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Current Women’s Health Reviews, 2008, 4, 218-222
Single Embryo Transfer: Double Remedy for Complications After Assisted Reproduction Delbaere Ilse*, De Sutter Petra, Gerris Jan and Temmerman Marleen Department of Obstetrics and Gynaecology, University Ghent, De Pintelaan 185, 9000 Ghent, Belgium Abstract: Thanks to assisted reproductive technologies (ART), the majority of subfertile couples are no longer set aside from one of the deepest desires mankind has in life. However, since the early days of ART - application, two major disadvantages derived. First, the transfer of multiple embryos in order to obtain acceptable pregnancy rates brought about an epidemic of multiple pregnancies. Second, in studies comparing pregnancy outcomes between naturally conceived children and children after ART, higher incidences of preterm birth and low birth weight were assessed in the ARTgroup. Single embryo transfer (SET) in IVF/ICSI proved the only answer to the epidemic of multiple pregnancies. Moreover, studies assessing outcomes of singletons after SET are promising and indicate that a wider application of SET may positively affect pregnancy outcome after ART as well.
Key Words: SET, DET, ART, multiple pregnancy, pregnancy outcome, hCG. SINGLE EMBRYO TRANSFER: DOUBLE REMEDY FOR COMPLICATIONS AFTER ASSISTED REPRODUCTION This year, Louise Brown celebrates her 30th birthday. Thanks to assisted reproductive technologies (IVF/ICSI), subfertile couples have plausible chances to fulfil their child wish for three decades now. Studies evaluating pregnancy outcomes after assisted reproduction indicated two major disadvantages when compared with naturally conceived pregnancies. The first drawback is high rates of multiple – and twin pregnancies and associated morbidities after assisted reproductive technologies. Second, even in singleton pregnancy after ART, outcomes are less favourable when compared with naturally conceived singletons. The only effective answer to the first issue is the use of single embryo transfer in IVF/ICSI – cycles and this procedure is likewise increasingly and successfully implemented in infertility centres. Currently, there is growing evidence that SET may be an answer to the less advantageous outcome in singletons after ART as well. FROM MET, THROUGH DET TO SET: A SHORT HISTORY In the early days, assisted reproduction was less efficient than it currently is. In order to achieve acceptable pregnancy rates, multiple embryos were transferred (multiple embryo transfer or MET) in the uterus after IVF or ICSI [1]. As such, the chances to become pregnant increased, as did the chance to conceive twins or higher order multiples (HOM). Incidences of preterm birth, associated low birth weights and perinatal mortality are important in twin pregnancies and are of even superior concern in HOM [2]. As such, with the multiple gestation epidemic, ART was responsible for an important increase of neonatal morbidity. In order to avoid
*Address correspondence to this author at the Department of Obstetrics and Gynaecology, University Ghent, De Pintelaan 185, 9000 Ghent, Belgium; Tel: 0032 9 332 48 53; Fax: 0032 9 332 38 31; E-mail:
[email protected] 1573-4048/08 $55.00+.00
HOM, studies in the late nineties assessed the efficacy of double embryo transfer (DET). The application of DET was successful in order to avoid multiple pregnancies after ART without having much effect on the pregnancy rates. However, the incidence of twin pregnancies after ART did not change [3, 4]. In order to achieve changes at this level, the move towards single embryo transfer (SET) was the next logic step. Even so, there was some reluctance to adopt this procedure. Early studies comparing pregnancy rates after double embryo transfer versus single embryo transfer were disappointing. Nevertheless, these results were biased, since in the SET – group women with only one embryo available were included. This type of SET is called compulsory SET (cSET), there is no other choice than to transfer one embryo. Studies including women with several embryos available for transfer, but in which deliberately only one embryo was transferred (elective SET or eSET) showed acceptable pregnancy rates. Moreover, the somewhat lower pregnancy rates after eSET in comparison with DET were compensated by the possibility to cryopreserve one or more embryos after eSET for subsequent cycles [5-7]. In the eSET – procedure, embryo selection is crucial. It is difficult to identify a top embryo; however, embryos with no multinucleated blastomeres, four or five blastomeres on day two, seven or more cells on day three and less than 20% anucleated fragments have been described as embryos with good chances to implant [8]. Next to these parameters, also cleavage speed is of importance. The study of Van Royen et al. points out that embryos complying to the above criteria have an ongoing implantation rate of 49%. Embryo characterization is widely accepted in the IVF/ICSI – procedure in order to increase pregnancy chances; genetic screening is less adopted and its efficiency has now been questioned. With the preimplantation genetic screening (PGS) - technique, a single blastomere is aspirated from each embryo in order to perform genetic analysis. As such, transfer of abnormal embryos may be prevented. This may be particularly important in women of advanced age whose oocytes are more © 2008 Bentham Science Publishers Ltd.
Single Embryo Transfer
Table 1.
Current Women’s Health Reviews, 2008, Vol. 4, No. 4
219
Legal Impositions in Number of Embryo are Transferred in Order to Justify IVF/ICSI Reimbursements (Law 1st July 2003)
Women aged up to 35 years: •
First cycle: transfer of one fresh embryo or maximum two cryo embryo’s
•
Second cycle: transfer of one fresh embryo if good quality embryo available. If no good quality embryo available, two embryo’s may be transferred
•
From third cycle on: transfer of maximum two fresh embryo’s
Women aged 36 – 39 years: •
First and second cycle: transfer of maximum two fresh embryo’s
•
From third cycle on: transfer of maximum three fresh embryo’s
Women aged 40 – 42 years: •
No imposition of maximum number embryo’s to be transferred
frequently of poor quality due to chromosomal anomalies. However, PGS is a rather invasive technique and therefore not frequently applied. Moreover, the recent trial of Mastenbroek et al. (2007) pointed out that PGS did not increase the rate of ongoing pregnancy in these women, on the contrary [9].
of 33.7 years. In 2005, 5342 transfers of a single embryo were performed out of 14363 cycles in women aged up to 35 years (37%). In the first cycle, eSET was performed in 97% of the cases, in the second cycle 49% of the patients aged 35 or younger received eSET.
HEALTH – ECONOMIC ISSUES, GOVERNMENT MEASURES IN BELGIUM AND REPERCUSSIONS ON TWIN PREGNANCIES
The transfer of one embryo in IVF/ICSI procedures proved the only answer to the first important disadvantage of assisted reproduction: the twin epidemic. However, unfavourable outcome after assisted reproduction was not only attributable to the higher incidence of multiple pregnancies, also singletons after ART were assessed to have poorer outcomes when compared with naturally conceived singletons [12-14]. Higher incidences of preterm birth and low birth weight were generally found in iatrogenically conceived singletons, whereas studies comparing naturally conceived twins with twins after assisted reproduction hardly found any difference between both groups [12, 13].
Health – economic studies pointed out that the use of DET was significant more costly in comparison with SET due to the high neonatal costs (prematurity and hospitalisation) of twin pregnancies after DET [10, 11]. These findings encouraged the Belgian government to introduce a reimbursement law for IVF/ICSI. Since July 1st 2003, up to six IVF/ICSI attempts per couple are reimbursed in women aged maximum 42 years. In order to justify these costs, single embryo transfer is systematically performed in first attempts of women aged 35 or younger (Table 1). With this measure, it was estimated that the risk of triplet pregnancies could be overruled and that the risk of twin pregnancies could be halved. Already in 2004, the effect of this government measure was visible in the birth statistics (Fig. 1).
Fig. (1). Evolution of twin pregnancies in Flanders, Belgium (% of total deliveries).
In Belgium, the female age distribution in infertility programs ranges from 26 to 43 years old, with a median age
OTHER ADVANTAGEOUS OUTCOMES
Some recent studies focussed on pregnancy outcome in singletons after eSET and compared these children with naturally conceived singletons [15] or singletons after DET [16]. These studies indicated that incidences of preterm birth and low birth weight are considerably better in singletons after eSET when compared with singletons after DET (Table 2) and even comparable with incidences in naturally conceived singletons (Fig. 2). These findings were challenged by the study of Poikkeus et al., who found that number of embryos transferred did not affect neonatal outcome, but that subject - and infertility – related aspects rather were responsible for more adverse outcomes in IVF – pregnancies when compared with natural conceptions. However, Poikkeus did not differentiate between elective SET and compulsory SET. This procedure may have biased their results, since both groups are not comparable as has been given above [17]. The reason why singletons after SET fare better than singletons after DET was not completely clear. It was hypothesized that this was due to a vanishing twin – effect in the latter group. Pinborg et al. indicated a difference in birth weight of 178 grams in between singletons who started as a twin and ‘real singletons’, in favour of the latter group [18]. In the study of De Sutter et al., seven percent of the singletons after DET started as a twin (two gestational sacs were seen at first ultrasound). However, in the weeks before
220 Current Women’s Health Reviews, 2008, Vol. 4, No. 4
Table 2.
Ilse et al.
Outcome Parameters of Single Embryo Transfer and Double Embryo Transfer Singleton Pregnancies (Gestational Age, Birth Weight, Preterm Birth and Low Birth Weight), Adjusted for Maternal Age, Parity, Cycle Rank Number, Indication for Assisted Reproduction, Assisted Reproductive Method, Embryo Quality and Sex of the Child Set (n = 404)
Det (n = 431 )
Adjusted P - Value
Gestational age (days)
276.2 (± 10.5)
273.4 (± 15.0)
< 0.01
Birth weight (grams)
3324.6 (±509.7)
3204.3 (±617.5)
< 0.01
%
%
6.2
10.4
1.77
1.06 – 2.94
1.77
1.06 – 2.94
11.6
2.99
1.69 – 5.27
3.38
1.86 – 6.12
Preterm birth (< 37 weeks) Low birth weight (< 2500 grams)
4.2
this first ultrasound there may have been more vanishing twins in the DET – group. Moreover, another study of our group reported a higher incidence of first – trimester bleeding in singletons born after DET compared with singletons after SET, which is also indicative for the vanishing twin syndrome [19]. 5000
Adjusted OR (95% CI)
pregnancies after DET, both embryos have 100% implantation potential, which may be an indicator of successful pregnancy outcome.
44 43
Gestational age (weeks)
4500
Birth weight (g)
Crude OR (95% CI)
4000 3500 3000 2500
42 41 40 39 38 37 36
2000
35
1500
34
Spontaneous singletons n = 59 535
SET SET singletons singletons 251 nn == 251
Spontaneous singletons n = 59 535
SET singletons n = 251
Fig. (2). Mean birth weight and gestational age in naturally – conceived singletons versus singletons after SET.
Since mean hCG – values are higher in twin pregnancies than in singleton pregnancies, it may be expected that higher hCG – values are present after double embryo transfer. We tested this hypothesis in 456 eSET – patients versus 334 DET – patients who delivered from a singleton. Contra – intuitively, mean logHCG – values were significantly higher in the first group for the first 30 days. LoghCG – values in the DET group started slower when compared with SET (Fig. 3). As such, it could be concluded that better outcomes in singletons after SET were not due to a vanishing twin effect. Our results rather indicated that only one embryo implants in the majority of the DET – cases, with a certain hindering effect of the non – implanting embryo on the implanting embryo. However, some studies are indicative for a ‘collaborative’ effect of several transferred embryos, since the number of multiple pregnancies is higher than expected [20-22]. Tummers et al. indicated that the risk of pregnancy loss per gestational sac is lower in twin pregnancies after DET when compared with singleton pregnancies after SET [21]. In twin
Fig. (3). Mean logHCG – values by days after oocyte pick – up in eSET – women versus DET – women who gave birth to a singleton child and DET – women who gave birth to a twin (2000 – 2006).
As was mentioned above, earlier studies found no specific differences in pregnancy outcome between naturally conceived twins and iatrogenically conceived twins, whereas the differences between naturally conceived singletons and singletons after assisted reproduction was significant. However, the majority of these studies date from the pre – SET era and as such, the pregnancies after ART assessed originated from double embryo transfer. Consequently, the twin pregnancies resulted from embryos with maximum implantation potential; whereas in the singletons pregnancies, half of the embryos were wasted. In singletons after SET this is not the case, which may be an explanation for the advantageous outcomes found in these pregnancies [21]. THE FUTURE Although the number of twins decreased substantially in 2004, in 2005 a new increase was observed with a status quo
Single Embryo Transfer
in 2006. Probably this trend was attributable to the notable success of the IVF – reimbursement with a substantial extension in the number of patients entering infertility – programs. Furthermore, young women entering the program in 2003 without conceiving may currently have evolved to their second or third cycle in which more embryos may have been transferred. Since a large number of these women become pregnant of a twin, it is recommended to further explore the possibilities of SET. It would be of interest to explore pregnancy rates after SET in women aged 35 to 40 with good – quality embryos available, in that this age group performs a growing number of patients entering infertility – programs. Also the possibilities of SET in cryo – cycles merits further exploration [23]. Transfer of the embryo is a critical step in ART. Procedures and techniques aiming to improve implantation rates have been and still are studied extensively. The optimal day of embryo transfer is one such item which is still subject of discussion. At the blastocyst – stage (day five or six after oocyte retrieval), selection of embryos and the decision which embryo(s) to cryopreserve is easier. Moreover, uterine contractions progressively decrease during the luteal phase and day five or six is the day on which embryos arrive in the uterus in physiologic cycles [24]. The stage at which embryos reach the uterus in vivo corresponds with the embryo of at least four days in vitro culture. The early cleavage stage embryo is considered too premature to exhibit to the uterine environment, particularly when the endometrium has been exposed to superovulation [25]. Transfer at the blastocyst – stage shows high success rates, although this procedure is more time-consuming and more costly [26]. Milki et al. found an increased incidence of iatrogenic monozygotic twins after blastocyst transfer (5,6% MZ twins after blastocyst transfer, compared with 3% after day 3 embryo transfer [27]. Furthermore, embryo quality may decrease with prolonged culture in vitro. In a Cochrane review, Blake et al. included 18 randomised controlled trials which compared the effectiveness of early cleavage versus blastocyst stage transfers. They concluded that the live – birth rate per couple was higher after blastocyst – culture in good prognosis patients. In day 2 – 3 transfer, there was a higher possibility of embryo freezing and a lower failure to transfer any embryo per couple [25]. Possibly and hopefully future studies will further increase our understanding on optimal embryo transfer.
Current Women’s Health Reviews, 2008, Vol. 4, No. 4
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[18]
CONCLUSION
[19]
SET is not only an effective answer to the twin epidemic; also pregnancy outcome is comparable with naturally conceived singletons. As such, with the implementation of SET, two previous major disadvantages of assisted reproduction are by – passed.
221
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Petra De Sutter is holder of a fundamental clinical research mandate by the Flemish Foundation for Scientific Research (FWO-Vlaanderen).
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Received: July 18, 2008
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Revised: August 1, 2008
Accepted: September 30, 2008
