Hum. Reprod. Advance Access originally published online on January 4, 2007
Human Reproduction 2007 22(4):1021-1025; doi:10.1093/humrep/del470
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Single embryo transfer in preimplantation genetic diagnosis cycles for women <36 years does not reduce delivery rate
1 Centre for Reproductive Medicine, University Hospital, Dutch-Speaking Brussels Free University (Vrije Universiteit Brussel), Brussels, Belgium 2 Centre for Medical Genetics, University Hospital, Dutch-Speaking Brussels Free University (Vrije Universiteit Brussel), Brussels, Belgium
3 To whom correspondence should be addressed at: Centre for Reproductive Medicine, University Hospital, Dutch-Speaking Brussels Free University (Vrije Universiteit Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium. Tel.: +32(0)24774009; E-mail: pdonoso{at}alemana.cl
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Abstract |
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BACKGROUND: The Belgian legislation imposes single embryo transfer (SET) on women of <36 years in their first treatment cycle to avoid multiple pregnancies. The aim of this study is to assess the impact of this legislation on the outcome of preimplantation genetic diagnosis (PGD) for inherited diseases in young women undergoing SET.
METHODS: A retrospective analysis of PGD cycles for monogenic disorders and translocations in women <36 years on their first treatment cycle. Two groups of patients were defined according to the implementation of the Belgian legislation: (i) double embryo transfer (DET), January 2001–June 2003 (ii) SET, July 2003–June 2005. The primary and secondary outcome measures were delivery per embryo transfer and multiple pregnancy rates, respectively. A subgroup analysis for monogenic disorders and translocations was performed.
RESULTS: 62 cycles were included in the DET group and 73 cycles in the SET group. The mean age, number of cumulus–oocyte complexes, number of fertilized oocytes, number of biopsied and cryopreserved embryos were comparable between both groups. There was no significant difference in the delivery rates between the DET and the SET groups (33.9% versus 27.4%, respectively). Multiple pregnancies were avoided when SET was performed. When monogenic disorders and chromosomal translocations were separately evaluated, no significant difference in the delivery rate after SET was observed.
CONCLUSIONS: The implementation of a SET policy in young women undergoing PGD for monogenic disorders and translocations enables a significant reduction of multiple pregnancies without significantly affecting the delivery rate.
Key words: ICSI/multiple pregnancy/preimplantation genetic diagnosis/single embryo transfer
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
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It has been established that multiple pregnancies represent the main iatrogenic complication of assisted ART given that 25% of all IVF/ICSI pregnancies are twins (Land and Evers, 2003
). Furthermore, the incidence of high-order multiple pregnancies is 50 times higher than in the general population (9% versus 0.18%) (Wright et al., 2003). The impact of multiple pregnancies is considerable since a 4- to 10-fold increase in perinatal morbidity and mortality and a 3- to 7-fold increase in maternal complications compared to singleton pregnancies has been reported (ESHRE Capri Workshop, 2000). The increasing awareness of these risks led to the development of strategies focused at reducing the number of embryos to be transferred (Staessen et al., 1993; Svendsen et al., 1996; Templeton and Morris, 1998; Hellberg et al., 2005). Although high-order multiple pregnancies can be almost abolished by the replacement of two instead of three embryos, this strategy does not enable a significant reduction in the incidence of twin pregnancies (20–35%) (ESHRE Campus Course Report, 2001; Bergh, 2005), hence, elective single embryo transfer (e-SET) was introduced as the most rational approach, particularly in good prognosis patients (Vilska et al., 1999; Gerris et al., 1999; Strandell et al., 2000; Martikainen et al., 2001; Gardner et al., 2004; Thurin et al., 2004; Lukassen et al., 2005, Pandian et al., 2005).
As a matter of public health, several countries have developed regulations concerning this issue (Tiitinen et al., 2004; Ombelet et al., 2005; Saldeen and Sundstrom 2005). In Belgium the Ministry of Social Affairs established in 2003 a new legislation by which six IVF cycles are reimbursed in a lifetime up to the age of 43 years (Belgisch Staatsblad, 2003). The number of embryos to be transferred is determined according to the age of the patient, the embryo quality and the number of previous IVF attempts, imposing SET on women <36 years in their first treatment cycle. Although this strategy has proven effective by means of lowering twin pregnancies without compromising overall success rates (Debrock et al., 2005; Gordts et al., 2005), concerns have been raised regarding a possible adverse effect of establishing a SET policy in young patients undergoing preimplantation genetic diagnosis (PGD) for inherited diseases, since a lower pregnancy rate has been suggested after PGD compared to conventional IVF/ICSI cycles (Vandervorst et al., 2000; Harper et al., 2006). However, the technical complexities along with the high costs associated with this technique must be taken into consideration when deciding the most suitable number of embryos to be transferred following PGD (Gerris, 2005). On the other hand, the follow-up of pregnancies after PGD has revealed that multiplicity represents the most significant source of perinatal and maternal morbidity in these patients (Harper et al., 2006). To date, no data are available on the effect of implementing e-SET in this group of patients.
The aim of this study was to assess the impact of imposing SET in women of <36 years undergoing PGD for monogenic disorders and chromosomal translocations.
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Material and methods |
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Study design
A retrospective analysis of PGD cycles performed to avoid the transmission of a monogenic disorder or unbalanced chromosomal translocation (Robertsonian and reciprocal) was conducted, including the treatment cycles carried out from January 2001 to June 2005.
Patients
The inclusion criteria for patient selection were: (i) women of <36 years of age, (ii) first treatment cycle and (iii) patients had undergone embryo transfer. Two groups of patients were defined according to the implementation of the new Belgian legislation (1 July 2003): (i) double embryo transfer (DET) (previous to the implementation of the new legislation): patients undergoing PGD for a monogenic disorder or chromosomal translocation, who had two embryos transferred between 1 January 2001 and 30 June 2003 and (ii) single embryo transfer (SET) (after the implementation of the new legislation): patients undergoing PGD for a monogenic disorder or chromosomal translocation, who had one embryo replaced between 1 July 2003 and 30 June 2005.
Ovarian stimulation and ICSI procedure
A GnRh-agonist or a GnRh-antagonist protocol, along with recombinant FSH or urinary gonadotropins, was used (Papanikolaou et al., 2005). Ten thousand International Unit of urinary HCG (Pregnyl®) were administered when at least 
3 follicles 17 mm were present. Oocyte retrieval was carried out 36 h after HCG administration. ICSI was used in all cycles instead of IVF to prevent contamination with residual sperm adhered to the zona pellucida (ZP) when PCR was used as diagnostic tool, or in general to prevent failure of fertilization after regular IVF (Liebaers et al., 1998; Sermon et al., 2004). The surrounding cumulus and corona cells were then removed and the nuclear maturation of the oocytes was assessed under an inverted microscope. The ICSI procedure on metaphase-II oocytes was performed as previously described (Joris et al., 1998; Van Landuyt et al., 2005). Fertilization was assessed after 16–18 h and embryo development was further evaluated on day 2 and 3 prior to biopsy (Van Landuyt et al., 2005). Embryo culture was done in sequential media (GI–GIII Vitrolife, Gothenburg, Sweden).
Embryo biopsy
Embryo biopsy was performed on embryos at a six-cell or later stage of development, as described elsewhere (Joris et al., 2003). A hole was made in the ZP using two or three laser pulses of 5–7 ms of a non-contact 1.48 µm diode laser system (Fertilase; Octax, Herbron, Germany) coupled to a micromanipulator on an inverted microscope (Joris et al., 2003). One or two blastomeres containing a nucleus were gently aspirated through the opening. In cases of monogenic disorders, one or two blastomeres were removed according to the available PCR test (multiplex PCR or multiple markers). For chromosomal translocations two blastomeres were always removed. Among patients in the SET and DET groups, an equivalent number of PGD cycles with removal of one or two cells were done.
Genetic diagnosis
For monogenic disorders, embryo diagnosis was performed by specific PCR-based diagnostic procedures (Sermon et al., 2004). In cases of X-linked disorders, where the specific analysis of the gene defect could not be applied, gender determination of the embryos was carried out by fluorescence in situ hybridization (FISH) (Staessen et al., 1999). FISH analysis was also used for cases of chromosomal translocations (Van Assche et al., 1999).
Embryo evaluation and selection for transfer
Embryo transfer was performed on day 5. Blastocyst quality was assessed according to the criteria of Gardner and Schoolcraft (1999). Preferably full or advanced blastocysts with many cells in the inner cell mass (ICM) and in the trophectoderm were selected. A top quality blastocyst (EQ1) was considered as being at least BL3, type A for ICM and type A or B for trophectoderm. Supernumerary embryos were frozen at the blastocyst stage (day 5 or 6).
Luteal phase supplementation
Luteal phase supplementation was performed with vaginal administration of 600 mg natural micronized progesterone in three separate doses (Utrogestan; Besins, Brussels, Belgium), starting 1 day after oocyte retrieval and continued until 7 weeks of gestation if pregnancy was achieved (Pritts and Atwood, 2002).
Outcome measures
The main outcome measure to be compared between the DET group and the SET group was the delivery rate per embryo transfer. The secondary outcome measure was the multiple pregnancy rate. A separate analysis was conducted for monogenic disorders and translocations.
Statistical analysis
An independent Student's t-test was used to compare mean values between the DET and the SET groups. Outcome measures were evaluated with the Fischer's exact test. All results are presented as mean ± SD. A P value of <0.05 was considered statistically significant.
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Results |
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During the study period, 62 patients fulfilled the inclusion criteria in the DET group and 73 patients in the SET group. The mean age (29.8 ± 2.9 versus 29.8 ± 3.2), number of cumulus–oocyte complexes (16.5 ± 9.3 versus 14.6 ± 8.0), number of fertilized oocytes (13.0 ± 6.9 versus 11.0 ± 6.3), embryo quality (1.6 ± 0.7 versus 1.6 ± 0.7) and number of cryopreserved embryos (0.6 ± 1.0 versus 0.9 ± 1.4) were not significantly different between the DET and SET groups (Table I).
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Autosomal dominant monogenic disorders were the most prevalent indication for PGD (32.6%), followed by chromosomal translocations (27.4%), autosomal recessive (21.5%) and X-linked recessive diseases (18.5%). There was no significant difference regarding the indications between the DET and SET groups (Table II). The two main indications in patients undergoing PGD for monogenic disorders were myotonic dystrophy (14.9% DET group and 19.6% SET group) and cystic fibrosis (21.3% DET group and 3.9% SET group). Chromosomal translocations (Robertsonian and reciprocal) represented 24.2% (n = 15) of the DET group and 30.2% (n = 22) of the SET group. In the DET group, there were eight couples who were carriers of a Robertsonian translocation and seven couples who were carriers of a reciprocal translocation. In the SET group, eight couples carried a Robertsonian translocation and 14 a reciprocal translocation. Robertsonian translocations were present in six female carriers and 10 male carriers, and five female carriers and 16 male carriers in the reciprocal translocation group.
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In the SET group, 27 patients (36.9%) had two or more embryos available for transfer (at least one cryopreserved embryo) from which 57.7% had two or more cryopreserved embryos (n = 26) (mean number of cryopreserved embryos 2.2 ± 1.3). In the DET group, 29% of the patients (n = 18) had at least one cryopreserved with a mean of 1.8 ± 1.0 cryopreserved embryos.
Table III summarizes the delivery rates after DET and SET. There was no statistically significant difference on the delivery rates between the DET and the SET groups (33.9% versus 27.4%; P = 0.45). Multiple pregnancies were, however, avoided after the implementation of SET (28.6% versus 0%; P = 0.02). If only patients who had at least one cryopreserved embryo of the SET group were considered for analysis, the delivery rate was similar to the DET group (37% versus 33.9%, respectively). Patients in the SET group in whom the transferred embryo was selected from among two or more embryos had a higher delivery rate than patients who had only one available embryo to transfer (37% versus 21.7%), though this difference was not significant (P = 0.18).
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Delivery rates per embryo transfer for non-PGD cycles during the same period and complying with the same inclusion criteria were 38.3% for the DET group and 27.2% for the SET group (P = 0.02). Multiple pregnancy rate was reduced from 30.9% during the DET period to 0.7% in the SET period (P < 0.05).
When only monogenic diseases were analysed, no significant difference on the delivery rates between the DET and SET groups was observed (34% versus 29.4%; P = 0.66). Similarly, in the case of Robertsonian and reciprocal translocations, no significant difference was observed when DET had been performed compared to SET (33.3% versus 22.7%; P = 0.70). There were four twin gestations in the monogenic disorder group, two twin pregnancies in Robertsonian translocation carriers and no twin pregnancies in reciprocal translocation carriers.
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Discussion |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
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To the best of our knowledge, this study represents the first attempt to evaluate the effect of restricting the number of embryos to be transferred in patients undergoing PGD. Our results show that a comparable delivery rate can be achieved when a SET policy is imposed on young women undergoing PGD to avoid the transmission of a genetic disorder to their offspring. Moreover, this strategy allows, as previously reported for non-PGD cycles (Pandian et al., 2005
), for a significant reduction of the twin pregnancy rate (28.6% versus 0%), representing the main advantage of this strategy. These results are in agreement with those obtained in cycles without PGD during the same time period at our centre, where a significant reduction in multiple pregnancy rates was observed (30.9% versus 0.7%) along with a reduced but acceptable delivery rate per embryo transfer (38.3% versus 27.2%).
The process of embryo selection constitutes the most important difference between patients undergoing PGD and conventional ICSI cycles. In the case of non-PGD cycles embryo selection is based on morphological criteria, whereas in PGD couples, only embryos of good morphological quality in which the specific disease has been excluded are suitable for transfer, hence limiting the number of embryos available to select for transfer. This specific method of embryo selection significantly contributes to the fact that in the present study, only 36.9% of the patients undergoing SET had more than one embryo available for replacement, despite the young age of the women and an adequate ovarian response. According to our results and in agreement with previous reports (Van Montfoort et al., 2005), patients in whom the transferred embryo was selected from among two or more embryos had a higher delivery rate than patients with only one available embryo (37% versus 21.7%) though this difference was not significantly different, possibly due to the limited number of analysed patients. Nevertheless, overall, patients in the SET group achieved a delivery rate comparable to those in the DET group, reinforcing this strategy as the best choice for minimizing the chances of a twin pregnancy without reducing delivery rates.
PGD allows for the detection of inherited conditions before implantation occurs, therefore, preceding the establishment of a pregnancy, avoiding the negative psychological effects of termination of pregnancy when prenatal diagnosis has identified an affected fetus (Lavery et al., 2002). Even though reported clinical pregnancy rates per embryo transfer following PGD are acceptable (25% for single gene disorders, 25% for Robertsonian translocations and 18% for reciprocal translocations) (Harper et al., 2006), these figures are lower compared to standard ICSI cycles (clinical pregnancy rate per embryo transfer of 36.6% in Belgium 2002) (Nyboe Andersen et al., 2006). It has been suggested that blastomere removal could be responsible for this difference, as it might interfere with the process of early cell differentiation through a reduction in the cellular mass and alteration of embryo polarization towards trophectoderm and ICM (Tarin et al., 1992; Liu et al., 1993). However, several studies have suggested the absence of an adverse effect of the embryo biopsy on in vitro development to the blastocyst stage (Carter et al., 2004; Cieslak-Janzen et al., 2006) and implantation rate (Van de Velde et al., 2000).
In translocation carriers, a lower pregnancy rate after PGD has been associated with a reduced chance of finding a chromosomally normal embryo (balanced translocation carrier) (
one-fourth for Robertsonian translocations and one-fifth for reciprocal translocations) (Harper et al., 2006). In addition, a high incidence of aneuploidy in chromosomes not involved in the translocations possibly due to an interchromosomal effect has been proposed (Gianaroli et al., 2002; Pujol et al., 2006), though this issue remains under controversy (Munné et al., 2005). The results of the present study showed no significant reduction on the delivery rate when the number of embryos transferred was limited; however, no definite conclusion can be drawn, since a limited number of couples were included.
In conventional IVF, e-SET followed if necessary by a frozen-thawed cycle has shown comparable live birth rates (38.8% for e-SET versus 43.4% for DET) with a significant reduction in multiple pregnancy rates (0.8% for e-SET versus 33.1% for DET) (Thurin et al., 2004). Furthermore, cumulative pregnancy rates per patient of more than 60% have been reported after blastocyst e-SET (Catt et al., 2003; Uchiyama et al., 2004). An important drawback to this approach in PGD couples is a significant reduction in the survival rate of biopsied embryos after cryopreservation (Joris et al., 1999; Magli et al., 1999; Ciotti et al., 2000), associated with the opening of the ZP, since under the framework of a SET policy the likelihood of achieving a pregnancy through the transfer of frozen-thawed supernumerary embryos is reduced. Therefore, considering this evidence, it is possible that some patients undergoing PGD because of chromosomal translocations could benefit from a more flexible policy concerning the number of embryos to be replaced, since fewer transferable embryos are obtained.
In conclusion, our results support the implementation of a SET policy in young women undergoing PGD, since it enables a considerable reduction of twin gestations without a significant decrease in delivery rate. More data with a larger number of patients and also assessing cumulative delivery rates with frozen-thawed cycles will provide valuable information to decide the most suitable number of embryos to be transferred in young patients following PGD.
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Submitted on August 19, 2006; resubmitted on November 6, 2006; accepted on November 11, 2006.
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