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Objectives To investigate the effects of single blastocyst transfer (SBT) on live birth and multiple pregnancy in women undergoing in vitro fertilisation (IVF).
Design Descriptive cohort study.
Setting A London private IVF/postgraduate training unit.
Sample A total of 700 fresh and 102 frozen blastocyst cycles performed between January 2005 and December 2006.
Methods Young women aged 25–37 years and those aged 38–43 years were further divided into those who had SBT and those who received two blastocysts (double blastocyst transfer [DBT]). Live birth and multiple pregnancy rates were compared between groups. Cumulative live birth was compared between women who had DBT and those who received a SBT followed by a frozen blastocyst if the fresh cycle was unsuccessful.
Main outcome measures Live birth rate, cumulative live birth rate, multiple pregnancy rate, uptake of SBT.
Results Among women aged 25–37 years, live birth rate following SBT was 59.0 versus 60.7% following DBT. The twin pregnancy rate in this group was 2.3 and 47.6% respectively. For women aged 38–43 years, live birth following SBT was 29.4% and multiple pregnancy rate was 33.3%. DBT in older women gave a higher live birth rate (44.3%) and a multiple pregnancy rate of 36.4%. Cumulative live birth following SBT in women aged 25–37 years was 72.8% versus 60.5% following DBT. Among the women aged 38–43 years, cumulative live birth was higher (63.3%) following DBT versus 28.6% following SBT.
Conclusion Single blastocyst transfer followed by transfer of a frozen blastocyst if the preceding fresh cycle was unsuccessful resulted in a better cumulative live birth and lower twin pregnancy in young women. In older women, two fresh blastocysts gave better results than one fresh followed by a frozen cycle. Older women should have the option of replacing two fresh blastocysts as this optimises their chances of taking home a baby.
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Twin and higher-order multiple (HOM) pregnancies remain the bane of assisted reproduction technology (ART). In the UK, while the incidence of triplets following ART has plummeted significantly and is now comparable to natural conception, long-term analysis of the Human Fertilisation and Embryology Authority (HFEA) Registered data show that the rate of twin pregnancy has remained static since 1992.1 This high incidence of twins remains a major concern and the biggest challenge facing ART. The medical, social and economic consequences of multiple gestations have been well described.2–4 Not only is multiple pregnancy associated with life-threatening maternal morbidities, including hypertension and pre-eclampsia, postpartum haemorrhage, gestational diabetes, preterm labour and preterm rupture of membranes, it is also associated with a five-fold increase risk of neonatal death, a four-fold increase in cerebral palsy and an eight-fold increase in low birthweight compared with singletons.5–7 Apart from the health and social consequences on the families, these medical complications of multiple pregnancy also present a significant financial burden on the NHS. Antenatal surveillance is more intensive and more likely to involve hospitalisation; rate of caesarean section is higher and neonatal costs are increased because of higher preterm delivery rates and greater number of low-birthweight infants. In 2002, ART twins, costs the NHS, 14 million pounds, with a total cost per twin family of £9122, three times the cost of singletons.8 Although they represent less than one-third of the total number of maternities in the UK, multiple pregnancies following ART are associated with a disproportionate 56% of the direct cost of in vitro fertilisation (IVF) pregnancies.8 The challenge facing practitioners of ART today, therefore, is to significantly reduce the incidence of multiple pregnancy and to achieve this without impacting on the success rate of ART. Among the interventions aimed at achieving this goal is the reduction of the number of embryos transferred. In Sweden, a policy of routine single embryo transfer has drastically reduced the multiple pregnancy rates without significantly impacting on the cumulative delivery rate.9 With increasing experience in blastocyst culture using sequential culture media, higher implantation rates have been reported following blastocyst transfers compared with transfer of cleavage stage embryos.10,11 A direct consequence of this high implantation rate is a higher risk of multiple pregnancy with blastocyst transfer. A policy of single blastocyst transfer (SBT) has therefore been advocated to reduce the risks of twin pregnancy. SBT has been reported to reduce twin multiple pregnancy without compromising pregnancy rates.12–14 Although two of these studies were randomised,12,13 the number of women studied was small and in all three studies12–14 the subjects were mainly young women in the age range of 30–34. The transfer of a single blastocyst (SBT) in this group of young women was associated with a significant reduction in multiple pregnancy, while maintaining an impressive pregnancy rate. While this is true for this group, extrapolating the findings in women of all ages may be inaccurate. The HFEA is launching a consultation on various measures aimed at reducing the incidence of ART twins. It is anticipated that where blastocyst transfer is contemplated, the regulator could insist that in all cases, only a single blastocyst is transferred. While the role of SBT in young (good prognosis) women has been reported,12–14 there is insufficient information on the effect of elective SBT in older women.
In this observational study we investigated treatment outcome of women who underwent blastocyst transfer at the Lister Fertility Clinic. We analysed the data to show the effect of SBT on pregnancy rate as well as multiple pregnancy in young women and more importantly in their older counterparts. We postulated that if the fresh cycle was unsuccessful, then SBT followed by transfer of a frozen blastocyst may result in an equal or better cumulative live birth with a lower rate of twin pregnancy compared with transfer of two fresh blastocysts in the first instance. Furthermore, we discussed the uptake of SBT by couples, as doctors and staff gain experience and knowledge regarding the outcome.
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Between January 2005 and December 2006, a total of 700 women underwent fresh blastocyst transfer at the Lister Fertility Clinic. Five hundred were aged 25–37 years and 200 were aged 38–43 years. Two hundred and eighty of the 700 women opted for SBT giving an uptake rate of 40%. The remaining 420 women declined SBT and consented for the transfer of two blastocysts. In the group of women aged 25–37 years, uptake of SBT was 45.8% (229/500). Among women aged 38–43 years, SBT uptake was lower at 25.5% (51/200). One hundred and forty-nine women in this group requested the transfer of double blastocysts (DBT). In the group aged 25–37 years, 135 of 229 (59.0%) had a live birth following SBT and 164 of 210 women (60.7%) had a live birth after DBT. The twin pregnancy rate in this group was 2.3% after SBT and 47.6% following the transfer of two blastocysts. Multiple pregnancy in the two blastocysts group include one set of triplets and one set of monozygotic twins.
In women aged 38–43 years, 15 of 51 women (29.4%) had a live birth following SBT and 66 of 149 (44.3%) had a live birth when two blastocysts were replaced. In this group, the multiple pregnancy rate was 33.3% following SBT and 36.4% when two blastocysts were replaced. These include two sets of triplets among those who had two blastocysts replaced (Table 1).
Table 1. Outcome of blastocyst transfer at the Lister Fertility Clinic January 2005 to December 2006
| ||No. cycles||Pregnancy rate per cycle||P value||Singleton pregnancy rate||Twin pregnancy rate||P value||Live birth rate||P value||Singleton live birth rate||Twin live birth rate||P value|
|Age 25–37, single embryo transfer||229||73.8% (169/229)||NS||98.2% (166/169)||1.8% (3/169)||<0.001||59.0% (135/229)||NS||97.7% (132/135)||2.3% (3/135)||<0.001|
|Age 25–37, two embryos transfer||271||77.5% (210/270)||46.2% (97/210)||53.8% (113/210)*||60.7% (164/210)||52.4% (86/164)||47.6% (78/164) *|
|Age 38–43, single embryo transfer||51||47.1% (24/51)||0.033||79.2% (19/24)||20.8% (5/24)||0.084||29.4% (15/51)||0.024||66.6% (10/15)||33.3% (5/15)||0.453|
|Age 38–43, two embryos transfer||149||63.1% (94/149)||61.7% (58/94)||38.3% (36/94)**||44.3% (66/149)||63.6% (42/66)||36.4% (24/66)**|
Women with extra blastocysts to cryopreserve
Three hundred and twenty-six women (46.6%) had extra blastocysts to cryopreserve following their first IVF treatment cycle. Two hundred and forty-eight (76.1%) were aged 25–37 years and 78 (23.9%) were aged 38–43 (Figure 1). In this subset, 81 of 129 (62.8%) of women aged 25–37 had a live birth following SBT and 72 of 119 (60.5%) had a live birth following DBT. The twin pregnancy rate was 1.2% following SBT as against 50.0% when two blastocysts were replaced (Table 2).
Table 2. Live birth rate of blastocyst transfer following fresh plus frozen embryo transfer (FET) in women in their first attempt who had extra embryos to freeze
| ||No. of cycles||Live birth rate||Singleton live birth rate||Twin live birth rate|
|Age 25–37 single embryo transfer||129||62.8% (81/129)||98.8% (80/81)||1.2% (1/81)|
|FET after unsuccessful cycle*||40||32.5% (13/40)||76.9% (10/13)||23.1% (3/13)|
|Cumulative success rate**||129||72.8% (94/129)***|| |
|Age 25–37 two embryos transfer||119||60.5% (72/119)||50.0% (36/72)||50.0% (36/72)|
|FET after unsuccessful cycle*||34||23.5% (8/34)||87.5% (7/8)||12.5% (1/8)|
|Cumulative success rate**||119||67.2% (80/119)***|| |
|Age 38–43 single embryo transfer||21||23.8% (5/21)||80.0% (4/5)||20.0% (1/5)|
|FET after unsuccessful cycle*||14||7.1% (1/14)||100% (1/1)||0% (0/1)|
|Cumulative success rate**||21||28.6% (6/21)****|| |
|Age 38–43 two embryos transfer||57||63.2% (36/57)||63.9% (23/36)||36.1% (13/36)|
|FET after unsuccessful cycle*||14||21.4% (3/14)||100% (3/3)||0% (0/3)|
|Cumulative success rate**||57||68.4% (39/57)****|| |
Among the women aged 38–43 with extra blastocysts to cryopreserve, 5 of 21 (23.8%) had a live birth following SBT, and 36 of 57 (63.2%) had a live birth following DBT. The transfer of two blastocysts resulted in a higher live birth rate in this group of older women. The twin pregnancy rates were 20.0 and 36.1% following SBT and DBT respectively (Table 2).
Cumulative live birth rates
One hundred and two women returned for FBT following an unsuccessful fresh cycle. Seventy-four (72.5%) were aged 25–37 and 28 (27.5%) were aged 38–43.
A subgroup of 40 women aged 25–37 had received SBT in the fresh cycle and 34 received DBT in the fresh cycle. In this subgroup 13 of 40 women in SBT group (32.5%) had a live birth following FBT, of whom 3 (23%) were twins. (In this group 37 had double FBT of whom 10 [27%] had live birth of whom 3 (30%) were twins. Thirteen had a single FBT of whom three (23%) had live birth.) The cumulative live birth rate (after fresh plus FBT) was 72.8% (94/129) among women who received SBT versus 67.2% (80/119) among women who received two blastocysts (Table 2). (8 of 34 [23.5%] in the DBT subgroup had a live birth following the transfer of frozen blastocyst).
Among the 28 women aged 38–43, 14 had received SBT in the fresh cycle and 14 received DBT. One of 14 (7.1%) had a live birth following FBT in the SBT subgroup and 3 of 14 (21.4%) had a live birth among those in the DBT subgroup.
The cumulative live birth rate was 28.6% (6/21) in women who had SBT followed by FBT and 68.4% (39/67) in women who had DBT followed by FBT (Table 2).
A proportion of women who did not achieve a live birth from fresh embryo transfer are yet to undergo FBT. Assuming that these women will achieve similar success rates to those who have had FBT, the total estimated cumulative live birth rate (LBR of fresh and frozen embryo transfers) for each group will be 75.2% (97/129) for women aged 25–37 following SBT and 69.7% (83/119) following DBT. Among women aged 38–43 the estimated cumulative live birth rate would be 28.6% (6/21) following SBT and 71.9% (41/57) following the transfer of two blastocysts.
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In the UK, one in four pregnancies derived from IVF results in a twin birth and this has remained static since 1992.1 This high incidence of twins remains a major concern and the biggest challenge facing ART.16 A policy of SBT is among interventions aimed at reducing the incidence of multiple pregnancy.9 Although the HFEA encourages clinics to reduce the incidence of multiple pregnancy by moving towards a policy of single embryo transfer, there is currently no legislation in the UK to enforce this policy. In a healthcare system where majority of ART is self-funded,8 reducing the number of embryos to one will be more acceptable if such a measure does not impact significantly on the live birth rate.
Our data show that SBT significantly reduces multiple gestations without compromising pregnancy rates in young women. Following the transfer of a single blastocyst, young women in our series achieved a live birth rate of 59.0%, comparable to 60.7% when two blastocysts were replaced (Table 1).
Women who opt for DBT may do so because of perception of a higher chance of pregnancy. The decision may also be influenced by other factors, such as embryo quality or because of bad experience or previous failed attempts. Furthermore, SBT could have been performed because there was no more than the one transferred or that the extra ones were not of good quality. To obviate the effect of all these factors, we further analysed only those women who were in their first attempt and who had extra embryos to cryopreserve. (We only freeze good-quality embryos.) This analysis ensures that the quality of blastocyst(s) transferred in both groups was good and as such any difference in the outcome will be attributed to the number transferred rather than apparent quality of these blastocysts or some other relevant factor in the participant’s history that may have influenced the decision regarding the number transferred.
Interestingly, when only these women were considered, the cumulative live birth rate was higher among those who opted for SBT followed by a FBT if the fresh cycle was unsuccessful, compared with those who opted for DBT in the first instance. (The difference, however, was not significant.) Furthermore, we achieved a significantly lower incidence of twin pregnancy following SBT in this age group (Tables 1 and 2). Our results are consistent with previous reports12–14 that demonstrated that in appropriately selected participants single embryo transfer can be performed without compromising pregnancy rates. Gardner et al.14 compared single versus two blastocyst transfer in women under 35 and demonstrated no significant difference in implantation or pregnancy rates, but showed a marked reduction in the number of twin pregnancies following SBT. Ryan et al.17 found a significant drop in twin pregnancies (41–15%) when they implemented a mandatory policy of SBT in young women. They did not notice any decline in pregnancy rate. In an effort to reduce triplet and HOM pregnancies, Grifo et al.18 implemented a policy of two-blastocyst transfer in their IVF programme. Although they achieved a successful reduction of triplets and HOM, they reported a twin pregnancy rate of 37% in women below 38, in keeping with our results. It is obvious that DBT in young is associated with unacceptably high twin pregnancy rates. Our results like those of others show that SBT in young women reduces twin pregnancies without impacting on live birth rate. The significant drop in twin pregnancies makes a routine policy of SBT worthwhile in this age group.
While previous studies limited SBT to good prognosis women, (generally defined as women under the age of 38) in our study, we also offered single blastocysts to women older than 38 with informed consent.
In this group of women aged 38–43 years, the transfer of two blastocysts resulted in a significantly higher pregnancy and live birth rate than when only one blastocyst was replaced (Table 1). Even when only women with extra blastocysts to cryopreserve were considered, the cumulative live birth rate remained lower among older women who opted for SBT followed by a FBT, compared with those who opted for DBT in the first instance. This finding is significant, as authorities contemplate a global policy of single embryo transfer. A global policy may compromise results in older women. In this group the transfer of two fresh blastocysts gave a better chance of achieving a live birth.
The effects of SBT on the incidence of multiple pregnancy in this age group cannot be reliably deduced from these data. Although our results suggest there is no significant difference in the incidence of multiple pregnancy between older women who received one blastocyst compared with those who received two, the numbers involved (5/15 versus 24/66) are too small to make a logical deduction. These small numbers and the non-randomised nature of our study is a potential weakness. However, what is clear from our data is that in women with good prognosis, a policy of SBT significantly reduces multiple pregnancies while maintaining the live birth rate, but in older women it reduces live birth rate, while the effect on multiple pregnancy remains unclear.
In a recent retrospective study, Davis et al.19 reported their experience with elective blastocyst transfer in relatively older women. They reported a pregnancy rate of 62.2% and a continuing pregnancy rate of 51.1% following SBT in this group of women. There were no twin gestations in their series. This study is different from ours in a number of ways. First, the age of women in their series was 35–42. Women in our series were older (38–43). Second, their study did not provide data on DBT in this age group for comparison, and finally the number of women involved was extremely small. More information is therefore still required to determine the true impact of SBT on twin pregnancies in this older age group. In our series, most women aged 38–43 desired the replacement of two blastocysts in the hope of improving pregnancy rate. The potential high risk of multiple pregnancy following DBT in these women should be weighed against the lower chance to conceive after SBT. This is important, as older mothers carrying twins are a particularly high-risk group, more prone to complications of multiple gestations including gestational diabetes, hypertension, pre-eclampsia, postpartum haemorrhage, low birthweight, venous thromboembolism and the need for caesarean section.20 Multiple pregnancies in older women, therefore, should be least desirable.
The overall uptake of SBT at the Lister Fertility Clinic has risen from zero in January 2005 to 65% by the end of 2006 (Figure 2). This trend continues till date, keeping down our multiple pregnancies. Adequate counselling is vital to increase SBT uptake. From our experience, couples will opt for SBT if they are reassured that pregnancy rates will not be compromised. Our practice is to introduce this concept much in advance, usually at the beginning of treatment, to give couples ample time to research the concept. Counselling is reinforced during the treatment at which time worries and questions are addressed. In most cases, couples would have made an informed decision on the number of embryos that they wish replaced prior to the day of embryo transfer. Adequate counselling and education seems to be responsible for the high uptake of SBT in our unit. Similarly Ryan et al.17 showed that a significant number of couples changed their desired outcome to a lower gestational number, following an educational summary of comparative risks of twins versus singletons to maternal and child health.17
Our report is the largest study of SBT from the UK. More significantly, ours is the first study to investigate the outcome of SBT in older women. Furthermore, ours is the first study to examine women with good prognosis at depth in their first attempt, looking at the exact effect of transferring good-quality embryos either one at a time or both together. The fact is simple: in these young women the transfer of two blastocysts serves only to increase multiple pregnancy rate without increasing live birth rate. If these observations are confirmed by others, it may have a significant impact on clinical practice, as well as on the concept of SBT as a strategy to reduce multiple pregnancies. We also hope that these findings will be acknowledged by primary care trusts and health authorities and help to convince them to include frozen cycles when they are commissioning IVF treatment. We recommend that the HFEA and other bodies publishing success rate should find ways to include the cumulative effect of the frozen cycles so as to encourage the transfer of lower number of embryos. Relying on fresh cycles only may encourage some clinics to transfer more embryos in the hope that they improve their position in the league table.