From biology to practice: Transferring a healthy embryo to a receptive uterus

Published 17 November 2020

The organisation of an online Campus meeting in November by three ESHRE SIGs – Embryology, Implantation & Early Pregnancy, and Stem Cells – reflected the range and complexity of achieving successful implantation in assisted reproduction. This well attended course of three half-days considered implantation from clinical, hormonal, embryological and endometrial perspectives.

More than 250 registered for this online Campus meeting in November, and there were rarely fewer than 100 taking part in any session. What they heard was a detailed deconstruction of successful – and failed – implantation from the perspectives of the meeting’s three organising SIGs. But what Lisbon embryologist Carlos Plancha told them, whatever the range and perspectives of his fellow speakers, was that the quality of an embryo and its developmental competence was mainly determined by the female gamete. And oocytes, explained Plancha, acquire this developmental competence with progressive folliculogenesis and cross-talk within the follicle - such that only a developmentally viable oocyte is able to complete meiosis, fertilisation, embryogenesis, and term development.

Yet despite this complex signalling cross-talk within the follicle, maternal age, said Plancha, ‘remains the most significant factor influencing conception and offspring health in human reproduction’ – largely as a function of the embryo’s chromosomal status. Indeed, it was later in the meeting that US embryologist Denny Sakkas from Boston IVF, citing his own recent findings in a presentation on embryo selection, described euploidy in the embryo as ‘more important’ than morphology in explaining an embryo’s likely progression to live birth.(1)

However, neither Plancha nor any of his fellow speakers failed to acknowledge the place of the uterine environment as a determinant of implantation. Sakkas in a simple model of contributing factors to successful implantation attributed ’70-80%’ to the egg, ‘10-15%’ to the sperm, and ’10-15%’ to the uterus. Indeed, said Plancha, the uterus actually ‘allows’ embryo implantation and ensures a ‘tolerant environment while modulating invasion’. Thus, with developmentally competent embryos the surface epithelium of the uterus amplifies embryonic signals to the underlying stroma to optimise post-implantation development, while with developmentally compromised embryos that same epithelial surface
favours the withdrawal of decidual factors in the stroma causing tissue breakdown and elimination of the compromised conceptus.

With such an emphasis on female factors, it was no surprise to hear Nottingham, UK, biologist Adam Watkins describe the male’s role in this equation as ‘largely ignored’. Yet, as Watkins readily acknowledged, there is now new interest in the role of male diet on sperm quantity and quality, the embryo’s development in utero, and the offspring’s propensity to non-communicable disease – all this, said Watkins, a progression of the Barker hypothesis of the developmental origins of health and disease (DOHaD). He reported data showing evidence of male-line transgenerational response in humans, but his own work on the effects of male diet on fetal development and the health of offspring was in mice. A study just published showed how paternal diet impaired vascular function through sperm and seminal plasma mechanisms.(2) His most recent work looked at the effects of three dietary models – normal, low protein and ‘Western’ (characterised by high fat and sugar) – and implications for testicular gene expression and embryo development. There were ‘abnormalities’ associated with the Western diet in embryonic metabolism and development, ‘cell cycle’ and immune responses, as well as in non-coding RNA metabolic responses in the low protein diet. There were many questions from the virtual floor on these findings, notably whether they might be extrapolated from mice to men – particularly in low-protein (vegan) or high-protein (supplemented) diets. However, there were no firm answers, only the much repeated wisdom of a well balanced diet.

So is it possible, as this Campus title implied, to select an optimally fertilised egg which is guaranteed to implant and achieve a healthy pregnancy? Early session presentations appeared to concentrate on pre- and periconceptional factors of influence on the gamete, and left the hand of real-time intervention to the embryologist. Thus, Denny Sakkas saw four factors in the viable embryo offering opportunities for selection: its morphological growth progression (different from a non-viable embryo); euploidy; metabolic profile; and its rate of nutritional uptake.

As noted above, Sakkas put great emphasis on chromosomal status, and great hopes on the prospect of non-invasive testing. Indeed, he projected that ‘biopsies will be a thing of the past in the next few years’, looking ahead to an embryology lab defined by time-lapse imaging for both morphology and artificial intelligence, big data and deep learning, and non-invasive testing (sequencing culture medium, cell-free DNA).(3) And the metabolic markers of embryonic viability might be screened by non-invasive imaging techniques such as FLIM (fluorescence lifetime imaging microscopy), an imaging technology recently shown able to differentiate between euploid and aneuploid embryos and detect metabolic activity in discarded blastocysts.

These, as Sakkas noted and predicted, were technologies which the lab might adopt for its selection of embryos for optimal implantation, but there was another more basic component in these Campus presentations which will also affect the fate of embryos selected for transfer. And that was simply – or not so simply – the day-to-day working methods of the lab itself, which we summarise in part 2 of this report.

1. Shear MA, Vaughan DA, Modest AM, et al. Blasts from the past: is morphology useful in PGT-A tested and untested frozen embryo transfers? Reprod Biomed Online 2020; doi: 10.1016/j.rbmo.2020.07.014.
2. Morgan HL, Paganopoulu P, Akhtar S, et al. Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice. J Physiol 2020; 598: 699-715. doi: 10.1113/JP278270.
3. Tran D, Cooke S, Illingworth PJ, Gardner DK. Deep learning as a predictive tool for fetal heart pregnancy following time-lapse incubation and blastocyst transfer. Hum Reprod 2019; 34: 1011-1018,
doi: 10.1093/humrep/dez064.

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