Many women and couples are unlikely to get pregnant and have a baby without medical treatment, due to infertility. Doctors have developed a variety of assisted reproductive technologies (ARTs), such as in vitro fertilisation (IVF), which involve the manipulation of eggs and sperm outside a woman's body, to try to increase her chances of getting pregnant.
Typically, in assisted conception, doctors collect eggs from a woman and fertilise them in a laboratory, leading to the formation of embryos. An embryo is the early stage of human development. Doctors commonly transfer one or several embryos into a woman’s womb (uterus) at one of two stages of embryo development: either the cleavage stage, which is 2 or 3 days after egg collection when an embryo typically consists of between 2 and 128 cells; or the blastocyst stage, which is 5 or 6 days after egg collection when an embryo consists of between 70 and 100 cells.
Until recently, doctors usually transferred embryos at the earlier, cleavage, stage. However, there has been a trend to transferring embryos at the later, blastocyst, stage. Researchers believe that only those embryos capable of surviving make it to the blastocyst stage; in other words, viable embryos will self-select. So, it is thought that transferring embryos at the later stage may improve a woman's chances of becoming pregnant and having a healthy baby.
We wanted to find out if transferring embryos into a woman's womb at cleavage stage (day 2 to 3) or blastocyst stage (day 5 to 6) is better, in terms of:
– number of babies born alive (live birth rate) following embryo transfers using only 'fresh' embryos; that is, embryos that have not been frozen and subsequently thawed;
– total number of pregnancies achieved following embryo transfers using both 'fresh' and frozen then thawed embryos, collected from a single egg collection procedure (cumulative clinical pregnancy rate);
– multiple pregnancy rate (when a woman is carrying more than one baby at a time);
- miscarriage rate (the loss of a pregnancy before the 20th week of development in the womb).
We included 32 randomised controlled trials (studies in which participants are assigned randomly to 2 or more treatment groups), which included 5821 women or couples. The evidence is current to October 2021.
– Transferring 'fresh' embryos at the blastocyst stage (day 5 to 6) may lead to more live births than when 'fresh' embryos are transferred at the cleavage stage (day 2 to 3). This suggests that if 31% of women achieve live birth after 'fresh' cleavage-stage embryo transfer, between 32% and 41% would do so after 'fresh' blastocyst-stage transfer.
– Transferring 'fresh' embryos at the blastocyst stage probably leads to more clinical pregnancies – defined as evidence of fetal heart activity on an ultrasound scan – than when 'fresh' embryos are transferred at the cleavage stage. This suggests that if 39% of women achieve a clinical pregnancy after 'fresh' cleavage-stage transfer, between 42% and 47% will probably do so after 'fresh' blastocyst-stage transfer.
– We are uncertain whether blastocyst-stage transfer favors cumulative clinical pregnancy rates (i.e. pregnancies from both fresh and thawed cycles deriving from a single egg collection procedure).
– We are uncertain whether blastocyst-stage transfer increases multiple pregnancy rates compared to cleavage-stage transfer, when we consider all the studies that reported information on this.
– When we consider evidence only from higher-quality studies and studies that transferred the same number of embryos in both embryo stages, we found that multiple pregnancy rate is probably higher in the blastocyst-stage transfer group.
– We are uncertain whether blastocyst-stage transfer increases miscarriage rates compared to cleavage-stage transfer.
Future studies should report rates of live birth, cumulative live birth, and miscarriage, to enable women, couples and their doctors to make well-informed decisions on the best treatment option available.
Quality of the evidence
We have low to moderate confidence in the quality of the evidence for most outcomes. The main limitation was the failure of some studies to describe acceptable methods of assigning women or couples at random to treatment groups.
There is low-quality evidence for live birth and moderate-quality evidence for clinical pregnancy that fresh blastocyst-stage transfer is associated with higher rates of both than fresh cleavage-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR derived from fresh and frozen-thawed cycles following a single oocyte retrieval. Although there is a benefit favouring blastocyst-stage transfer in fresh cycles, more evidence is needed to know whether the stage of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage. They should also evaluate women with a poor prognosis to enable those undergoing assisted reproductive technology (ART) and service providers to make well-informed decisions on the best treatment option available.
Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer. The rationale for blastocyst-stage transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.
To determine whether blastocyst-stage (day 5 to 6) embryo transfer improves the live birth rate (LBR) per fresh transfer, and other associated outcomes, compared with cleavage-stage (day 2 to 3) embryo transfer.
We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL, from inception to October 2021. We also searched registers of ongoing trials and the reference lists of studies retrieved.
We included randomised controlled trials (RCTs) which compared the effectiveness of IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer.
We used standard methodological procedures recommended by Cochrane. Our primary outcomes were LBR per fresh transfer and cumulative clinical pregnancy rates (cCPR). Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy, high-order multiple pregnancy, miscarriage (all following first embryo transfer), failure to transfer embryos, and whether supernumerary embryos were frozen for transfer at a later date (frozen-thawed embryo transfer). We assessed the overall quality of the evidence for the main comparisons using GRADE methods.
We included 32 RCTs (5821 couples or women).
The live birth rate following fresh transfer was higher in the blastocyst-stage transfer group (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 to 1.51; I2 = 53%; 15 studies, 2219 women; low-quality evidence). This suggests that if 31% of women achieve live birth after fresh cleavage-stage transfer, between 32% and 41% would do so after fresh blastocyst-stage transfer.
We are uncertain whether blastocyst-stage transfer improves the cCPR. A post hoc analysis showed that vitrification could increase the cCPR. This is an interesting finding that warrants further investigation when more studies using vitrification are published.
The CPR was also higher in the blastocyst-stage transfer group, following fresh transfer (OR 1.25, 95% CI 1.12 to 1.39; I2 = 51%; 32 studies, 5821 women; moderate-quality evidence). This suggests that if 39% of women achieve a clinical pregnancy after fresh cleavage-stage transfer, between 42% and 47% will probably do so after fresh blastocyst-stage transfer.
We are uncertain whether blastocyst-stage transfer increases multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; I2 = 30%; 19 studies, 3019 women; low-quality evidence) or miscarriage rates (OR 1.12, 95% CI 0.90 to 1.38; I2 = 24%; 22 studies, 4208 women; low-quality evidence). This suggests that if 9% of women have a multiple pregnancy after fresh cleavage-stage transfer, between 8% and 12% would do so after fresh blastocyst-stage transfer. However, a sensitivity analysis restricted only to studies with low or 'some concerns' for risk of bias, in the subgroup of equal number of embryos transferred, showed that blastocyst transfer probably increases the multiple pregnancy rate.
Embryo freezing rates (when there are frozen supernumerary embryos for transfer at a later date) were lower in the blastocyst-stage transfer group (OR 0.48, 95% CI 0.40 to 0.57; I2 = 84%; 14 studies, 2292 women; low-quality evidence). This suggests that if 60% of women have embryos frozen after cleavage-stage transfer, between 37% and 46% would do so after blastocyst-stage transfer.
Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; I2 = 36%; 17 studies, 2577 women; moderate-quality evidence). This suggests that if 1% of women have no embryos transferred in planned fresh cleavage-stage transfer, between 2% and 4% probably have no embryos transferred in planned fresh blastocyst-stage transfer.
The evidence was of low quality for most outcomes. The main limitations were serious imprecision and serious risk of bias, associated with failure to describe acceptable methods of randomisation.