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Fertilisation, the fourteen day rule, and beyond

7 June 2021
By Dr Sigal Klipstein
Dr Klipstein practices reproductive endocrinology and infertility at InVia fertility specialists in Chicago, Illinois. She is an assistant clinical professor at the University of Chicago and is the chair of the Ethics Committee of the American Society for Reproductive Medicine.
Appeared in BioNews 1098

The first IVF baby was born in 1978, and represented a milestone at the cross section of basic science, clinical research and patient care. The birth was the culmination of decades of research into culturing both animal and human embryos in the laboratory setting. Indeed, the first reports of fertilisation of human oocytes were published over a decade prior.

While the birth of the first extracorporeally conceived baby was a proof of concept, success rates of early IVF cycles were quite low. It was only through robust embryo research, including optimisation of embryo culture conditions, that embryologists were able to continue to improve these rates. The current ability to grow embryos to the blastocyst phase, during which time they can be screened for both aneuploidy and genetically inherited disorders, has improved both success rates and the health of the resultant children. And yet, many knowledge gaps remain.

Even in the best labs, success rates per embryo transferred do not exceed 70 percent. Human reproduction is not particularly efficient, though much more so with IVF when compared to natural conception. In both in vivo and in vitro reproduction, implantation failures, stalled embryo development, spontaneous abortions, and congenital anomalies can occur. Not all of these can be explained by genetic factors. Epigenetic and other factors likely play a role in failed or aberrant embryo development.

Many of the yet unsolved mysteries of human reproduction occur in the window between implantation and the appearance of an embryo on ultrasound – between approximately day five and day 28 of embryo development. This is the 'black box' period of human reproduction. Understanding the factors that allow for successful embryo development will help minimise spontaneous abortions, decrease the burden of birth defects, and improve IVF success rates. Knowledge gleaned from studying this critical stage of embryo development has the potential to optimise human reproduction and decrease the suffering of intended parents who are otherwise unable to achieve a healthy ongoing pregnancy. 

Four decades ago, the ability to grow embryos to the eight cell stage represented the pinnacle of scientific achievement in the field of reproduction. It stimulated both robust enthusiasm and extensive debate into the ethics of embryo research, a debate that continues to this day (ASRM Ethics in Embryo Research 2020). In hindsight, that momentous achievement was one of many to come. It is against this background that the International Society for Stem Cell Research (ISSCR) released its recent Guidelines for Stem Cell Research and Clinical Translation. This report touches upon one of the frontiers of reproductive research – the expanding ability to nurture embryos in culture for an extended period.

The revised ISSCR guidelines address the possibility that embryos may be grown beyond the development of the primitive streak, and how such research might be undertaken. The primitive streak, which appears at approximately fourteen days' post fertilisation of human oocytes, marks the start of gastrulation. This is a period during which the inner cell mass of the blastocyst begins the process of development of the three germ layers from which all fetal structures ultimately develop. This fourteen day 'limit' was suggested in the early stages of embryo research, at a time when the possibility that embryos could develop to this stage in vitro was a distant if not an impossible reality. While not yet considered feasible, those at the forefront of this research feel that the technology to traverse this fourteen day line in the sand may soon be possible.

As is often the case with emerging technologies in the field of reproductive science, each new potential advancement stimulates debate of the ethical permissibility of the research and its subsequent clinical applications. Growth of embryos beyond fourteen days is no exception. Among the recommendations in the ISSCR guidelines is a call to action for 'national academies of science, academic societies, funders, and regulators to lead public conversations touching on the scientific significance as well as the societal and ethical issues raised by allowing such research.'

These conversations often hinge around a debate pinning what can be done against what should be done. What will be done usually occurs somewhere between these two extremes. The guidelines go on to suggest a path forward when a number of conditions are met: broad public support is present, specialised scientific and ethical oversight is undertaken, growth of embryos beyond 14 days is justified by scientific objectives, and a minimal number of embryos are used to achieve the research objectives.

Given the profound implications inherent in extending the time that embryos are allowed to be cultured, the path forward must be approached with great caution. Each small incremental development is best evaluated on its own merits before further expanding the boundaries of research.

An assessment of knowledge gleaned from a slight lengthening of the time span of embryo development should be continually undertaken. This knowledge should focus at every stage on the goal of expanding fundamental knowledge or improving human health and decreasing human suffering. Investigators have a responsibility to share in the ethical debate by ensuring that they clearly delineate the rationale for examining more advanced embryos, and disseminate their research findings and implications broadly, in a manner that is able to be understood by the public at large. It is only in this way that an appropriately robust and well informed debate can occur at all levels of society, including in the scientific, social, ethical and legislative realms.

While science marches on, it must keep in step with the moral compass of the society it serves. At every step, the various stakeholders should insist on a constant evaluation of the research findings, any ethical conundrums they raise, and the benefits that may be obtained from investigating ever more developed human embryos.

22 November 2021 - by Dr George Janes 
High-resolution single-cell gene expression analysis has been performed on a gastrulating human embryo, providing landmark insights...
1 June 2021 - by Sandy Starr 
The International Society for Stem Cell Research has published wide-ranging new guidelines, covering a number of contentious areas of research and clinical practice...
26 April 2021 - by Dr Patrick Foong 
Is an international conversation on the 14-day rule needed in the light of the development of iBlastoids?...
8 March 2021 - by Joseph Hamilton 
The 14-day limit on culturing human embryos in the lab should be extended, according to an international group of researchers...
15 February 2021 - by Sophia McCully 
The '14-day rule', initially proposed in 1979 in the USA, was first recommended in the UK by the Warnock Committee in 1984. It limits research on intact human embryos 'prior to 14 days' gestation or the beginning of primitive streak formation' and is part of the Human Fertilisation and Embryology Act 2008...
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