How the IVF lab influences the chance of implantation after embryo transfer

Published 17 November 2020

A well attended online Campus meeting in November considered implantation from clinical, embryological and endometrial perspectives, but also focused on the day-to-day working of the IVF lab.

An online Campus meeting in November, with more than 250 remotely registered, reviewed the latest on successful – and failed – implantation from the perspectives of the meeting’s three organising SIGs (Embryology, Stem Cells and Implantation & Early Pregnancy). But what was also high on the meeting’s agenda were the effects which everyday laboratory practices might have on the fate of the embryo after transfer.

Barcelona embryologist Gemma Arroyo noted chromosomal testing and culture conditions as prominent factors but also added quality management systems, lab design and location, ambient conditions (lighting, air quality), biosecurity and culture equipment as important in the optimisation of embryo viability. For example, air conditioning, she said, should have air recycling at least 15 times per hour, with control of circulating particles and air pressure.(1) Similarly, she advised that oxygen concentrations during incubation would affect outcome, noting a Cochrane review supporting embryo culture with low oxygen concentrations for improved success rates in IVF and ICSI.(2) However, a recent study in which oxygen levels were reduced from 5% (low) to 2% (ultra low) found no added benefit.(3) Similarly, fluctuations in pH concentrations have been evident in blastulation rate reduction and alterations in gene expression (raised pH) and in fetal weight (lower pH).

While the introduction of time-lapse systems has allowed labs to maintain consistent and controlled culture environments, no such consistency is yet evident in the culture media – single-step or sequential - behind the huge global shift to blastocyst transfer. Arroyo described several studies – meta-analyses and RCTs – reflecting inconsistent comparative results in blastulation and outcome. For example, a systematic review performed by ESHRE’s SIG Embryology co-ordinator Ioannis Sfontouris and colleagues found insufficient evidence to identify either one as superior, despite the ‘practical advantages’ of single-step and higher blastocyst formation rates.(4) Similarly, Ubaldi’s group in Rome found no differences in cumulative delivery rates between the two approaches.(5)

While acknowledging the no-touch stability which time-lapse systems provide, Arroyo nevertheless recommended that their routine adoption should remain ‘an experimental strategy’. She noted that no single morphokinetic parameter has so far been consistently shown to predict implantation - indeed, with ‘considerable disagreement’ over which parameters are even useful, normal or abnormal. This echoed the conclusions of ESHRE’s recent recommendations on time-lapse, that ‘a clear clinical benefit’ of its use, an increase in IVF success rates, ‘remains to be proven’.(6) However, as the recommendations also noted, hopes of an outcome advantage ‘are not lost’.

So, as Ioannis Sfontouris asked of the lab, ‘are we better than nature?’ Well, nature is certainly not perfect, as Johannes Ott emphasised before his presentation on routine office hysteroscopy before IVF. Citing a recent meta-analysis, he reported that reproductive failure is more common than success, and that embryo quality is implicated in many of these failures.(7) So is embryo culture, and notably extended culture, responsible for compromising embryo quality, asked Sfontouris. He reviewed the pros and cons of embryo transfer from day 1 to day 7 and concluded that, despite the potential for extended culture to trigger epigenetic changes, blastocyst transfer is associated with a higher pregnancy and live birth in the fresh cycle (though similar rates in cumulative cycles), a shorter time to pregnancy, and a more pronounced benefit in good-prognosis patients (while poor prognosis patients ‘may benefit from cleavage-stage transfer’.

Abha Maheshwari from the Aberdeen Fertility Centre in Scotland also found a distinction between the effect of ovarian stimulation in the fresh and frozen cycle, indicating that supraphysiological estrogen doses may affect implantation via the uterus. Describing ovarian stimulation as ‘the most important thing in ART’, and recognising the shift in defined success from pregnancy per cycle to cumulative healthy delivery, she urged the need of a ‘very delicate balance’ between generating an adequate number of eggs while not impairing uterine receptivity.

1. Mortimer D, Cohen J, Mortimer ST, et al. Cairo consensus on the IVF laboratory environment and air quality: report of an expert meeting. Reprod Biomed Online 2018; 36: 658-674. doi:10.1016/j.rbmo.2018.02.005.
2. Bontekoe S, Mantikou E, van Wely M, et al. Low oxygen concentrations for embryo culture in assisted reproductive technologies. Cochrane Database Syst Re 2012; CD008950. doi:10.1002/14651858.CD008950.pub2.
3. De Munck D, Janssens R, Segers I, et al. Influence of ultra-low oxygen (2%) tension on in-vitro human embryo development. Hum Reprod 2019; 34: 228-234. doi:10.1093/humrep/dey370.
4. Sfontouris IA, Martins WP, Nastri CO, et al. Blastocyst culture using single versus sequential media in clinical IVF: a systematic review and meta-analysis of randomized controlled trials. J Assist Reprod Genet 2016; 33: 1261–1272. doi:10.1007/s10815-016-0774-5.
5. Cimadomo D, Scarica C, Maggiulli R, et al. Continuous embryo culture elicits higher blastulation but similar cumulative delivery rates than sequential: a large prospective study. J Assist Reprod Genet 2018; 35: 1329-1338. doi:10.1007/s10815-018-1195-4.
6. ESHRE working group on time-lapse technology. Good practice recommendations for the use of time-lapse technology. Hum Reprod Open 2020; 2:
6. Craciunas L, Gallos I, Chu J, et al. Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update 2019; 25: 202-223. doi:10.1093/humupd/dmy044.

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