scholarly journals Misjudging early embryo mortality in natural human reproduction

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 702
Author(s):  
Gavin E. Jarvis
Keyword(s):  
Human Embryo ◽  
Expert Witness ◽  
Laboratory Data ◽  
Large Body ◽  
Early Embryo ◽  
Human Reproduction ◽  
Human Embryos ◽  
Natural Conditions ◽  
Embryo Mortality

In 2002, in a judgment relating to the use of the morning-after pill, Mr Justice Munby held that pregnancy begins with the implantation of an embryo into the uterus of a woman. The case involved a large body of expert witness evidence including medical and physiological details of human reproduction. Munby J. emphasised one particular aspect of this evidence: namely, the developmental failure rate of human embryos after fertilisation. Under natural conditions, embryo loss is approximately 10-40% before implantation, and total loss from fertilisation to birth is 40-60% (Jarvis, 2016). By contrast, and based on expert witness testimony, Munby J. stated that not much more than 25% of successfully fertilised eggs reach the implantation stage, and that fewer than 15% of fertilised eggs result in a birth, figures that do not accurately represent scientific knowledge regarding human embryo mortality and pregnancy loss under natural conditions. Rather, these figures were derived from experimental laboratory data and clinical outcomes from in vitro fertilisation treatment. Testimony provided by other expert witnesses directly contradicted these specific numerical claims. In emphasising these figures, Munby J. gave the impression that human embryo mortality is substantially higher than available scientific evidence indicated. In this critique, all the scientific expert witness evidence is presented and reviewed, and an explanation provided for why the emphasised figures are wrong. Whether there are implications of Munby J.’s scientific misjudgment on the legal outcome is for others to consider.

scholarly journals Early embryo mortality in natural human reproduction: What the data say

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2765 ◽  
Author(s):  
Gavin E. Jarvis
Keyword(s):  
Human Embryo ◽  
Early Embryo ◽  
Study Data ◽  
Human Reproduction ◽  
Human Embryos ◽  
Natural Conditions ◽  
Embryo Mortality ◽  
Fertilisation Rate ◽  
Embryo Loss ◽  
Insight Into

It is generally accepted that natural human embryo mortality during pregnancy is high – losses of 70% and higher from fertilisation to birth are frequently claimed. The first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period. Establishing the fate of embryos before this is challenging, and hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are cited to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet  is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data suggests that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, it is clear that some published estimates of natural embryo mortality are exaggerated. Although available data do not provide a precise estimate, natural human embryo mortality is lower than is often claimed.

scholarly journals Early embryo mortality in natural human reproduction: What the data say

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2765 ◽  
Author(s):  
Gavin E. Jarvis
Keyword(s):  
Human Embryo ◽  
Early Embryo ◽  
Study Data ◽  
Human Reproduction ◽  
Human Embryos ◽  
Natural Conditions ◽  
Embryo Mortality ◽  
Fertilisation Rate ◽  
Embryo Loss ◽  
Insight Into

How many human embryos die between fertilisation and birth under natural conditions? It is widely accepted that natural human embryo mortality is high, particularly during the first weeks after fertilisation, with total prenatal losses of 70% and higher frequently claimed. However, the first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period, and establishing the fate of embryos before this is challenging. Calculations are additionally hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are used to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet  is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data concluded that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, natural human embryo mortality is lower than often claimed and widely accepted. Estimates for total prenatal mortality of 70% or higher are exaggerated and not supported by the available data.

La fine del concetto di “pre-embrione” nella Convenzione di Oviedo / The end of the concept of “pre-embryo” in the Oviedo Convention

2018 ◽  
Vol 66 (6) ◽  
pp. 735-745
Author(s):  
Carlo Casini ◽  
Marina Casini
Keyword(s):  
Human Embryo ◽  
Legal Status ◽  
Human Embryos ◽  
Specific Reference ◽  
Constitutional Court ◽  
The European Union ◽  
Council Of Europe ◽  
European Court ◽  
The Moment

Il contributo si sofferma sulla questione riguardante la ricerca scientifica sugli embrioni generati in vitro. L’articolo 18 della Convenzione riguarda specificamente la sperimentazione sull’embrione in vitro e per questo esso è sottoposto ad una riflessione particolarmente approfondita. L’obiettivo è quello di capire se dalla Convenzione emergono linee idonee a definire lo statuto giuridico dell’embrione umano. Gli Autori concludono nel senso che nonostante il concetto di pre-embrione (formulato proprio per teorizzare l’insignificanza dell’embrione umano nei primi 14 giorni dalla fecondazione) sia stato accolto in alcune leggi e abbia implicitamente guidato l’interpretazione di alcuni aspetti relativi alla valutazione del valore dell’embrione, la Convenzione di bioetica lo ha definitivamente respinto con il massimo di autorevolezza. La conclusione è raggiunta attraverso l’esame dell’art. 18 considerandone anche la precedente formulazione contenuta in una bozza; mediante una interpretazione sistematica della Convenzione che esige il riconoscimento del concepito, fin dalla fecondazione, come un “essere umano”; esaminando i contributi preparatori elaborati dalla Assemblea Parlamentare del Consiglio d’Europa e del Parlamento Europeo; prendendo in considerazione gli sviluppi della Convenzione di Oviedo con specifico riferimento al tema del pre-embrione. L’indagine si avvale poi anche di ampi riferimenti alla giurisprudenza della Corte europea dei diritti dell’uomo del Consiglio d’Europa, alla giurisprudenza della Corte di Giustizia dell’Unione Europea, ad alcune recenti decisioni della Corte Costituzionale italiana. ---------- The paper focuses on the question concerning scientific research on human embryos generated in vitro. Article 18 of the Oviedo Convention specifically concerns the experimentation on the in vitro embryos and for this reason it is subject to a particularly in-depth reflection. The goal is to understand if the Convention shows suitable lines to define the legal status of the human embryo. The authors conclude that despite the concept of pre-embryo (formulated to theorize the insignificance of the human embryo in the first 14 days of fertilization) has been accepted in some laws and has implicitly guided the interpretation of some aspects related to the evaluation of the value of the embryo, the Bioethics Convention definitively rejected it with the utmost authority. The conclusion is reached through the examination of the art. 18 also considering the previous formulation contained in a draft; through a systematic interpretation of the Convention which requires the recognition of the conceived, from the moment of fertilization, as a “human being”; examining the preparatory contributions prepared by the Parliamentary Assembly of the Council of Europe and the European Parliament; taking into consideration the developments of the Oviedo Convention with specific reference to the theme of the pre-embryo. The investigation also makes use of extensive references to the jurisprudence of the European Court of Human Rights of the Council of Europe, to the jurisprudence of the Court of Justice of the European Union, to some recent decisions of the Italian Constitutional Court.

scholarly journals Mitochondria and human preimplantation embryo development

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 619-624 ◽  
Author(s):  
Martin Wilding ◽  
Gianfranco Coppola ◽  
Brian Dale ◽  
Loredana Di Matteo
Keyword(s):  
Embryo Development ◽  
Preimplantation Embryo ◽  
Anaerobic Respiration ◽  
Mitochondrial Metabolism ◽  
Human Reproduction ◽  
Aerobic Respiration ◽  
Human Embryos ◽  
Developmental Potential ◽  
Preimplantation Embryo Development

Human reproduction, like all biological systems, is characterised by a large level of variability. In this field, the variability is observed as a large difference in implantation potential of human embryos developing in vitro, despite similarities in observable parameters such as rate of development and morphology of these embryos. One of the underlying factors that determines developmental potential in these embryos is the availability of energy in the form of ATP for development. Here, we suggest that, despite the evidence suggesting that mitochondrial metabolism is relatively inactive during preimplantation embryo development, aerobic (mitochondrial) metabolism contributes a major role in the supply of ATP. A second pathway, anaerobic respiration, is also active and the two pathways work in synchrony to supply all the ATP necessary. We discuss the differences in the two forms of energy production and suggest that, although anaerobic respiration can supplement deficiencies in the energy supply in the short term, this is not sufficient to substitute for aerobic respiration over long periods. Therefore, we suggest that deficiencies in the levels of aerobic respiration can explain variability in the implantation potential of apparently equivalent embryos.

scholarly journals Modelling human embryogenesis: embryo-like structures spark ethical and policy debate

2020 ◽  
Vol 26 (6) ◽  
pp. 779-798
Author(s):  
Ana M Pereira Daoud ◽  
Mina Popovic ◽  
Wybo J Dondorp ◽  
Marc Trani Bustos ◽  
Annelien L Bredenoord ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Development ◽  
Human Embryo ◽  
Embryoid Bodies ◽  
Embryo Research ◽  
Human Embryos ◽  
Pubmed Database ◽  
Human Embryo Research ◽  
Post Implantation

Abstract BACKGROUND Studying the human peri-implantation period remains hindered by the limited accessibility of the in vivo environment and scarcity of research material. As such, continuing efforts have been directed towards developing embryo-like structures (ELS) from pluripotent stem cells (PSCs) that recapitulate aspects of embryogenesis in vitro. While the creation of such models offers immense potential for studying fundamental processes in both pre- and early post-implantation development, it also proves ethically contentious due to wide-ranging views on the moral and legal reverence due to human embryos. Lack of clarity on how to qualify and regulate research with ELS thus presents a challenge in that it may either limit this new field of research without valid grounds or allow it to develop without policies that reflect justified ethical concerns. OBJECTIVE AND RATIONALE The aim of this article is to provide a comprehensive overview of the existing scientific approaches to generate ELS from mouse and human PSCs, as well as discuss future strategies towards innovation in the context of human development. Concurrently, we aim to set the agenda for the ethical and policy issues surrounding research on human ELS. SEARCH METHODS The PubMed database was used to search peer-reviewed articles and reviews using the following terms: ‘stem cells’, ‘pluripotency’, ‘implantation’, ‘preimplantation’, ‘post-implantation’, ‘blastocyst’, ‘embryoid bodies’, ‘synthetic embryos’, ‘embryo models’, ‘self-assembly’, ‘human embryo-like structures’, ‘artificial embryos’ in combination with other keywords related to the subject area. The PubMed and Web of Science databases were also used to systematically search publications on the ethics of ELS and human embryo research by using the aforementioned keywords in combination with ‘ethics’, ‘law’, ‘regulation’ and equivalent terms. All relevant publications until December 2019 were critically evaluated and discussed. OUTCOMES In vitro systems provide a promising way forward for uncovering early human development. Current platforms utilize PSCs in both two- and three-dimensional settings to mimic various early developmental stages, including epiblast, trophoblast and amniotic cavity formation, in addition to axis development and gastrulation. Nevertheless, much hinges on the term ‘embryo-like’. Extension of traditional embryo frameworks to research with ELS reveals that (i) current embryo definitions require reconsideration, (ii) cellular convertibility challenges the attribution of moral standing on the basis of ‘active potentiality’ and (iii) meaningful application of embryo protective directives will require rethinking of the 14-day culture limit and moral weight attributed to (non-)viability. Many conceptual and normative (dis)similarities between ELS and embryos thus remain to be thoroughly elucidated. WIDER IMPLICATIONS Modelling embryogenesis holds vast potential for both human developmental biology and understanding various etiologies associated with infertility. To date, ELS have been shown to recapitulate several aspects of peri-implantation development, but critically, cannot develop into a fetus. Yet, concurrent to scientific innovation, considering the extent to which the use of ELS may raise moral concerns typical of human embryo research remains paramount. This will be crucial for harnessing the potential of ELS as a valuable research tool, whilst remaining within a robust moral and legal framework of professionally acceptable practices.

scholarly journals Fertility Technology Research and the Use of Human Beings as Property

2020 ◽  
Vol 87 (4) ◽  
pp. 376-380
Author(s):  
Cynthia Jones-Nosacek
Keyword(s):  
Human Reproduction ◽  
Human Embryos ◽  
Human Beings ◽  
Vitro Fertilization ◽  
Poor Women ◽  
Gonadotropin Releasing Hormone Antagonists ◽  
Uterine Curettage ◽  
Hormone Antagonists ◽  
Uterine Lavage

In January 2020, an article in the Journal of Human Reproduction exploring whether human embryos could be obtained via uterine lavage and to compare their quality to embryos created via in vitro fertilization. Any embryo that was not removed via lavage was either prevented from implanting by giving the women injections of gonadotropin releasing hormone antagonists or aborted with either methotrexate or uterine curettage. This research was done using women in Mexico, who were paid the equivalent of over two months’ wages and who signed away their rights to their embryos, including agreeing to have an abortion if implantation did occur. Not only is this another instance of human beings being treated as property but is against the dignity of these women by turning them into, as one ethicist says, “human petri dishes.” Summary: Researchers continue to use people as objects to obtain their goals. In this case, it was poor women in Mexico and their embryos. The Editors of Journal of Human Reproduction enabled this by publishing the report.

scholarly journals Prymat prawa nad etyką? Nowy etap włoskiego sporu o metodę in vitro

2015 ◽  
Vol 13 (2) ◽  
pp. 45-67
Author(s):  
Andrzej Kobyliński
Keyword(s):  
Human Embryo ◽  
Human Embryos ◽  
Constitutional Court ◽  
Human Being ◽  
Legal Regulations ◽  
Human Beings ◽  
Artificial Reproduction ◽  
The Public ◽  
The Law

In April 2014 The Constitutional Court in Italy was called to judge parts of the Law 40/2004 and canceled the prohibition of the methods of heterological artificial reproduction. !is decision opened a new stage of the public dispute about artificial reproduction that has been held in Italy for the last 20 years. The most significant principle of the legislation from the year 2004 was the recognition of the human embryo as a human being from the very moment of conception. The law in Italy forbade, among others, producing human embryos for scientific purposes, freezing and destroying human beings. The opponents of such legal regulations evoked the nationwide referendum in 2005 which did not manage to repeal the operative legislation. In 2015 the Italian Parliament will adopt a special law regulating the use of the methods of heterological artificial reproduction.

scholarly journals The effects of hyaluronate-containing medium on human embryo attachment to endometrial epithelial cells in vitro

2020 ◽  
Vol 2020 (2) ◽  
Author(s):  
Peter T Ruane ◽  
Chelsea J Buck ◽  
Phoebe A Babbington ◽  
Wedad Aboussahoud ◽  
Stéphane C Berneau ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Embryo Transfer ◽  
Human Embryo ◽  
Research Network ◽  
Human Embryos ◽  
Ishikawa Cell ◽  
Practitioner Training ◽  
Cell Layers ◽  
Endometrial Epithelial Cells

Abstract STUDY QUESTION Does embryo transfer medium containing hyaluronate (HA) promote the attachment phase of human embryo implantation? SUMMARY ANSWER HA-containing medium does not promote human blastocyst attachment to endometrial epithelial cells in vitro. WHAT IS KNOWN ALREADY Embryo transfer media containing high concentrations of HA are being used to increase implantation and live birth rates in IVF treatment, although the mechanism of action is unknown. STUDY DESIGN, SIZE, DURATION Expression of HA-interacting genes in frozen-thawed oocytes/embryos was assessed by microarray analysis (n = 21). Fresh and frozen human blastocysts (n = 98) were co-cultured with human endometrial epithelial Ishikawa cell layers. Blastocyst attachment and the effects of a widely used HA-containing medium were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Blastocyst-stage embryos were transferred at day 6 to confluent Ishikawa cell layers; some blastocysts were artificially hatched. Blastocyst attachment was monitored from 1 to 48 h, and the effects of blastocyst pre-treatment for 10 min with HA-containing medium were determined. MAIN RESULTS AND THE ROLE OF CHANCE Human embryos expressed the HA receptor genes CD44 and HMMR, hyaluronan synthase genes HAS1–3, and hyaluronidase genes HYAL1–3, at all stages of preimplantation development. Attachment of partially hatched blastocysts to Ishikawa cells at 24 and 48 h was related to trophectoderm grade (P = 0.0004 and 0.007, respectively, n = 34). Blastocysts of varying clinical grades that had been artificially hatched were all attached within 48 h (n = 21). Treatment of artificially hatched blastocysts with HA-containing medium did not significantly affect attachment at early (1–6 h) or late (24 and 48 h) time points, compared with control blastocysts (n = 43). LIMITATIONS, REASONS FOR CAUTION Using an adenocarcinoma-derived cell line to model embryo-endometrium attachment may not fully recapitulate in vivo interactions. The high levels of blastocyst attachment seen with this in vitro model may limit the sensitivity with which the effects of HA can be observed. WIDER IMPLICATIONS OF THE FINDINGS Morphological trophectoderm grade can be correlated with blastocyst attachment in vitro. HA-containing medium may increase pregnancy rates by mechanisms other than promoting blastocyst attachment to endometrium. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by a grant from the Wellbeing of Women, the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility, the Department of Health Scientist Practitioner Training Scheme, and the Ministry of Higher Education, The State of Libya. None of the authors has any conflict of interest to declare.

scholarly journals Lysophosphatidic Acid Signaling in Late Cleavage and Blastocyst Stage Bovine Embryos

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Ana Catarina Torres ◽  
Dorota Boruszewska ◽  
Mariana Batista ◽  
Ilona Kowalczyk-Zieba ◽  
Patricia Diniz ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Culture Medium ◽  
Marker Gene ◽  
Blastocyst Stage ◽  
Early Embryo ◽  
Human Embryos ◽  
Lipid Mediator ◽  
Bovine Embryos ◽  
Pluripotency Marker

Lysophosphatidic acid (LPA) is a known cell signaling lipid mediator in reproductive tissues. In the cow, LPA is involved in luteal and early pregnancy maintenance. Here, we evaluated the presence and role of LPA in bovine early embryonic development. In relevant aspects, bovine embryos reflect more closely the scenario occurring in human embryos than the mouse model. Transcription of mRNA and protein expression of enzymes involved in LPA synthesis (ATX andcPLA2) and of LPA receptors (LPAR1–4) were detected in Days 5 and 8in vitroproduced embryos. Embryonic LPA production into culture medium was also detected at both stages of development. Supplementation of culture medium with LPA (10−5 M) between Days 2 and 8 had no effect on embryo yield and quality and on blastocyst relative mRNA abundance of genes involved in prostaglandin synthesis (PTGS2,PGES, andPGFS) and steroidogenesis (3βHSD). However, LPA treatment affected transcription levels of embryo quality markers, decreasingBAX(apoptotic) and increasingBCL2(antiapoptotic) andIGF2R(growth marker) gene transcription levels. Blastocyst transcription ofOCT4(pluripotency marker) was not affected by LPA stimulation. In conclusion, LPA is an early bovine embryonic autocrine/paracrine signaling mediator, and LPA action may be relevant in early embryo-maternal interactions leading to embryonic survival.

scholarly journals Genesis of embryonic stem cells

2003 ◽  
Vol 358 (1436) ◽  
pp. 1397-1402 ◽  
Author(s):  
Mia Buehr ◽  
Austin Smith
Keyword(s):  
Kinase Inhibitor ◽  
Time Window ◽  
Es Cells ◽  
Primary Cultures ◽  
Embryonic Stem ◽  
Early Embryo ◽  
Human Embryos ◽  
Es Cell

Embryonic stem (ES) cells are permanent pluripotent stem cell lines established from pre–implantation mouse embryos. There is currently great interest in the potential therapeutic applications of analogous cells derived from human embryos. The isolation of ES cells is commonly presented as a straightforward transfer of cells in the early embryo into culture. In reality, however, continuous expansion of pluripotent cells does not occur in vivo, and in vitro is the exception rather than the norm. Both genetic and epigenetic factors influence the ability to derive ES cells. We have tracked the expression of a key marker and determinant of pluripotency, the transcription factor Oct–4, in primary cultures of mouse epiblasts and used this to assay the effect of experimental manipulations on the maintenance of a pluripotent cell compartment. We find that expression of Oct–4 is often lost prior to overt cytodifferentiation of the epiblast. The rate and extent of Oct–4 extinction varies with genetic background. We report that treatment with the MAP kinase/ERK kinase inhibitor PD98059, which suppresses activation of the mitogen–activated protein kinases Erk1 and Erk2, results in increased persistence of Oct–4–expressing cells. Oct–4 expression is also relatively sustained in cultures of diapause embryos and of isolated inner cell masses. Combination of all three conditions allowed the derivation of germline–competent ES cells from the normally refractory CBA mouse strain. These findings suggest that the genesis of an ES cell is a relatively complex process requiring epigenetic modulation of key gene expression over a brief time–window. Procedures that extend this time–window and/or directly regulate the critical genes should increase the efficiency of ES cell derivation.

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