Blastocyst versus cleaved embryo transfer: do we have enough evidence?

The first IVF pregnancy was achieved after transfer of day 2 embryos   (Steptoe and Edwards 1978) 

Improved laboratory standards and improved culture media have made extended culture to blastocyst a reality

Why extended culture? To mimic natural physiology of a blastocyst reaching the uterine cavity day 5-6 Embryo selection: to ensure embryonic genome activation at 8 cell stage, and successful extended culture to blastocyst.

Does extended culture improve IVF outcome?

27 RCTs (4031 women)

This means that if 29% of women achieved live birth after fresh cleavage stage, between 32% to 42% will achieve live birth after blastocyst transfer.

Cochrane Review: Cleavage vs Blast LBR/transfer higher for blastocyst transfer. Failure to transfer any embryos higher with blastocyst ET. OR 2.50 (95% CI 1.76-3.55). Higher cumulative pregnancy rate with cleavage stage ET (2012), however, update of review (2016) showed no significant difference. More embryos cryopreserved after cleavage stage ET. Lower cumulative LBR in blastocyst stage. Glujovsky D et al Cochrane Systematic Rev2016;6

Blastocyst versus cleavage stage embryo transfer: a meta analysis (Martins et al., 2016) Most recent metanalysis: 12 studies = 1200 women No significant difference in live birth/ongoing pregnancy in both single transfer or cumulative live birth rate. (RR 1.11, 95% CI 0.92-1.35) Low quality evidence

A problem of most of the studies, that patients with good number of zygotes (at least 4) are randomized to day 3 or day 5 transfer. So all bad cases are excluded from extended culture. The study should be carried out per started cycles.(Aboulghar 2016)

The objective was to have a single birth at term However, new data showed that transfers on blastocyst stage are associated with higher risk of preterm labor, large for gestational age babies, monozygotic twins and altered sex ratio (Maheshwari 2016) The objective was to have a single birth at term

Risk of extended culture By committing to ET on blastocyst stage there is a risk of loosing some embryos which might not survive extended culture but might have survived in vivo had it been transferred to the uterus.

Large for gestational age babies This is a questionable issue Zhu et al., 2014 suggest that this happens in human and animals. It could be due to a different culture media. A study from Devos et al., 2015 seems to refuse this.

Altered male: female ratio Several reports suggested the same findings

In a population based Swedish study (Ginström Ernstad et al In a population based Swedish study (Ginström Ernstad et al., 2016) including all singleton deliveries after blastocyst transfer from 2002 to 2013, outcome of delivery was compared with deliveries after cleaved embryos as well as deliveries after spontaneous pregnancy.

Outcome of babies No increased risk of congenital malformation Perinatal mortality was significantly higher in blastocyst transfer versus cleaved stage transfer (OR, 1.61; 95% CI, 1.14-2.29). Blastocyst ET have a higher risk of preterm labor (OR, 1.17; 95% CI, 1.05-1.31), the risk of placenta previa and placental abruption was higher in pregnancies after blastocyst transfer.

Reasons of adverse perinatal outcome A possible explanation could be that extended culture may trigger genetic and epigenetic changes in trophodermal cells that can lead to abnormal placentation and implantation. (Rizos et al., 2002)

Why do we still continue extended culture? The key driver is the higher pregnancy rate after transfer of a single blastocyst which is the routine in Europe now.

Conclusion There is small (low quality) evidence of improved pregnancy rate after day 5 transfer (early studies) There is no significant difference in the CPR between Day 3 and Day 5 embryo transfer There is an extensive literature which shows no difference in pregnancy rate between day 3 and day 5 There are certain risk of blastocyst transfer The WHO idea of extended culture is to transfer one blastocyst