of the uterus wall following IVF treatment. Implantation happens at 6–7 days after conception and involves the embedding of the growing embryo into the mothers uterus and a connection being formed. A successful implantation can be determined by using an ultrasound to view the sac which the baby grows in, inside the uterus.

Ovum quality is the measure of the ability of an oocyte to achieve successful fertilisation. The quality is determined by the maturity of the oocyte and the cells that it comprises, which are susceptible to various factors which impact quality and thus reproductive success. This is of significance as an embryo's development is more heavily reliant on the oocyte in comparison to the sperm.

Oocytes are immature egg cells that develop to maturity within a follicle in the ovary. Oocyte abnormalities can occur due to several factors, including premature ovarian insufficiency (POI), other maturation abnormalities, maternal ageing, and mitochondrial abnormalities.

References

  1. 1 2 Rebmann, V.; Switala, M.; Eue, I.; Grosse-Wilde, H. (2010). "Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: A German multi-centre study". Human Reproduction. 25 (7): 1691–1698. doi: 10.1093/humrep/deq120 . PMID   20488801.
  2. ↑ Nasiri, Nahid; Eftekhari-Yazdi, Poopak (8 October 2013). "An Overview of The Available Methods for Morphological Scoring of Pre-Implantation Embryos in In Vitro Fertilization". Cell Journal. 16 (4, Winter 2015): 392–405. doi:10.22074/cellj.2015.486. PMC   4297478 . PMID   25685730.
  3. ↑ Kaser, D. J.; Racowsky, C. (2014). "Clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring: a systematic review". Human Reproduction Update. 20 (5): 617–631. doi: 10.1093/humupd/dmu023 . ISSN   1355-4786. PMID   24890606.
  4. ↑ Freour, T.; Basile, N.; Barriere, P.; Meseguer, M. (2014). "Systematic review on clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring". Human Reproduction Update. 21 (1): 153–154. doi: 10.1093/humupd/dmu054 . ISSN   1355-4786. PMID   25293345.
  5. ↑ Rubio, I.; Kuhlmann, R.; Agerholm, I.; Kirk, J.; Herrero, J.; Escribá, M. A. J.; Bellver, J.; Meseguer, M. (2012). "Limited implantation success of direct-cleaved human zygotes: A time-lapse study". Fertility and Sterility. 98 (6): 1458–1463. doi: 10.1016/j.fertnstert.2012.07.1135 . PMID   22925687.
  6. ↑ Campbell, A.; Fishel, S.; Bowman, N.; Duffy, S.; Sedler, M.; Hickman, C. F. L. (2013). "Modelling a risk classification of aneuploidy in human embryos using non-invasive morphokinetics". Reproductive BioMedicine Online. 26 (5): 477–485. doi: 10.1016/j.rbmo.2013.02.006 . PMID   23518033.
  7. ↑ Meseguer, M.; Herrero, J.; Tejera, A.; Hilligsøe, K. M.; Ramsing, N. B.; Remohí, J. (2011). "The use of morphokinetics as a predictor of embryo implantation". Human Reproduction. 26 (10): 2658–2671. doi: 10.1093/humrep/der256 . PMID   21828117.
  8. ↑ Dal Canto, M.; Coticchio, G.; Mignini Renzini, M.; De Ponti, E.; Novara, P. V.; Brambillasca, F.; Comi, R.; Fadini, R. (2012). "Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation". Reproductive BioMedicine Online. 25 (5): 474–480. doi:10.1016/j.rbmo.2012.07.016. PMID   22995750.
  9. ↑ Reichman, D. E.; Jackson, K. V.; Racowsky, C. (2010). "Incidence and development of zygotes exhibiting abnormal pronuclear disposition after identification of two pronuclei at the fertilization check". Fertility and Sterility. 94 (3): 965–970. doi: 10.1016/j.fertnstert.2009.04.018 . PMID   19476942.
  10. 1 2 3 4 5 6 7 8 9 10 The Evian Annual Reproduction (EVAR) Workshop Group 2010; Fauser, B. C. J. M.; Diedrich, K.; Bouchard, P.; Domínguez, F.; Matzuk, M.; Franks, S.; Hamamah, S.; Simón, C.; Devroey, P.; Ezcurra, D.; Howles, C. M. (2011). "Contemporary genetic technologies and female reproduction". Human Reproduction Update. 17 (6): 829–847. doi:10.1093/humupd/dmr033. PMC   3191938 . PMID   21896560.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  11. ↑ Traver, S.; Assou, S.; Scalici, E.; Haouzi, D.; Al-Edani, T.; Belloc, S.; Hamamah, S. (2014). "Cell-free nucleic acids as non-invasive biomarkers of gynecological cancers, ovarian, endometrial and obstetric disorders and fetal aneuploidy". Human Reproduction Update. 20 (6): 905–923. doi: 10.1093/humupd/dmu031 . ISSN   1355-4786. PMID   24973359.
  12. 1 2 3 4 5 6 7 Mastenbroek, S.; Twisk, M.; Van Der Veen, F.; Repping, S. (2011). "Preimplantation genetic screening: A systematic review and meta-analysis of RCTs". Human Reproduction Update. 17 (4): 454–466. doi: 10.1093/humupd/dmr003 . PMID   21531751.
  13. ↑ Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S (8 September 2020). "Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation". Cochrane Database Syst Rev. 9: CD005291. doi:10.1002/14651858.CD005291.pub3. PMC   8094272 . PMID   32898291.
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