Hum. Reprod. Advance Access published online on June 24, 2008
Human Reproduction, doi:10.1093/humrep/den241
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DEBATE CONTINUED |
What next for preimplantation genetic screening? A clinician’s perspective
VKF American Hospital of Istanbul, Assisted Reproduction Unit, Guzelbahce Sokak No. 20, Nisantasi, Istanbul 34365, Turkey
1 Correspondence address. Tel: +90-212-3112000; Fax: +90-212-3112339; E-mail: kyakin{at}yahoo.com, kayhany{at}amerikanhastanesi.com.tr, kyakin{at}hotmail.com
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Abstract |
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 Top Abstract Scientific validity of PGS...Are we satisfied with...Are the results of...References |
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Preimplantation genetic screening (PGS) is a technique that has been introduced into clinical practice to screen and eliminate aneuploid embryos from transfer with the intention to improve implantation rates and decrease pregnancy wastage. Although practiced widely throughout the world, PGS unfortunately has been adopted without being subjected to rigorous scientific validation. Data from recent randomized trials have shed doubt on the efficacy of the procedure when used in women with advanced age, one of the target populations for PGS. Other purported indications for the application of this complicated technique such as recurrent implantation failure and recurrent spontaneous abortion have not been subjected to randomized controlled trials. For the best interest of patients, we feel it is timely for a debate regarding the efficacy and safety of PGS.
Key words: preimplantation genetic screening/aneuploidy/advanced maternal age/recurrent implantation failure/recurrent spontaneous abortion
In view of the debate fuelled by the recent report of Mastenbroek et al., the clinicians are more than ever faced with uncertainties regarding the safety and efficacy of preimplantation genetic screening (PGS) as a diagnostic test for selecting the genetically normal embryo endowed with the highest potential for implantation. It is time to reconsider whether PGS has lived up to its expectations and whether we as clinicians should be offering this test to our patients in the absence of evidence attesting to its safety and efficacy. This became very obvious after the report published by Mastenbroek et al. (2007
). The authors should be commended for undertaking such a randomized study, one that has been curiously lacking, despite the wide application of PGS for over a decade. What they showed us was that PGS did not significantly improve the outcome, moreover, even had a detrimental effect on the outcome of assisted reproduction treatment in couples with advanced maternal age (AMA). The study by Mastenbroek was immediately put under scrutiny and heavily criticized by several authors who have pioneered the technique (Cohen and Grifo, 2007; Munne et al., 2007b,c; Kuliev and Verlinsky, 2008). We should be thankful to them for triggering the already-late discussion on the indications, guidelines, technical standards, safety and efficacy of PGS.
Mastenbroek et al. were not the first to claim that PGS may not be as beneficial as expected. In the first randomized controlled trial (RCT) published on the subject, Staessen et al. (2004) also showed that AMA patients undergoing ART treatment did not benefit from the application of PGS. These authors were similarly criticized by the same groups (Cohen and Munne, 2004). Criticism directed at these two studies can be summarized under four points: (i) poor embryo biopsy technique, (ii) embryo damage by double blastomere biopsy, (iii) suboptimal FISH technique and (iv) poor embryo culture/laboratory conditions.
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Scientific validity of PGS as a diagnostic test |
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TopAbstractScientific validity of PGS...Are we satisfied with...Are the results of...References |
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Despite the fact that PGS is being performed by a substantial number of IVF laboratories around the world, so far there has been only five randomized studies aimed to determine its safety and efficacy (Staessen et al., 2004
; Stevens et al., 2004; Mastenbroek et al., 2007; Jansen et al., 2008; Mersereau et al., 2007). PGS is not a unique example of unproven interventions in assisted reproduction. The quality of ovarian reserve testing has never been established for pregnancy (Broekmans et al., 2006), and IVF itself was offered for non-tubal disease for over two decades before the first trial demonstrated its effectiveness (Hughes et al., 2004).
There seems to be a general consensus among professionals that the use of preimplantation genetic diagnosis (PGD) is acceptable for medical indications if a high risk of a serious genetic disorder exists (Soini et al., 2006). European Society of Human Reproduction and Embryology PGD Consortium reported that between the years 1999 and 2004, over 4000 PGD cycles were performed for monogenic diseases, sex-linked diseases and balanced translocation carriers (Sermon et al., 2007). On the other hand, 
4800 PGS cycles were performed with the aim to improve the outcome of ART.
PGS is expected to improve the outcome of ART in couples at high risk of aneuploidy via increasing implantation and livebirth rates and decreasing the incidence of spontaneous abortions, trisomic pregnancies and multiple pregnancies (Munne et al., 2002). Current PGS indications can be listed as (i) AMA, (ii) recurrent early pregnancy loss, (iii) recurrent implantation failure and (iv) severe male factor infertility. In addition, history of an aneuploid conception, poor embryo quality and abnormal gamete cell morphology were also proposed as indications for PGS in several reports (Harper et al., 2008).
In the clinical setting, there are many questions without answers. As clinicians who are faced with the couples’ questions and expectations, can we comfortably offer PGS to improve the outcome of ART? Are we content with the scientific evidence present in the literature? Which studies should lead us to make sensible decisions; RCTs or descriptive data coming from currently PGS performing centers?
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Are we satisfied with the present data on PGS? |
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TopAbstractScientific validity of PGS...Are we satisfied with...Are the results of...References |
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PGS data in the literature are mainly based on retrospective cohort studies (level II evidence) or case series (level III evidence). The majority of the reports are observational data presenting the authors’ own experiences of PGS in selected group of patients. What most of these studies show is that (i) the rate of aneuploidy is higher in embryos derived from couples who have risk factors such as advanced female age, recurrent pregnancy loss or recurrent implantation failures (Gianaroli et al., 1997a
,b, 1999; Munne et al., 1999, 2003, 2005, 2006; Kuliev et al., 2002; Pehlivan et al., 2003; Rubio et al., 2003, 2005; Ferraretti et al., 2004; Verlinsky et al., 2004, 2005; Platteau et al., 2005, 2006), (ii) the rate of aneuploidy increases in parallel with the number of FISH probes used for diagnosis (Gianaroli et al., 2005; Baart et al., 2006), (iii) embryo morphology and development are significantly correlated with the ploidy status of the embryo (Magli et al., 2007; Munne et al., 2007a) and (iv) embryo morphology or blastocyst culture cannot totally eliminate aneuploid embryos (Sandalinas et al., 2001; Munne et al., 2007a,b,c,d).
Comparative studies are mostly retrospective, non-randomized or employ inappropriate controls (matched patient groups, theoretical modeling, mathematical risk calculations, previous pregnancy history, gender selection cases, etc.). The majority of the studies come from a few clinics, nearly all underlining the efficacy of PGS, whereas only a few contradictory reports have been published so far with a following stream of critics and commentaries. Data integrity is also questionable particularly due to losses from consultation to follicle aspiration and embryo transfer. When the data are analyzed according to the ‘intention to treat’ principle, suggested benefits disappear. In the case series reported by Verlinsky et al. (2004), the clinical pregnancy rate that was stated as 23.3% per transfer decreased to 19% when outcome per initiated cycle PGS was analyzed (722 pregnancies in 3747 PGS cycles). Similarly, the suggested significant difference between pregnancy rates per embryo transfer in PGS and control groups (39% versus 31%) was not valid when rates were calculated per cycle (30.1% versus 29.8%) (Gianaroli et al., 1999). Publication bias may also result from negative studies being less likely to be published.
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Are the results of the present RCTs reliable? |
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TopAbstractScientific validity of PGS...Are we satisfied with...Are the results of...References |
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Of the randomized studies that were performed, the first prospectively analyzed 289 oocyte retrieval cycles from 400 screened patients whose embryos were tested for aneuploidy with a double blastomere biopsy using seven FISH probes (13, 16, 18, 21, 22, X and Y) (Staessen et al., 2004
). There was no significant increase in implantation (17.1% for PGS versus 11.5% for controls) or ongoing implantation rates (16.5% for PGS versus 10.4% for controls). However, less than expected success of PGS was attributed to a higher number of embryos transferred in the control group (2.8 versus 2.0) and the possible adverse effect of double blastomere biopsy.
In the study of Stevens et al. (2004), 39 patients >35 years of age having at least five good quality embryos on Day 3 were analyzed in a randomized setting. Twenty-one patients were assigned to PGS and 18 were assigned to the control group. In this small group of patients with a relatively favorable prognosis, PGS did not show any benefit in terms of increasing implantation or ongoing pregnancy rates. However, these data were not published in a peer reviewed journal.
The third double-blind controlled trial randomized 408 women with AMA having no previous IVF failures to undergo up to three cycles of IVF with or without PGS (Mastenbroek et al., 2007). A maximum of two embryos was transferred on Day 4 after fertilization. In the PGS group, a single blastomere was biopsied and FISH analysis was performed using probes for chromosomes 1, 13, 16, 17, 18, 21, X and Y. If no chromosomally normal embryo with adequate morphology was available in women assigned to the PGS group, undiagnosed embryos were transferred. Overall, the study compared outcomes observed in 434 PGS cycles with 402 control cycles. Cumulative ongoing pregnancy and livebirth rates in the PGS group (25% and 24%, respectively) were significantly lower than those observed in the control group (37% and 35%, respectively). This study was criticized mainly for inadequate probe selection, possible biopsy-induced embryo damage, a low average number of embryos biopsied and a high rate of undiagnosed embryos (Cohen and Grifo, 2007; Kuliev and Verlinsky, 2008).
The fourth RCT published recently was an interim analysis on 53 blastocyst transfer cycles which were randomized into PGS and non-PGS groups. The study showed that in young patients with expected good prognosis, there was a non-significant increase in pregnancy (50% versus 32%), implantation (25.4% versus 20.0%) and livebirth rates (39.3% versus 29.2%) in PGS cycles compared with controls (Mersereau et al., 2007).
The latest study is a randomized clinical trial of single blastocyst transfer following trophectoderm biopsy and PGS in young infertile women <38 years of age (Jansen et al., 2008). Trophectoderm biopsy and FISH for chromosomes 13, 18, 21, X and Y were performed on Day 5 or 6 in 55 patients who were assigned to the PGS group. Zonal opening without embryo biopsy was performed in 46 patients who were assigned to the control group. In contrast to the a priori hypothesis that PGS improves the outcome of IVF, pregnancy rates following single embryo transfer were similar in both groups (45.5% in the PGS and 60.9% in the control group, P = 0.16). Additionally, in contrast the hypothesis that PGS decreases the incidence of spontaneous abortions, livebirth rates were significantly lower in the PGS group compared with the control group (35.7% versus 58.7%, P = 0.03). The authors also interestingly noted that livebirth rates in the PGS group were lower than 554 patients who did not participate in the study while they were eligible and had single blastocyst transfer without any embryo manipulation (35.7% versus 48.9%, P = 0.09), but the difference was not statistically significant.
In five trials involving 946 patients, differences between implantation rates of PGS and control patients were 5.6%, 12% and 5.4% in the favor of PGS (Staessen et al., 2004; Stevens et al., 2004; Mersereau et al., 2008). On the other hand, the differences were 3.0% and 19.4% in the favor of the control group in the other two studies (Mastenbroek et al., 2007; Jansen et al., 2008). In three trials reporting livebirth rates, for 507 patients, differences between PGS and control patients were 11% and 2.3% in the favor of the control group (Mastenbroek et al., 2007; Jansen et al., 2008) and 10.1% in the favor of the PGS group (Mersereau et al., 2008).
Negative results were attributed by proponents of PGS to poor embryo biopsy and FISH techniques, suboptimal culture conditions and transfer technique not suitable for biopsied embryos. Munne et al. summarized briefly how an optimal PGS system should be and stressed the fact that suboptimal techniques may decrease the efficacy of the procedure (Munne et al., 2007c). Although standardization and optimization of the technique should be implemented for PGS laboratories worldwide, it should be stressed that randomized comparison of technical issues is lacking.
The rate of the undiagnosed embryos must also be taken into consideration. In the Mastenbroeck study, the rate of undiagnosed embryos was higher than other series (20% versus ESHRE’s 14%). Diagnostic errors will inevitably compromise the efficacy of PGS. Undiagnosed embryos may be rescued by the technique suggested by Colls et al. (2007).
One of the major concerns is potentially harming the embryo by removing two blastomeres for FISH analysis. The lack of any positive effect of PGS in RCTs that reported no benefit was attributed to the detrimental effect of the loss of more than one blastomere (Cohen and Grifo, 2007;Cohen et al., 2007). However, this notion was challenged by a recent report by Goossens et al. who showed that although removal of two blastomeres significantly decreased the likelihood of blastocyst formation compared with removal of one blastomere, the implantation rate of the embryos did not differ significantly as similar delivery rates were achieved in both groups (Combelles, 2008; Goossens et al., 2008).
Are the indications well-set? Is there any scientific evidence proving the efficacy of PGS for different indications? Is there any subgroup of patients who would really benefit from the application of this technique?
The rate of chromosomally normal embryos decreases with advancing maternal age (Gianaroli et al., 2005; Munne et al., 2007a). Since it is not possible to totally eliminate chromosomally abnormal embryos by the assessment of their morphological characteristics or cleavage patterns, the only option remaining for selection of the euploid embryo would be PGS (Munne et al., 2005, 2007a,d). It is logical to assume that couples with AMA would be the ideal subgroup who would benefit from the application of this technique. Retrospective case series and descriptive reports suggest an increase in pregnancy and implantation rates as well as a reduction in trisomic pregnancies (Munne et al., 2006). Although it is plausible that certain group of patients or couples with certain characteristics may benefit from the application of PGS combined with ART treatment, RCTs performed in women of advanced reproductive age do not support these findings. Munne et al. (2003) showed that in order to improve the clinical outcome, couples should have at least eight or more fertilized oocytes and no history of previous implantation failures. It is possible that older age women with a well-preserved ovarian reserve may benefit from PGS.
Recurrent implantation failure (RIF) is a poorly understood complex phenomenon of which the etiology is most probably multifactorial and at the cellular level (Urman et al., 2005a,b). A recent review on RIF summarized the assumed etiologies as defective embryonic development (genetic abnormalities, zonal hardening and suboptimal culture conditions), decreased endometrial receptivity (uterine cavity abnormalities, thin endometrium, altered expression of adhesive molecules, immunological factors and thrombophilias) and multifactorial effectors (endometriosis, hydrosalpinges and suboptimal ovarian hyperstimulation) (Margalioth et al., 2006). Embryonic aneuploidy may be responsible for RIF in certain couples; however, if this is the etiologic factor in a minority of cases, published trials to date might have been short of reaching the required sample size to demonstrate the alleged beneficial effect of PGS (Urman et al., 2005a,b). The only randomized trial reported so far evaluated only 19 patients with RIF and showed no benefit in the clinical outcome (Werlin et al., 2003). There are contradicting reports in the literature regarding the efficacy of PGS when applied in couples with RIF (Gianaroli et al., 1999; Kahraman et al., 2000; Pehlivan et al., 2003, Munne et al., 2003; Caglar et al., 2005; Harper et al., 2006). In a multivariate logistic regression analysis, Platteau et al. (2006) showed that in order to have a high probability of having an embryo transfer after PGS for RIF, the patient should have at least 10 metaphase II and 8 normally fertilized oocytes, as well as six embryos for biopsy.
Recurrent spontaneous abortions (RSA) also represent a heterogeneous group of patients. When karyotype analysis of the abortion material confirms a chromosomally abnormal fetus, it is likely that PGS may help to solve the problem. However, in many cases, the etiology for RSA cannot be defined (Stephenson and Kutteh, 2007). Retrospective case series and comparisons with mathematical risks, previous pregnancies or inappropriate control groups suggest a benefit from PGS (Munne et al., 2005; Rubio et al., 2005); however, there is no convincing scientific evidence showing a significant increase in the ongoing pregnancy and delivery rates following PGS for RSA.
Similarly, no scientific evidence is present for indications like severe male factor (SMF) infertility. There are reports presenting personal experience in arbitrarily selected patient groups (Kahraman et al., 2000; Yak
n et al., 2001; Donoso et al., 2006; Dubey et al., 2008). These show a high risk of aneuploidy in embryos derived form the fertilization of oocytes with spermatozoa from men with severe seminal defects. The use of testicular spermatozoa may also lead to a higher rate of chromosomally abnormal embryos (Silber et al., 2003; Platteau et al., 2005).
Despite the limitations, RCTs are considered to be the most reliable source of evidence, but the vast majority of the data on PGS is based on descriptive reports, and retrospective or non-randomized studies. The rate of aneuploidy was found to be higher in patients with AMA, RIF, RSA and SMF, but there is no scientific evidence that selecting embryos to be transferred by PGS improves livebirth rates in these groups of patients. Unfortunately, no RCTs have been published by the groups that cite their experience as evidence of the value of PGS. There is an urgent need for reliable data.
Do the present data convince us that PGS is backed up with reliable scientific evidence to readily serve our patients?
This is the main question and is difficult to answer. It is worth mentioning that currently the American Society for Reproductive Medicine does not advocate the routine use of PGS for the commonly proposed indications (The Practice Committee of the American Society for Reproductive Medicine and the Practice Committee for the Society of Assisted Reproductive Technology, 2007). PGS is a promising technique and after 15 years of experience needs to be validated by studies of high scientific rigor. It is not easy to perform a randomized trial evaluating PGS in poor prognosis patients such as with recurrent failed implantations; mainly due to couples’ expectations of a new and different treatment as well as ethical concerns (Platteau et al., 2006; Soini et al., 2006; Ankum et al., 2008). As first priority, as clinicians, we have to set our level of expectations from PGS. To be considered truly effective, the rise in the pregnancy rate with PGS should be as much as 20% and that difference would not require a very large trial.
Despite difficulties in recruiting patients, well-designed RCTs in the future will establish the validity of PGS. ESHRE with its easy access to many PGS performing centers is already aware of the ongoing debate and announced a forthcoming multicenter RCT (Harper et al., 2008). Future RCTs must address all aspects of PGS, including indications, patient selection, benefit to be expected in different patient subgroups, potential adverse effects of embryo biopsy, probe choices, fixation, culture conditions and even embryo transfer techniques. Until then patients should be counseled openly about the significant lack of data attesting to the efficacy of the technique.
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