Key messages
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The chance of having a live-born baby after one IVF (in vitro fertilisation) cycle may slightly improve when the embryo is transferred on day 5 to 6 ('blastocyst' stage) rather than day 3 ('cleavage' stage), in women with a 'good prognosis' (that is, characteristics that make getting pregnant easier). This measure included all transfers from eggs collected in one cycle (fresh and frozen).
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When looking only at results for embryos transferred fresh (placed into the womb a few days after fertilisation), we found that transferring embryos at the blastocyst stage rather than the cleavage stage probably increases the chance of having a baby.
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Transferring embryos at blastocyst stage rather than cleavage stage probably increases the risk of having a baby born preterm (early) at between 32 and 36 weeks as opposed to at full term (40 weeks).
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More research is needed to understand long-term effects, especially in people with a lower chance of IVF success.
What is assisted conception?
Assisted conception refers to medical treatments used to help people achieve a pregnancy when it has not happened naturally. In vitro fertilisation (IVF) is a fertility treatment where eggs are collected from a woman and fertilised with sperm artificially outside the body, and then one or more embryos are put into the woman's womb (i.e. 'transferred'). Embryos can be transferred a few days after fertilisation ('cleavage' stage, day 2 to 3) or a little later ('blastocyst' stage, day 5 to 6).
Transferring blastocyst-stage embryos may improve the chance of pregnancy by better matching the timing between the embryo and womb, and by helping to select embryos that are more likely to develop successfully. However, some people may lose embryos that would not survive to day 5 in the laboratory, even though they could have developed in the womb. We do not yet know if one strategy clearly leads to better outcomes over the full course of treatment, or if it affects pregnancy complications.
What did we want to find out?
We wanted to know the effects of transferring blastocyst-stage embryos versus cleavage-stage embryos on:
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the chance of having a live birth after using all embryos from one cycle (including fresh (new) embryos and embryos that have been frozen and then later thawed) or until a live birth occurs (called 'per cycle' or 'cumulative');
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the chance of having a live birth after one transfer (called 'per fresh transfer');
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the risk of complications during pregnancy or at birth (such as preterm birth);
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pregnancy rates;
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the risk of miscarriage;
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whether embryos are frozen for later use; and
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the chance that no embryo could be transferred.
What did we do?
We searched for studies known as 'randomised controlled trials' that compared blastocyst-stage and cleavage-stage embryo transfers in women undergoing IVF. We combined the studies' results and assessed our confidence in them. Our judgements are presented below in brackets.
What did we find?
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We included 36 studies involving 8389 women. Most studies took place in IVF settings and included participants with a good chance of pregnancy (i.e. they were generally younger and produced several embryos).
Chance of having a baby (live birth)
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Per IVF cycle, with fresh and frozen embryos (cumulative live birth rate): blastocyst transfer might slightly improve the chance of having a baby (low confidence).
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After a single fresh transfer: blastocyst transfer probably increases the chance of having a baby. For example, if 32 out of 100 women have a baby with cleavage-stage transfer, between 37 and 43 would have a baby with blastocyst-stage transfer (moderate confidence).
Preterm birth
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Blastocyst transfer probably increases the chance of having a baby born between 32 and 36 weeks (late preterm) (moderate confidence).
Chance of becoming pregnant ('clinical pregnancy')
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Blastocyst transfer may increase the chance of becoming pregnant after a fresh transfer (low confidence).
Miscarriage
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There may be little to no difference between blastocyst transfer and cleavage transfer in the miscarriage rate (low confidence).
Freezing of extra embryos
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Blastocyst transfer might reduce the chance of having embryos to freeze for later use (low confidence).
Failure-to-transfer rate
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Blastocyst transfer may increase the chance that no embryo successfully transfers (e.g. because no embryo develops to day 5) (low confidence).
What are the limitations of the evidence?
We are not fully confident in the results. Many studies were small, and there was variation in how the IVF treatment was given. People in the studies knew whether they were getting cleavage-stage or blastocyst-stage embryos, which may have affected the results. In some studies, most people had only one embryo transfer, so the results might be different if they were measured later once any frozen embryos had also been used. Most studies included women with a good chance of getting pregnant, so the findings may not apply to women with characteristics that make getting pregnant more difficult.
How current is this evidence?
The evidence is based on searches conducted up to October 2024.
อ่านบทคัดย่อฉบับเต็ม
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.
วัตถุประสงค์
To assess the effects of blastocyst-stage (day 5 to 6) embryo transfer compared with cleavage-stage (day 2 to 3) embryo transfer on cumulative live birth rate per woman (defined as the occurrence of at least one live birth resulting from the fresh transfer and all subsequent frozen–thawed embryo transfers derived from the same oocyte retrieval), live birth rate per fresh transfer, and cumulative preterm birth outcomes using the same definition.
วิธีการสืบค้น
On 1 October 2024, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. In addition, we searched two trial registries, reference lists of relevant papers, and contacted experts in the field for any additional trials.
เกณฑ์การคัดเลือก
We included randomised controlled trials (RCTs) which compared the effectiveness of IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer.
การรวบรวมและวิเคราะห์ข้อมูล
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.
ผลการวิจัย
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.
ข้อสรุปของผู้วิจัย
In the first 12 months of follow-up, cumulative live birth rate (cLBR) may be higher after blastocyst-stage embryo transfer than cleavage-stage transfer in women with a good prognosis for pregnancy. However, while some participants may have used all available embryos within this timeframe, others would have had embryos remaining, so cLBR estimates may be different after complete embryo exhaustion. Fresh blastocyst-stage transfer probably increases live birth rates and may improve clinical pregnancy rates compared to cleavage-stage transfer in women with a good prognosis, but may have little to no effect on miscarriage rate. Cumulative preterm birth (< 37 weeks) probably increases with blastocyst-stage transfer. Embryo freezing may be more common and failure-to-transfer less frequent with cleavage-stage embryos. However, it remains unclear whether these differences translate into higher cumulative live birth rates or instead reflect longer treatment trajectories with increased costs and time to pregnancy. None of these findings should be generalised to women with poor prognoses, who were underrepresented in most included studies.
Future research should prioritise the assessment of cumulative live birth rate at extended follow-up, the measurement of miscarriage rates, and the evaluation of obstetric outcomes, particularly in women with poor prognoses.
แหล่งทุน
This Cochrane review had no dedicated funding.
การลงทะเบียน
Protocol available via DOI 10.1001/14651858: https://doi.org/10.1002/14651858.CD002118. Review versions: https://doi.org/10.1002/14651858.CD002118.pub2; https://doi.org/10.1002/14651858.CD002118.pub3; https://doi.org/10.1002/14651858.CD002118.pub4; https://doi.org/10.1002/14651858.CD002118.pub5; https://doi.org/10.1002/14651858.CD002118.pub6.
