Original- und Übersichtsarbeiten ó Schwerpunkt: Kontroversen in der Kardiologie óó Pro & Contra: Therapie des Vorhofflimmerns Die Ablationstherapie wird der neue Goldstandard LARS LICKFETT, BONN1 Abstract óóóó Vorhofflimmern ist die häufigste anhaltende Herzrhythmus- störung. Die Prävalenz, die in der Gesamtbevölkerung bei 0,4—1% óó Die Indikation zu den Sinusrh
Bardzo tanie apteki z dostawą w całej Polsce kupic viagra i ogromny wybór pigułek.
Jacques.testart.free.frHuman Reproduction vol.13 no.4 pp.783–788, 1998
Safety of embryo cryopreservation: Statistical facts and artefacts
Episcientific aspects of the epigenetic
environmentally induced disturbance (Walker et al., 1996).
factors in artificial procreation
Nevertheless it is important to note that adult liveweightsappear not to be affected and birthweight appears not to be an Jacques Testart
inheritable trait. In contrast, certain epigenetic events in theearly mouse embryo can affect the adult phenotype; in nucleo- INSERM Unite´ 355, 32 rue des Carnets, 92140 Clamart, cytoplasmic hybrids, transcriptional repression of certain genes and Laboratory for Medically Assisted Procreation, has been observed as well as mouse growth deficiency resulting American Hospital of Paris, 63 Boulevard Victor Hugo, in reduced adult body weight (Reik et al., 1993).
The point is that these experimental results were reported This debate was previously published on Webtrack on at a time when MAP was already responsible for Ͼ100 000 human births. Although IVF, embryo transfer and embryofreezing–thawing procedures seem unable to induce anomalies For 20 years artificial methods for helping sterile couples to in babies and be capable only of transmitting parental anomalies procreate have been expanding rapidly. In addition to hormonal (notably the genetic anomalies which are frequent in male treatments for induction of numerous mature oocytes at each infertility treated by ICSI), continued investigations in animals stimulated menstrual cycle, laboratory techniques have been are legitimate. This cautious approach is especially important proposed, including principally in-vitro fertilization (IVF), because humans are long-lived mammals, with late puberty, which may include sperm microinjection into the oocyte and no babies have yet been born to a man or woman conceived (ICSI), embryo culture in medium alone or in co-culture with feeder cells, and embryo cryopreservation. These artificial So, looking for normality in newborns does not suffice and procedures have to be analysed, not only with respect to their recent studies demonstrating, for example, the capacity to clinical efficacy (percentage of successful attempts) but also reproduce and have normal offspring of mice born following in terms of their eventual impact on various aspects of human immature sperm injection (Kimura and Yamagimachi, 1995), life. In addition to potentially altering the health of patients or are welcome. Similarly, studies on the future of animals born their offspring, these techniques may have economic, social from freeze–thaw embryos are of interest for embryologists and psychological consequences. Animal experiments are and physicians involved in MAP. However the results of such necessary prior to the clinical application of any new technique.
studies are potentially disruptive in that they could seriously However their results are only indicative since there are species disturb parents who have already benefitted from MAP or specific factors and extrapolations to humans are more or less those who intend to, not to mention the political and ethical tentative. Moreover experimental animals are usually healthy authorities. For those reasons the design of such studies and whereas medically-assisted procreation (MAP) techniques con- the analysis of their results must leave no place for ambiguity cern individuals with abnormal performances stemming at times from genetic alterations which may interfere with off-spring characteristics.
Although several studies reveal lower developmental rates The case of embryo freezing
for IVF and cultured mammalian embryos (Massip et al., Several major series of frozen–thawed embryo transfers have 1984), no anomalies have been reported, even with frozen– now been carried out. The French national registry (FIVNAT, thawed embryos. The only differences found between experi- 1996) gives us the opportunity to compare Ͼ15 000 embryo mental and control animals were the higher birthweight of transfers following freezing and nearly one hundred thousand certain newborns in bovines produced by IVF (Behboodi et al., transfers of fresh embryos. From these data only transfers of 1995) and the decreased viability of bovines or ovines in case single embryos are summarized in Table I.
of in-vitro procedures or nuclear transfer (Willadsen et al., Significant differences were found for several parameters.
1991). In fact, enhanced fetal growth can result from in- Firstly the pregnancy rate was lower after transfer of a frozen vitro culture of embryos, asynchronous embryo transfer, or embryo, as could be anticipated given that only two out three progesterone treatment of the mother soon after ovulation.
frozen embryos survive the damage associated with freezing There is evidence to suggest that cell lineage differentiation and thawing procedures (Testart et al., 1987). However, from in the manipulated embryo is altered, resulting in preferential the time of implantation, pregnancies induced with a frozen allocation of cells to the trophectoderm and aberrant fetal embryo were no longer at a disadvantage compared with those growth with a larger than normal placenta. Changes in the induced with a fresh embryo. On the contrary, frozen embryo regulation of early gene expression could result from such single pregnancies were subject to fewer medical problems European Society for Human Reproduction and Embryology J.Testart
Table I. Comparative results of fresh and frozen–thawed embryo transfers (from FIVNAT, 1996)
Percentage pregnancies/transfers (one embryo) Percentage pathologies in single pregnancies: **Significant difference (P ); NSϭ not significant.
that, without cryopreservation procedures, the potential of Table II. Various relationships in a study on the long-term effects of mouse
supernumerary embryos could not be exploited.
embryo freezing (from Dulioust et al., 1995) Although no differences have been reported between children born from fresh versus frozen embryos (Olivennes et al.,1996), it is not possible to ascertain whether no differences will be found in the future. In the light of a study involving mouse embryos (Dulioust et al., 1995), we can anticipate epigenetic effects due to freezing and that these will be observed only in adults or in very old animals. As observed by Wood (1997) certain aspects of the experimental design of this study are a cause for concern. Notably the outbred foster mothers provided non-uniform uterine environments that could have contributed to the observed differences. Apart from this there are other possible biases which could also become increasingly common in published scientific papers.
ϩ ϭ significant; – ϭ not significant.
Table II summarizes the results published by Dulioust et al. (1995). They observed the statistical effects of embryo freezingon mouse behaviour, mandible morphometry and weight. Sur- Table III. Number of studied data to assess the effects of mouse embryo
prisingly, the weight differences emerged only in very old mice.
freezing (from Dulioust et al., 1995) Moreover this phenomenon was not observed in females and it occurred in males of only one of the two tested strains. As shown in Table II, similar or even more dramatic differences were foundby comparing groups of control mice, from non frozen embryos: Preweaning development
2 genotypes ϫ 2 sexesϫജ9 criteria
the studied parameters differed depending on both mouse sex Behaviour
and genotype. Given these conditions it becomes less clear that 2 genotypes ϫ 2 sexes ϫ 4 periodsϫജ5 tests cryopreservation procedures have an epigenetic effect.
2 genotypes ϫ 2 sexesϫജ11 measurements
Studies involving multiplication of comparisons lead inevit- ably to the detection of statistical differences between groups drawn from the same population. For example, given rejection of the null hypothesis at the typical 5% probability level, compar-ison of two experimental groups from the same homogeneous and the newborns were in better condition, with higher weight population with respect to 100 parameters will reveal differences at birth. This could be explained by the greater age of frozen embryo recipients and the fact that fresh embryo transfer was Returning to the Dulioust et al. (1995) study, numerous data often the origin of a first pregnancy. From the above study obtained in mice grown from frozen versus control embryos, and all recently published series it appears that the clinical were compared (Table III). By accumulating the parameters risk of freezing human embryos is only to slightly decrease studied, at least 172 different data pairs were compared and this the pregnancy rate. Complementing this observation is the fact may account for the discovery of certain differences. Moreover Safety of embryo cryopreservation
ically valid, artifactual differences between experimental andcontrol births, while the abuse of statistics and absence of con-firmatory experiments may reveal false differences.The recentavailability of automatic recording of experimental results,coupled with rapid, computerized data analysis in the search forstatistical differences, increases the chances of finding resultsgood enough for publication but not confirmation: the episcient-ific effect.
In my opinion, a replica of the Dulioust et al. (1995) experi- ment, with exactly the same procedures and measures, and eventhe same research team, would lead to the demonstration of othereffects of freezing, different from those already reported. Byplaying with statistics, several of my colleagues and myself havebeen able to find correlations between the pregnancy rate afterIVF/embryo transfer and such vitally significant parameters asthe first letter of the patients names or the position of the sun or Figure 1. Hypothesis for a selection bias in artificial procreation.
moon at the time of egg recovery. Imposition of two conditionson experimental research practises may limit misinterpretations.
it is well known that most published papers do not relate all Firstly, rather than a politics of fishing for significant differences the measures recorded, selecting only those revealing statistical with a sort of statistical net, research destined for publication differences. For example, in the paper under discussion, the should involve hypothesis testing. These hypothesis may be mean weight of the mice was indicated in two mouse strains, for based on rational considerations. They may also be empirical, males and females, and at three different ages. One can postulate resulting from the sort of statistical fishing practised by Dulioust that the weight of the mice was measured at other ages, giving et al. (1995). This is the second point: the production of such more chances of finding significant differences in the abundant empirical hypotheses is a legitimate and laudable activity. How- ever they remain to be tested and, perhaps, confirmed. Until While it is true that other studies suggest that the increased these simple rules are respected, we can expect the epigenetic weight of in-vitro derived calves is a reproducible effect of effects associated with embryo manipulation to be confounded embryo manipulations (Behboodi et al., 1995; Walker et al., with the episcientific effects associated with the unfortunately 1996; Kruip and den Daas, 1997), they do not suffice to demon- apt dictum: ‘publish or perish’. strate that the anomaly arises from the procedure itself. Theselection of embryos of different genotypes from a non-homo-geneous pool may well involve a bias. Such biased selection may References
be innate in human artificial procreation procedures (Figure 1).
Behboodi, E., Anderson, G., Bondurant, R. et al. (1995) Birth of large calves that developed from in vitro-derived bovine embryos. Theriogenology, 44,
From 100 recovered oocytes we currently obtain Ͼ50 embryos which give rise to about five babies. Although we are unable to Dulioust, E., Toyama, K., Busnel, M.C. et al. (1995) Long-term effects of embryo discriminate between different mature oocytes, it is obvious freezing in mice. Proc. Natl. Acad. Sci. USA, 92, 589–593.
that they have different characteristics even where they have FIVNAT (1996) Bilan des transferts d’embryons congele´s de 1987 a` 1994.
Contracept. Fertil. Sexual., 24, 700–705.
comparable spontaneous developmental potential. It is possible Kimura, Y. and Yanagimachi, R. (1995) Mouse oocytes injected with testicular that the artificial procedures, for example freezing, disfavour spermatozoa or round spermatids can develop into normal offspring.
certain oocytes or embryos, here of types A and B (see Figure Development, 121, 2397–2405.
Kruip, Th. and den Daas, J.(1977). In vitro produced and cloned embryos: effects 1), but are without effect on other oocytes, namely types E and on pregnancy, parturition and offspring. Theriogenology, 47, 43–52.
D in the example. Under such conditions, the babies born come Massip, A., Van der Zwalmen, P., Puissant, F. et al. (1984) Effects of in vitro mostly from a particular cohort of oocytes. They may have fertilization, culture, freezing and transfer on the ability of mouse embryo to particular characteristics, such as a different mean weight, com- implant and survive. J. Reprod. Fertil., 71, 199–204.
Olivennes, F., Schneider, Z., Remy, V. et al. (1996) Perinatal outcome and pared with babies born following natural procreation but such follow-up of 82 children aged 1–9 years and conceived from cryopreserved differences have been probably selected, rather than induced, by embryos. Hum. Reprod., 11, 1565–1568.
the artificial procreation procedures. In the Dulioust et al. (1995) Reik, W., Romer, I., Barton, S. et al. (1993) Adult phenotype in the mouse can study the effect of mouse embryo cryopreservation on prewean- be affected by epigenetic events in the early embryo. Development, 119,
ing development, when significant, almost exclusively con- Testart, J., Lassalle, B., Belaisch-Allart, J. et al. (1987) Human embryo viability cerned one of the two studied genotypes (C3D2). On the contrary related to freezing and thawing procedures. Am. J. Obstet. Gynecol., 157,
the weight increase between 39 and 67 weeks concerned the Walker, S., Hartwich, K. and Seamark, R. (1996) The production of unusually other genotype (B6CBA) as though freezing–thawing procedures large offspring following embryo manipulation: concepts and challenges.
were able to select different individual mice according to the Theriogenology, 45, 111–120.
Willadsen, S., Janzen, R., McAlister, R. et al. (1991) The viability of late morulae In conclusion, we postulate two ways in which the effects of and blastocyts produced by nuclear transplantation in cattle. Theriogenology,
the diverse MAP procedures lend themselves to misinterpreta- Wood, M.J.(1997) Embryo freezing: is it safe? Hum. Reprod., 12 (Natl. Suppl.),
tion. The selective effect (Figure 1) could explain certain statist- M.Ludwig et al.
No impact of cryopreservation and
after IVF or IVF/ICSI (2.1 and 2.4 respectively) and frozen– thawing on embryo developmental
potential – one more example for the
problems of retrospective,
Experience from cycles with threatened OHSS
The second group of studies included those with cycles, inwhich all embryos have been frozen, due to threatened OHSS Michael Ludwig1, Safaa Al-Hasani,
or other problems. In all of these studies but one (Awonuga Ricardo Felberbaum and Klaus Diedrich
et al., 1996) the clinical pregnancy rate and live birth rate Department of Gynecology and Obstetrics, Medical were satisfactory, and the authors were convinced, that this University of Lu¨beck, Ratzeburger Allee 160, 23538 could be a real treatment alternative for their patients in 1To whom correspondence should be addressed In the analysis of cycles at high risk for OHSS from This debate was previously published on Webtrack on Awonuga et al. (1996) the clinical pregnancy (35 versus 17%; P Ͻ 0.03) and the live birth (27 versus 12%; P Ͻ 0.05) ratesin patients receiving fresh embryo transfer was significantly In his debate article Testart (1998) claims that the statistical higher than in those who had elective cryopreservation of all significance between pregnancy rates in transfer cycles using embryos. However, the study was not prospectively random- frozen–thawed embryos and fresh embryos does not reflect ized. Therefore a selection bias of patients cannot be excluded.
the different implantation rate of those embryos. He proposed A pregnancy rate of 38.6% was achieved by Shaker et al. that other factors are present, which might explain the obvious (1996) under similar conditions in 13 patients. In another study difference in success rates, like the rate of high quality embryos among 23 patients at increased risk of OHSS, 15 clinical and the number of transferable embryos.
pregnancies after transfer of two to three frozen–thawed The question is difficult to answer from the general experi- embryos in natural cycles, with a 32.6% pregnancy and 22.7% ence in freeze–thaw cycles, because the mentioned problems implantation rate could be achieved by Tiitinen et al. (1995).
will always bias those data. In our mind, there are three In 96 patients a pregnancy rate after transfer of frozen–thawed possible ways to find a reliable answer: (i) the German embryos of 25.2% per transfer, with a cumulative pregnancy experience from the transfer of frozen–thawed oocytes at the rate of 40.6% was reported by Pattinson et al. (1994). Wada pronuclear stage, which cannot be selected by morphology; et al. (1992) reported their experience from 78 patients, who (ii) the experience from cycles, in which all embryos are had had their embryos frozen and underwent 125 frozen– frozen to avoid serious medical problems for the patient, e.g.
thawed embryo replacements. An implantation rate of 11% ovarian hyperstimulation syndrome (OHSS) or due to negative and pregnancy rates of 19 and 29% was achieved in cycles predictors of success; and (iii) prospective, randomized studies, with either hormonal replacement therapy or hormonal stimula- to compare directly fresh and frozen–thawed embryo transfers.
tion for the frozen–thawed transfers. Finally, Frederick et al.
(1995) also reported on a retrospective series of 36 patients,whose embryos were all cryopreserved, due to threatened German experience with cryopreservation of oocytes at the
OHSS or the absence of an optimal sonographic endometrial pronuclear stage
pattern at the day of transfer. After thawing a pregnancy rate It is well known, that embryo quality can be assessed by of 33.3% and a live birth rate of 28.6% per cycle was achieved.
morphological criteria (Staessen et al., 1995), but that oocytes The implantation rate per embryo was 9.1%, with an average at the pronuclear stage (PN) can not. To date we do not know number of 4.2 embryos replaced per cycle.
any publication, which deals with morphological criteria of All but one of these publications show that there was no PN, which are helpful to assess the implantation chance.
harm to the embryos, with regard to the capacity to implant.
Since in Germany, due to legal restrictions, only PN can be However, prospective randomization of fresh transfer versus cryopreserved, a selection bias on implantation rates is not all cryopreserved embryos has been carried out in only one possible. We reported recently a pregnancy rate of 17% and study (Shaker et al., 1996). Since these authors reported no 18% per transfer after in-vitro fertilization (IVF) and IVF/ pregnancies in fresh transfer cycles with threatened OHSS, intracytoplasmic sperm injection (ICSI) respectively, for and a pregnancy rate of 38% after freezing–thawing, these frozen–thawed PN (Al-Hasani et al., 1996). This is obviously data are not really representative of day-to-day experience.
lower than the pregnancy rate after the transfer of fresh, inthe PN stage, selected embryos (26% per transfer).
Experience from prospective, randomized studies
The German IVF Registry (Deutsches IVF Register, 1996), Selick et al. (1995) designed a prospective study, in which pooled which includes 2452, 11969, and 14866 transfer cycles for fertilizable oocytes from young oocyte donors were allocated frozen–thawed PN, IVF and IVF/ICSI cycles, confirms a lower after fertilization either to fresh or frozen–thawed embryo trans- pregnancy rate per transfer for frozen/thawed PN cycles fer cycles. This study was controlled for male, oocyte and endo- (10.4%), compared with fresh embryo transfers after conven- metrial factors. A total of 87 transfer cycles were included in tional IVF or IVF/ICSI (24.1 and 23.7% respectively). The this analysis. Implantation rate per embryo and delivery rate per mean number of replaced embryos was similar in fresh cycles transfer of 12.6 and 26.2% respectively, from fresh transfer Safety of embryo cryopreservation
cycles were not significantly different when compared with a procedure on human embryos seems to be wrong. However, per embryo implantation rate of 8.1 % and per transfer delivery the numbers in the cited studies were almost always very low.
rate of 13.3% from frozen–thawed transfer cycles. The lower Therefore, to really confirm this thesis, we have to await implantation and delivery rates in the frozen–thawed group were attributed to a statistically significant difference in the number This should teach us once more, that one can rely only on of embryos per transfer, the mean number of cells per embryo, well designed studies, and that retrospective analysis can only and the rate of high quality embryos.
help to raise questions, and not to answer them.
Horn et al. (1997) report on two randomly selected groups of patients. In the first group only two PN were allowed todivide, all other PN were cryopreserved (PN group). In the References
second group, a selection of the two best embryos was done Al-Hasani, S., Ludwig, M., Gagsteiger, F. et al. (1996) Comparison of in the cleavage stage, all other embryos were frozen (EC cryopreservation of supernumerary pronuclear human oocytes obtained after group). The livebirth rate per fresh embryo transfer in the EC intracytoplasmic sperm injection (ICSI) and after conventional in-vitro
fertilization. Hum. Reprod., 11, 604–607.
group (27.4%) was significantly higher than that for the PN Awonuga, A.O., Pittrof, R.J., Zaidi, J. et al. (1996) Elective cryopreservation of group (11.1%). Embryo survival following thawing was similar all embryos in women at risk of developing ovarian hyperstimulation for the PN (74.4%) and EC (77.4%) stages. Although not syndrome may not prevent the condition but reduces the live birth rate.
J. Assist. Reprod. Genet., 13, 401–406.
significant, the livebirth rate following the transfer of thawed Deutsches IVF Register (1996) Jabrbuch 1995. Deutsches IVF Register.
embryos was higher in the PN group (25%) than in the EC group (10.5%). Following one fresh and two freeze–thaw Frederick, J.L., Ord, T., Kettel, L.M. et al. (1995) Successful pregnancy outcome embryo replacements, the observed cumulative viable preg- after cryopreservation of all fresh embryos with subsequent transfer into an
unstimulated cycle. Fertil. Steril., 64, 987–990.
nancy rates were comparable for patients in both the PN (40%) Horne, G., Critchlow, J.D., Newman, M.C. et al. (1997) A prospective evaluation of cryopreservation strategies in a two-embryo transfer programme. Hum.
Reprod., 12, 542–547.
Pattinson, H.A., Hignett, M., Dunphy, B.C. and Fleetham, J.A. (1994) Outcome of thaw embryo transfer after cryopreservation of all embryos in patients at Conclusions
risk of ovarian hyperstimulation syndrome. Fertil. Steril., 62, 1192–1196.
Only the German experience, published by the Deutsches IVF Selick, C.E., Hofmann, G.E., Albano, C. et al. (1995) Embryo quality and Register seem to support the general idea, that cryopreservation pregnancy potential of fresh compared with frozen embryos—is freezing
detrimental to high quality embryos? Hum. Reprod., 10, 392–395.
has a severe impact on the implantation rate of embryos even Shaker, A.G., Zosmer, A., Dean, N. et al. (1996) Comparison of intravenous after exclusion of the possibility for selection. However, these albumin and transfer of fresh embryos with cryopreservation of all embryos data are the result of a retrospective, multicentre database, and for subsequent transfer in prevention of ovarian hyperstimulation syndrome.
Fertil. Steril., 65, 992–996.
are not controlled for embryo quality. Additionally, the impact Staessen, C., Nagy, Z.P., Liu, J. et al. (1995). One year’s experience with elective of different methods and the reliability of the data, have at transfer of two good quality embryos in the human in-vitro fertilization and least to be discussed. Finally, a much better indicator would intracytoplasmic sperm injection programmes. Hum. Reprod., 10, 3305–3312.
be the implantation rate per embryo or PN. However, these Testart, J. (1998) Episcientific aspects of the epigenetic factors in artificial procreation. Hum. Reprod., 13, 783–785.
numbers are not available from the Deutsches IVF Register Tiitinen, A., Husa, L.M., Tulppala, M. et al. (1995) The effect of cryopreservation in prevention of ovarian hyperstimulation syndrome. Br. J. Obstet. Gynaecol., The data from cycles, in which all embryos are cryopreserved 102, 326–329.
Wada, I., Matson, P.L., Troup, S.A. et al. (1992) Outcome of treatment subsequent due mainly to a threatening OHSS, show satisfactory results, to the elective cryopreservation of all embryos from women at risk of the which are in the range of those known from fresh transfers.
ovarian hyperstimulation syndrome. Hum. Reprod., 7, 962–966.
However, these data are not randomized, as are those fromAl-Hasani et al. (1996) and the Deutsches IVF Register (1996).
In conjunction with the results from the cycles, in which all Aspects of epigenetic factors in artificial
embryos are cryopreserved, the prospective studies are of the procreation
greatest importance in answering the question. The lowerpregnancy rate in the EC group after freezing–thawing, and a A.L.Speirs
similar pregnancy rate after freezing–thawing in the PN groupcompared with the fresh transfer in the EC group show, that Reproductive Biology Unit, Royal Women’s Hospital,132 Grattan Street, Carlton, Victoria 3053, Australia in fact the results of transfers after cryopreservation are biased by excluding the best embryos (Horne et al., 1997). Also To whom correspondence should be addressed Selick et al. (1995) reported no detrimental effect of freezing– This debate was previously published on Webtrack onWeb2 on January 27, 1998 as a letter thawing on the implantation and pregnancy rates.
However, since a loss rate of 20–40% due to freezing– For every question there is an answer that is simple, thawing has to be taken into account, and fresh and freeze– straightforward and wrong (H.L.Menken).
thaw cycles differ statistical significantly in the number oftransferable embryos, their cell number and the rate of high Testart (1998) makes a number of points which need frequent quality embryos (Selick et al., 1995), a fresh transfer should emphasis. It is now easier than ever for non-statisticians to do vast numbers of statistical tests looking for statistical The idea of a detrimental effect of the freezing–thawing significance. The discerning reader will look behind the written A.L.Speirs
word and recognize the many unreported non-significant com-parisons inherent in a study design. Dr. Testart alerts us to thiswith regard to the mouse study by Dulioust et al. (1995). Todemonstrate the same effect I reported a study of the letters inthe surnames of pregnant and non-pregnant in-vitro fertilization(IVF) patients (Speirs, 1991). Pregnancy was strongly linkedwith ‘GYN positive’ (having G, Y or N in the surname!) P Ͻ0.01. The naive reader might not realize how readily theundertaking of many statistical tests may be disguised or theway that many comparisons eventually produces a ‘significant’result. This inevitability arises from the very meaning of astatistical P value. Incorrectly rejecting the ‘null hypothesis’because of an impressive P value when samples are tested isdescribed as a type I error.
It should also be recalled that statistical significance implies that an observed difference is unlikely to have arisen bychance. It should not be taken to mean causation. Because itis plausible, Dr. Testart seems to have accepted that thawedembryos produce a lower pregnancy rate than do fresh transfersbecause of the freeze–thaw process. This is by no means theonly explanation. Single embryos transferred fresh will oftenbe the best embryo of several available whereas a singlethawed embryo will not have been selected on this basis. Thethawed embryo will often be single because it is the last oneavailable, even if nothing like the best of those originallyavailable.
Yet another bias could be introduced by looking at who might elect to have a single embryo transferred fresh when sooften many would be available. Some will be couples whoparticularly want to avoid twins because they have alreadybeen successful with past IVF and are returning for one morebaby. Couples with past IVF success have a somewhat betterchance of further pregnancy. It is not entirely the single freshembryo that is better than the average (sometimes final) thawedembryo but their reason for electing to have a single embryotransferred when they (often) had many to choose from.
It is, of course, not possible to know from these data the extent to which any or all of these influences producedthe observed difference between fresh and thawed embryotransfers.
Dulioust, E., Toyama, K., Busnel, M.C. et al. (1995) Long-term effects of
embryo freezing in mice. Proc. Natl. Acad. Sci. USA, 92, 589–593.
Speirs, A.L. et al. (1991) When predictions don’t predict. Aust. N.Z. J. Obstet. Gynaecol., 31, 346.
Testart, J. (1998) Episcientific aspects of the epigenetic factors in artificial procreation. Hum. Reprod., 13, 783–785.
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