1 Centre for Medical Genetics, University Hospital and Medical School of the Dutch-speaking Brussels Free University (Vrije Universiteit Brussel, VUB), Laarbeeklaan 101, 1090 Brussels, Belgium, 2 Service de la Biologie de la Reproduction, SIHCUS-CMCO, 19, Rue Louis Pasteur, BP120, 67303 Schiltigheim, France, 3 Department of Obstetrics and Gynaecology, University College Medical School, 8696 Chenies Mews, London WC1E 6HX, 4 PGD working group Maastricht, Department of Clinical Genetics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands, 5 Department of Cytogenetics, and Center for Preimplantation Genetic Diagnosis, Guy's and St Thomas' NHS Trust, Guy's Hospital, St Thomas Street, London SE1 9RT, UK, 6 Melbourne IVF, 320 Victoria Parade, 3002 East Melbourne, Victoria, Australia and 7 Day Surgery Clinic, SISMER, Via Mazzini, 12, 40137 Bologna, Italy
8 To whom correspondence should be addressed
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Abstract |
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Key words: data collection/ESHRE/PGD
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Introduction |
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One of the most prominent aims of the ESHRE PGD Consortium, that was formed at the ESHRE Annual Meeting in 1997 in Edinburgh, has been to collect detailed data on the practice of PGD. Therefore, PGD centres were asked to become members and to give data voluntarily on the patient referrals, PGD cycles, ensuing pregnancies and babies. These data were collected, first on paper forms, and later on Microsoft® Excel spreadsheets (ESHRE PGD Consortium Steering Committee, 1999, 2000
). Because the Steering Committee judged that speed was of importance in the early phase, data on cycles and on pregnancies and babies were collected from the same time frame. Thus, by the time the cycles were collected, the ensuing pregnancies had not reached term, and the pregnancies collected were from cycles from previous collections. This, and the limitations inherent to the spreadsheet, made it very difficult to link any given cycle to its pregnancy and further outcome (ESHRE PGD Consortium Steering Committee, 2002
). To remedy this problem, two important decisions were made: the first was that a more user-friendly database would be developed, that would also allow the easy link between the different stages of a PGD treatment. The second decision was that the cycles from a complete calendar year would be collected, as well as the ensuing pregnancies and babies in the following year until the end of October. The shift in timing led to the fact that no data would be collected the year following the decision, and this gave the Steering Committee the opportunity to take a closer look at the existing databases and to identify and correct shortcomings in these data.
In this report, two sets of data are presented. The first set, referred to as data IIII, concerns an updated corrected version of the data presented in the former reports (ESHRE PGD Consortium Steering Committee, 2002). The second set, referred to as data IV, was collected using the FileMaker Pro 6TM (FP6) database. It concerns cycles carried out between May 2001 and December 2001, and the pregnancies and babies ensuing from these cycles (i.e. born before October 2002).
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Materials and methods |
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Referral data were not corrected and re-analysed.
Data IV
A database was designed in FP6 by C.M., which contained the following forms. (i) A referral form with information on the indication and the patient's reproductive history, as well as the centre's and the patient's decision to go ahead with PGD. (ii) A form with information on the PGD cycle, such as cycle and patient identification, indication, type of ART and biopsy methods, and details on the biological material available. Relevant data entered in the referral form were automatically transferred to the cycle form. (iii) Frozen cycle form: this form is linked to the fresh cycle and can be introduced at several points in the fresh cycle, such as freezing before or after biopsy. (iv) Pregnancy form: this form also automatically takes over relevant data from the cycle form, and contains information about ultrasound data, prenatal diagnosis, possible miscarriages or other reasons for pregnancy loss, and date and gestational age at birth. (v) Baby form: contains data on the first month after birth and records basic data such as the birth weight of the baby, as well as possible malformations or neonatal complications. Each of these five forms is linked, allowing for the easy identification of, for example, the PGD cycle that led to a given pregnancy and birth. The PGD centres were sent these five forms along with a clear instruction manual, and were asked to fill in the referrals and cycles covering the period from May 1, 2001 until December 31, 2001 (except for the newly joined centres who were asked to give all their data from the beginning of their activities) and the data on the pregnancies and babies ensuing from these data. The total data were again divided into subsets, and the data were checked for mistakes and missing data. The corrected FP6 files were sent to the participating centres.
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Results and discussion |
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As mentioned above, the referral data IIII were not re-analysed.
Referral data IV
Due to the change in the way the data collection was carried out in the study period, a direct comparison between the absolute numbers of previous data collections and this round are only valid for a few items.
Looking at the referrals according to indication, it is clear that chromosomal indications are the main reason for referral during the present data collection (Table I).
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Because of the increase in referrals for chromosomal disorders, the proportion of referrals for monogenic disease has decreased, but the numbers of referrals have remained more or less constant if one takes into account that the study period comprised only 8 months. The most frequent referrals for X-linked disease were fragile X syndrome, Duchenne's or Becker's muscular dystrophy and haemophilia.
For autosomal recessive diseases, the most frequent referrals were similar between data collections: cystic fibrosis/congenital bilateral absence of vas deferens, -thalassaemia and spinal muscular atrophy (SMA). Also among autosomal dominant disease, myotonic dystrophy and Huntington's chorea remained the two most common reasons for referral.
Due to the bias in the data collection (see below), it is easily explained that centres accepted the patients for PGD in almost all cases. In nearly every case it was concluded that the patient was suitable for IVF, and that a diagnosis was technically possible and ethically acceptable.
The most important reason for the couples to refrain from treatment has changed from inconvenience and/or burden of the ICSI or IVF procedure to the low success rate of the procedure. The occurrence of a spontaneous pregnancy and the treatment costs were minor reasons for declining.
The change in the method of data collection that was introduced between collections III and IV has resulted in a significant shift in the completeness of the referral data. Previously, most referrals were reported at the time of initial contact between the couple and the centre. Since the retrospective data collection was introduced, all data are collected at one point in time, which sometimes is separated by more than a few years from the time of referral. Furthermore, retrospective data collections are directed preferentially towards those referrals which have resulted in treatment. Therefore, a number of the changes observed can be explained by the different methods of data collection. This partly includes the reason for referral. However, it is clear that the group of patients is changing dramatically. The number of chromosomal indications is growing exponentially. This is due primarily to PGS, mainly for advanced maternal age. Therefore, the data collection is split up into PGD for high-risk situations and PGS.
Data on cycles (Tables IVa and b)
Tables IVa and b summarize the cycle data for collections IIII and IV. The data for IIII, which were published previously (ESHRE PGD Consortium Steering Committee, 2002), differ slightly from the original report as some errors were found.
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Sexing (Table VIa and VIbTable VIa and VIb). The data of sexing only (IIII) using fluorescence in situ hybridization (FISH) or PCR are presented in Table VIa. The most common disorders for which sexing only was performed were haemophilia A and Duchenne's muscular dystrophy with 71 cycles each, and X-linked mental retardation with 22 cycles. The centres performing sexing mainly used FISH for diagnosis (85%). A total of 350 cycles reached OR with an average of 13.4 oocytes per retrieval, 71% fertilized and 96% successfully biopsied. Two cycles with thawed embryos were also included. A diagnosis was possible for 88% of embryos successfully biopsied, and 80% of the cycles with OR had an embryo transfer with an average of 2.0 embryos transferred per cycle. A clinical pregnancy of 19% per OR was achieved. The number of embryos frozen includes 13 cycles where embryos that were not biopsied or where the diagnosis failed were cryopreserved.
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Monogenic disease (Tables VIIa and b). Tables VIIa and b summarize the data for the specific diagnosis performed using PCR. A breakdown is only presented for the most common disorders. Concerning the data collection IIII (Table VIIa), for autosomal recessive disorders, the most common indications for treatment were cystic fibrosis (197 cycles), -thalassaemia (55 cycles), SMA (45 cycles), sickle cell anaemia (11 cycles) and epidermolysis bullosa (eight cycles). For the dominant disorders, myotonic dystrophy was the most common disorder treated (125 cycles), followed by Huntington's disease (66 cycles which included three cycles of exclusion testing), CharcotMarieTooth disease (11 cycles) and Marfan's syndrome (10 cycles). Specific diagnosis for X-linked disease was performed most commonly for fragile X (27 cycles), Duchenne's muscular dystrophy (25 cycles) and haemophilia A (12 cycles).
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Overall there was an average of 13.2 oocytes collected per oocyte retrieval, the biopsy was successful in 99% of embryos, the diagnosis was possible in 83% of the embryos successfully biopsied, 84% of cycles to OR had an embryo transfer and 20% of these patients achieved a clinical pregnancy.
The following points can be noted from data collection IV (Table VIIb). The most common indications either for autosomal recessive, dominant or X-linked disorders have not changed. Of notice is the relative decrease in the number of cycles performed for cystic fibrosis since it represented two-thirds of the cycles for recessive disorders in data collection IIII and only one-third in the data collection IV. A similar observation can be made for the dominant disorders, where there is a relative decrease of the number of cycles for myotonic dystrophy. In this category, amyloid polyneuropathy appears for the first time, with 10 cycles performed by one centre. No cycles are reported for Duchenne's muscular dystrophy in the specific diagnosis for X-linked disease. This is quite surprising since 25 cycles were reported in the previous report and this method has the important advantage of allowing the transfer of male unaffected embryos.
Again, for some recessive disorders (cystic fibrosis and -thalassemia), only about half of the diagnosed embryos are transferable. Such a distortion is also observed for myotonic dystrophy since only a third of the diagnosed embryos are transferable. A possible explanation could be the use of multiplex PCR that includes polymorphic markers allowing the detection of different (chromosomal) abnormalities.
Overall there was an average of 12.9 oocytes collected per OR, the biopsy was successful in 99% of embryos, the diagnosis was possible in 86% of the embryos successfully biopsied, nearly 80% of cycles going to OR had an embryo transfer and 21% of these patients achieved a clinical pregnancy.
A list of monogenic diseases for which PGD was performed can be found in the electronic version of the article (Tables VIIc and d).
PGD with aneuploidy screening (Table VIIIa and bTable VIIIa and b). Outcomes for PGS cycles are presented in Table VIIIa (collection I III) and VIIIbTable VIIIa (collection IIII) and VIIIb (collection IV). The use of PGS has increased substantially, with almost 35% more cycles reported in data collection IV than in data collections IIII combined. The mean number of oocytes collected was 13.2 per retrieval in both data collections. The fertilization rate was 71 and 73% and the proportion of embryos successfully biopsied was 98 and 97% in data collections IIII and IV, respectively. In collection IV, a diagnosis was obtained in 92% of all embryos successfully biopsied. As described in Table VIIIa, it was not possible to calculate this figure accurately from data collection IIII.
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The overall pregnancy rate per OR in data collection IIII was 20% with the subgroups of advanced maternal age, recurrent miscarriage and recurrent IVF failure having pregnancy rates of 24, 30 and 10%, respectively. In data collection IV, the overall pregnancy rate per OR was slightly lower at 16%. The pregnancy rate for the recurrent IVF failure patients was 15%, which was slightly higher than in data collection IIII. However, in data collection IV, patients with advanced maternal age had a pregnancy rate of only 9%. This may be partly explained by the reduced number of oocytes recovered per patient in the advanced maternal age group in data collection IV compared with data collection IIII. In the first three rounds of data collection, advanced maternal age patients had an average of 12.7 oocytes collected, which resulted in an average of 8.2 embryos and there was a mean of 2.4 embryos per transfer. In data collection IV, advanced maternal age patients had an average of 9.4 oocytes collected which resulted in 5.9 embryos with a mean of 1.9 embryos per transfer. The lower number of oocytes collected cannot be explained by a difference in maternal age, as this was 40 years in both data collections.
Social sexing (Table IXa and bTable IXa and b). Table IXa shows the data of PGD for social sexing (data collection IIII). The centres performing PGD for social sexing mainly used FISH for diagnosis. The female average age was 33 years. A total of 93 cycles reached oocyte retrieval with an average of 12.7 oocytes per OR. IVF was used in 77% of the cycles. The embryos were biopsied using the laser in 88% and all embryos were cleavage stage aspirated. Out of 91% successfully biopsied embryos, 88% were diagnosed. There was an embryo transfer in 78% of the cycles with OR, which resulted in a clinical pregnancy rate of 30% per OR. An average of 2.0 embryos was transferred. This pregnancy rate is high compared with other PGD pregnancy rates. No information was provided regarding the sex selected for.
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Pregnancies and babies data IIII
A significant effort was made to link the cycles with a positive HCG in the cycle database with the pregnancies and babies in the database. Five hundred and thirty-seven pregnancies were recorded, either in the cycle database or in the pregnancy database, or in both. In 204 of these, we only know that the cycle ended in a pregnancy, but no further data on the pregnancies and babies born were obtained. Data on 333 pregnancies were collected, of which 57 had no cycle data. This means that complete data concerning the cycle, the ensuing pregnancies and the babies born were collected for 276 pregnancies. The 333 pregnancies led to the birth of 315 babies (175 singletons, 128 twins and 12 triplets) or 243 pregnancies leading to birth.
The 333 pregnancies for which data are available are represented in Tables Xa, XIa, XIIa, XIIIa, XIVa and XVa.
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The misdiagnoses have already been discussed in ESHRE PGD Consortium Steering Committee, 2002 (Table XVa). However, more information has become available on the affected pregnancy with chromosome imbalance 47,XX, + der(22)t(11;22)(q23.3;q11.2)mat following PGD for the common reciprocal translocation between chromosomes 11 and 22 (Kyu Lim et al., 2004
). This is a well-studied reciprocal translocation, and tertiary trisomy for the derivative chromosome 22 (as found in this pregnancy that resulted in spontaneous abortion) is the only form of this translocation with chromosome imbalance found in recognizable pregnancies and live born children and is associated with multiple congenital abnormalities (Gardner and Sutherland, 2004). The probe strategy chosen by this centre did not include a probe on the derivative 22, and therefore this unbalanced form of the translocation was not detectable using their probe set (Mackie Ogilvie and Scriven, 2004
). This affected pregnancy underlines the need for thorough assessment of each reciprocal translocation referred for PGD (Scriven et al., 1998
; Ogur et al., 2002
; Scriven, 2003
), preferably in collaboration with a cytogenetics department with the necessary expertise (Mackie Ogilvie and Scriven, 2001
).
Taking the misdiagnoses discovered both pre- and postnatally, a total of three misdiagnoses were reported after PGD using FISH (one for sexing, one trisomy 21 after PGS and one for a reciprocal translocation), leading to a misdiagnosis rate of three out of 145 concepti tested (2%). After PGD using PCR, seven misdiagnoses were reported: two for sexing (for retinitis pigmentosa and Duchenne's muscular dystrophy), one for -thalassaemia and for myotonic dystrophy, and three for cystic fibrosis (one discovered prenatally, and twins where it was found after birth that both were carriers instead of homozygous normal). This gives a misdiagnosis rate after PCR of seven out of 85 concepti tested (8%). The overall misdiagnosis rate is then 10 out of 230 or 4%.
Pregnancies and babies data IV
The number of pregnancies submitted has increased, and reflects the increased number of cycles submitted by a larger number of centres. Because of the use of the FP6 software, it has been much easier to control the submission of pregnancies and baby data. This means that most cycles ending in a positive heartbeat also had a pregnancy sheet and, vice versa, that most of the pregnancies and babies had a cycle in the cycle database. Of the 296 cycles ending in a positive heartbeat, 18 (9%) had no pregnancy file. Conversely, of the 315 pregnancies, 14 had no concording cycle. Eight of these pregnancies were from cycles before April 2001, and these cycles can be found in the IIII cycle database, while for six of these (2%) no cycle was found. The characteristics of the pregnancies (evolution, complications Table Xb, XIbTable Xb, XIb), deliveries (multiple gestations, type of delivery Table XIIb) and babies (e.g. birth weight, complications at birth Tables XIIIb and XIVb) are very comparable with the data collection IIII, and with large series of ICSI pregnancies and babies (Bonduelle et al., 2002; Van Steirteghem et al., 2002
).
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General remarks |
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As with every new report, new indications in PGD or PGS appear: noteworthy is the increasing number of PGS cycles performed for male indications and for previous aneuploid pregnancies.
A new piece of information that was added when the FP6 was introduced was the number of cycles cancelled before OR. A comparison of the number of cancellations between categories and with regular IVF could yield important information on the correct management of PGD patients, who have a lower chance of achieving a pregnancy in all categories. From the low number of cycles cancelled (149 out of 1990 or 7%), it is difficult to draw conclusions, except that the bias which distorted the referral data is also at play here: diagnostic centres who only receive a fixed blastomere have no access to information concerning cycle cancellation before OR.
The ESHRE PGD Consortium will continue to collect PGD data, and this collection will be expanded to the follow-up of children born after PGD. The next data collection (V) will includ data from January 1, 2002 until December 31, 2002 and is currently being prepared for publication. The Consortium have also written PGD guidelines (Thornhill et al., 2005).
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Appendix I. |
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List of participating centres (Contact person, affiliation, city, country) |
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Braude, Peter: Center for Preimplantation Genetic Diagnosis, Guy's and St Thomas' NHS Trust, London, UK
Carvalho, Filipa: Faculty of Medicine of Porto-Hospital Sao Joao, Porto, Portugal
Chamayou Sandrine: HERA-UMR, Catania, Italy
Chen, Chun-Kai: Chang Chung Memorial Hospital and Medical College, Tao-Yuan, Taiwan
Coonen, Edith: PGD Working Group Maastricht, Maastricht, The Netherlands
Emiliani, Serena: Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Fernandez, Esther: Fundacion Jimenez Diaz, Madrid, Spain
Gianaroli, Luca: SISMER, Bologna, Italy
Gitlin, Sue: Jones Institute for Reproductive Medicine, Norfolk, Virginia, USA
Hanson, Charles: Sahlgrenska Hospital, Goteborg, Sweden.
Harper, Joyce: University College London, London, UK
Harton, Gary: Genetics and IVF Insitute, Fairfax, Virginia, USA
Hindkjaer, Johnny: Aarhus University Hospital, Aarhus, Denmark
Hussey, Nicole: University of Adelaide, Department of Obstetrics and Gynaecology, Adelaide, Australia
Hyden-Granskog, Christel: Helsinki University Central Hospital, Helsinki, Finland
Inn Soo Kang: Samsung Cheil Hospital, Seoul, Korea.
Kahraman, Semra: Istanbul Memorial Hospital, Istanbul, Turkey
Kontogianni, Elena: IVF and Genetics, Athens, Greece
Lavery, Stuart: Hammersmith Hospital, London, UK
Malcov, Mira: Tel-Aviv Sourasky Centre, Tel-Aviv, Israel
Manor, Dorit: Rambam Medical Centre, Haifa, Israel
Marshall, Jim: Sydney IVF, Sydney, Australia
McAdoo, Sallie: Baylor College of Medicine, Houston, Texas, USA
Montag, Marcus: University of Bonn, Bonn, Germany
Rubio, Carmen: Instituto Valenciano de Infertilidad, Valencia, Spain.
Salin, Paivi: AVA-Clinic, Tampere, Finland
Santalo, Josep: Unitat de Biologia Cellular, Universidad Autonoma Barcelona, Barcelona, Spain
Sermon, Karen: Centre for Medical Genetics Vrije Universiteit Brussel, Brussels, Belgium
Traeger-Synodinos, Joanne: Medical Genetics, Athens University, St. Sophia's Children's Hospital, Athens, Greece.
Van de Elst, Josiane: Infertility Centre, Ghent University Hospital, Ghent, Belgium
Vandamme, Brigitte: Leuven Insititute for Fertility and Embryology, Leuven, Belgium
Veiga, Anna: Instituto Dexeus, Barcelona, Spain
Vesela, Katerina: Sanatorium Repromeda, Brno, Czech Republic
Viville, Stéphane: Service de la Biologie de la Reproduction, SIHCUS-CMCO, Strasbourg, France
Wilton, Leeanda: Melbourne IVF, Melbourne, Australia
List of centres that failed to send in data
Alberola, Trinidad: Sistemas Genomicos SL, Valencia, Spain
Decherney, Alan: Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, USA
Frydman, Nelly: Service de Biologie Génétique de la Réproduction, Hopital Beclère, Paris, France
Gadou, Moutaz: Elaj Medical Center, Jeddag, Saudi Arabia
Givens, Carolyn: San Francisco Fertility Centers, San Francisco, California, USA
Kangpu Xu: Department of Obstetrics and Gynecology, Center for Reproductive Medicine and Infertility, New York, USA
Kearns, William: Shady Grove Centre for Preimplantation Genetics, Rockville, Maryland, USA
Krey, Lewis: New York University Medical Center, New York, USA
Lucena, Carolina: Cecolfes Ltda, Bogota, Columbia
Mi-Kyung Chung: Cha General Hospital, Seoul, Korea
Milad, Magdy: Northwestern Memorial Hospital, Chicago, Illinois, USA
Navarro, Joaquima: Unitat Biologia, Fisiologia e Immunologia, Universidad Autonoma de Barcelona, Barcelona, Spain
Petit, Christophe: Laboratoire de FIV, Maternité A Pinard, Nancy, France
Robinson, Mark: School of Biology, University of Leeds, Leeds, UK
Tucker, Michael: Georgia, USA
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References |
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ESHRE PGD Consortium Steering Committee (1999) ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: preliminary assessment of data from January 1997 to September 1998. Hum Reprod 14, 31383148.
ESHRE PGD Consortium Steering Committee (2000) ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: data collection II (May 2000). Hum Reprod 15, 26732683.
ESHRE PGD Consortium Steering Committee (2002) ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: data collection III (May 2001). Hum Reprod 17, 233246.
Gardner RJM and Sutherland GR (2004) Chromosome Abnormalities and Genetic Counseling, 3rd edn. Oxford University Press, New York.
Kyu Lim C, Hyun Jun J, Mi Min D, Lee HS, Young Kim J, Koong MK and Kang IS (2004) Efficacy and clinical outcome of preimplantation genetic diagnosis using FISH for couples of reciprocal and Robertsonian translocations: the Korean experience. Prenat Diagn 24, 556561.[CrossRef][ISI][Medline]
Mackie Ogilvie C and Scriven PN (2001) The scope and limitations of FISH for preimplantation genetic diagnosis. Fertil Steril 75, 227228.[Medline]
Mackie Ogilvie C and Scriven PN (2004) Preimplantation genetic diagnosis (PGD) for reciprocal translocations. Prenat Diagn 24, 553555.[CrossRef][ISI][Medline]
Ogur G, Van Assche E and Liebaers I (2002) Preclinical work-up of preimplantation genetic diagnosis for chromosomal translocation carriers. In Macek M Sr, Bianchi DW, and Cuckle H (eds) Early Prenatal Diagnosis, Fetal Cells and DNA in the Mother. Present State and Perspectives. The Karolinum Press, Charles University, Prague, pp. 236253.
Scriven PN (2003) Preimplantation genetic diagnosis for carriers of reciprocal translocations. J Assoc Genet Technol 29, 4959.[Medline]
Scriven PN, Handyside AH and Mackie Ogilvie C (1998) Chromosome translocations: segregation modes and strategies for preimplantation genetic diagnosis. Prenat Diagn 18, 14371449.[CrossRef][ISI][Medline]
Sermon K, Van Steirteghem A and Liebaers I (2004) Preimplantation genetic diagnosis. Lancet 363, 16331641.[CrossRef][ISI][Medline]
Thornhill AR, de Die-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN, Sermon KD, and Wilton L (2004) ESHRE PGD Consortium, Best Practice Guidelines for Clinical Preiemplantation Genetic Diagnosis (PGD) and Preimplantation Genetic Screening. Hum Reprod 20, 3548.
Van Steirteghem A, Bonduelle M, Devroey P and Liebaers I (2002) Follow-up of children born after ICSI. Hum Reprod Update 8, 111116.
Wilton L (2002) Preimplantation genetic diagnosis for aneuploidy screening in early human embryos: a review. Prenat Diagn 22, 312318.
Submitted on August 31, 2004; accepted on September 10, 2004.