Hum. Reprod. Advance Access published online on March 3, 2008
Human Reproduction, doi:10.1093/humrep/den062
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Does confined placental mosaicism account for adverse perinatal outcomes in IVF pregnancies?
1 Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, The Netherlands 2 Department of Clinical Genetics, University Medical Centre, Utrecht, The Netherlands 3 Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, The Netherlands 4 Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
5 Correspondence address. E-mail: b.c.jacod{at}students.uu.nl
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Abstract |
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BACKGROUND: IVF singletons have poorer perinatal outcomes than singletons from spontaneous conceptions. This may be due to the influence of ovarian stimulation on the chromosomal constitution of the embryos which could be translated into localized chromosomal anomalies in the placenta. The aim of this study was to compare the incidence of confined placental mosaicism (CPM) in IVF/ICSI pregnancies and spontaneous conceptions.
METHODS: We conducted a multi-centre retrospective analysis of karyotype results obtained by chorionic villus sampling (CVS), performed due to advanced maternal age (
36 years at 18 weeks of gestation), in the Netherlands between 1995 and 2005.
RESULTS: From a total of 322 246 pregnancies, 20 885 CVS results were analysed: 235 in the IVF/ICSI group and 20 650 in the control group. The mean age of women in both groups was 38.4 years (mean difference –0.08, 95% CI –0.35 to 0.18). Data relating to the fetal karyotype were missing in 143 cases in the control group. When taking into account missing data, the incidence of CPM was lower in the IVF–ICSI group than in the control group, 1.3% versus 2.2% (odds ratio 0.59, 95% CI 0.19–1.85), whereas the incidence of fetal chromosomal anomalies was increased 4.3% versus 2.4% (odds ratio 1.81, 95% CI 0.95–3.42). Neither differences were statistically significant.
CONCLUSIONS: The incidence of CPM is not increased in IVF/ICSI pregnancies compared with spontaneous conceptions. CPM probably does not account for the adverse perinatal outcomes following IVF/ICSI.
Key words: IVF/CPM/perinatal outcomes/CVS/preimplantation genetic screening
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Introduction |
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Almost 30 years after its introduction, IVF now accounts for about 3% of all live births in western countries (Andersen et al., 2007
). Although initial efforts were largely directed towards improving the pregnancy rate from IVF, increasing attention is now being paid to reducing the associated risks and burden of treatment. The negative consequences of the epidemic of multiple pregnancies which resulted from widespread implantation are now becoming clear (Fauser et al., 2005). Moreover, the short-term and possible long-term risks associated with high stimulation protocols have lead to a questioning of current approaches (Edwards, 1999; Fauser et al., 2005). Thanks to new insights and approaches to ovarian stimulation for IVF and improved laboratory technologies, practices are starting to change. Milder hormonal stimulation followed by the transfer of a single embryo is now becoming more widespread, and results to date are encouraging (Thurin et al., 2004; Heijnen et al., 2007). Although the trend of transferring fewer embryos can be expected to reduce perinatal morbidity arising from IVF multiple pregnancies, recent data have indicated that IVF singleton pregnancies are still associated with a greater incidence of adverse perinatal outcomes, such as intrauterine growth retardation, than spontaneous singleton pregnancies (Schieve et al., 2002; Helmerhorst et al., 2004; Jackson et al., 2004).
The reasons behind these observations remain unclear (Dhont et al., 1999; Koudstaal et al., 2000; Schieve et al., 2002). Although subfertile couples may represent a population at increased risk of poor perinatal outcomes, a recent study showed worse outcomes in subfertile couples who conceived with IVF compared with those who became pregnant by other means (Kapiteijn et al., 2006). There is also increasing evidence that ovarian stimulation rather than the IVF procedure itself is the primary cause (Ombelet et al., 2006). IVF has been shown to be associated with a high rate of embryo aneuploidy (Delhanty et al., 1997; Munne et al., 1998; Wells and Delhanty, 2000; Wilton, 2002; Bielanska et al., 2005; Baart et al., 2006). In particular, the rate of chromosomal mosaicism appears to increase following stimulation with exogenous gonadotrophins (Baart et al., 2006). Moreover, the incidence of aneuploidy in Day 3 embryos appears to be related to the level of ovarian stimulation. In a recent study, the incidence of chromosomal mosaicism in Day 3 embryos was reduced following mild versus a conventional stimulation protocol (Katz-Jaffe et al., 2005; Baart et al., 2007).
The clinical significance of early mosaicism is largely unknown but is likely to depend on its persistence in advanced gestation, on the specific chromosome and aberration involved, and on whether it affects embryonic or extra-embryonic cell lines. Chromosomal anomalies present in a proportion of the cells of Day 3 embryos can persist into later gestation in several ways. They can affect either the placenta or embryo, or both, and be present in all cells or in mosaicism. Localized mosaicism in the placenta, termed confined placental mosaicism (CPM), has been associated with intrauterine growth retardation (IUGR) (Kalousek et al., 1991; Lestou and Kalousek, 1998; Wilkins-Haug et al., 2006). The higher frequency of adverse perinatal outcomes such as IUGR in IVF singletons could therefore be due to persistence of chromosomal mosaicism into later gestation.
The aim of this study was to test the hypothesis that increased rates of embryo mosaicism during IVF persist into pregnancy and are revealed as a higher incidence of CPM than that observed in spontaneous pregnancies. This was done by comparing the incidence of CPM determined following chorionic villus sampling (CVS) at 10–14 weeks of gestation in IVF/ICSI pregnancies and spontaneous conceptions.
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Materials and Methods |
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Data pertaining to 8870 IVF/ICSI pregnancies and 313 376 spontaneous pregnancies in older women (
36 years old at 18 weeks of gestation) in the Netherlands between 1995 and 2005 were analysed. The results of all CVS procedures performed at 10–14 weeks gestation in these pregnancies were obtained. In order to avoid a possible referral bias arising from highly scrutinized pregnancies, CVS data performed for other indications were excluded except if, in addition to maternal age, it concerned ICSI. Those pregnancies which had arisen from an IVF or ICSI procedure were identified by analysing the registries of 11 of the 12 IVF clinics in the Netherlands for the corresponding period. Patient information was treated anonymously in accordance with the guidelines of the institutional ethical review board.
The results of the CVS procedure were analysed in all centres using uniform criteria for the definition of CPM based on the findings of large-scale studies (Breed et al., 1991; Ledbetter et al., 1992; Adler, 1994; Hahnemann and Vejerslev, 1997b; Smith et al., 1999). Karyotypes were considered abnormal if 2 or more cells analysed presented the same anomaly or if 3 or more cells presented the same anomaly in the case of a missing autosome. To establish the diagnosis of CPM, both the presence of chromosomal anomalies in placental cells and their absence in fetal material were required. Therefore, when abnormal karyotypes were found and there was a reason to suspect the presence of CPM, cytogenetic information was sought on material of fetal origin, fetal cells from amniotic fluid or cord-blood or tissue biopsy. No confirmatory analysis of fetal material was required in the following cases: 1, non-mosaic structural chromosomal anomaly; 2, non-mosaic trisomy 21; 3, non-mosaic trisomy 18 and 13 if both trophoblastic and mesenchymal cell lines had been analysed, i.e. both short-term (STC) and long-term culture (LTC), or 4, chromosomal anomaly found only in the trophoblast but not in the mesenchymal cells. In situations 1–3, the anomaly is considered to affect the fetus whereas in situation 4, the embryo is considered normal.
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Results |
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A total of 20 885 CVS procedures were performed in the Netherlands during the period 1995–2005 because of advanced maternal age. Of these, 235 were identified as concerning pregnancies following IVF/ICSI. Patients of one of the 12 IVF clinics could not be identified and may therefore have been erroneously classified as spontaneous conceptions. Their influence on the results is, however, negligible as they were estimated to represent <0.1% of the control group. Given those numbers and assuming a CPM rate of 2% in the general population, the study has 80% power to detect a difference in incidence of CPM of 3.8%.
The study and control groups obtained were identical in mean maternal age, although the age distribution differed slightly (Table I) and the presented analyses were therefore corrected for this effect. The technique used to analyse chorionic villus samples differed between the groups: in the IVF–ICSI group, they were less often analysed using one cell line only (STC or LTC) than in the control group. This does not reflect a difference in policy but a different distribution of IVF/ICSI patients and controls over the various centres.
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The incidence of CVS procedures in women whose indication was advanced maternal age was estimated in both groups. In the IVF–ICSI group, this was done by dividing the number of CVS procedures in women aged 36 or more by the number of intact pregnancies at 8 weeks, this being the criteria used routinely to assess the success of an IVF procedure. In the control group, data relating to early ultrasound assessment were lacking and the incidence was therefore calculated by dividing by the number of deliveries in women aged 36 or more. The rate of performing of CVS was found to be low in both groups but significantly lower in the IVF–ICSI group than in the control group; 2.6% versus 6.6% (odds ratio 0.34, 95% CI 0.34–0.44). Evaluation of the policies in terms of invasive prenatal diagnosis of the different centres involved in the study revealed that in most cases (76.4%), counselling given to the IVF–ICSI group on the risks of the procedure did not differ from that provided to women who had spontaneously conceived.
Abnormal karyotypes at CVS were found in a similar proportion in the IVF–ICSI and in the spontaneous conception groups (5.5%, respectively, and 4.6%) (Table II). Of these, about half required further cytogenetic examination of fetal material to investigate the involvement of embryonic cell lines (Fig. 1). This could be performed in all five cases in the IVF/ICSI group, but cytogenetic examination of fetal material was lacking in 143 cases (26.8%) in the control group. Detailed overviews of the anomalies found are provided in Tables III and IV. The number of cases is too low to make statistical comparison between the incidence of the different anomalies between the IVF–ICSI group and controls meaningful. The comparison between the anomalies found in the control group for which follow-up analysis was available and the missing data showed that, in a majority of cases, this concerns non-mosaic trisomy 13 and 18 and sex chromosomal anomalies. This is most likely due to a difference in the policies regarding the need for further cytogenetic testing used in certain participating centres and the unique criteria defined in the current study. The reasons in the remaining cases could, unfortunately, not be established with certainty but may have been due to refusal by the parents, or fetal anomaly on ultrasonic examination compatible with cytogenetic defect or spontaneous abortion before an amniocentesis could be performed without subsequent cytogenetic analysis of the fetus.
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In those cases where fetal karyotype was available, fetal cytogenetic anomalies were observed significantly more frequently in the IVF/ICSI group, 4.3%, than in the control group, 2.1% (odds ratio 2.21, 95% CI 1.16–4.21). In contrast, CPM occurred less often in the IVF/ICSI group (1.3% versus 1.8%), although this difference was not significant. The difference observed in the incidence of fetal anomalies is significant but should be interpreted with caution as cases with missing fetal karyotype data are not included in this comparison. These ‘missing data’ cases probably represent either CPMs or fetal anomalies and as such will influence the incidence found in the control group. To estimate their influence, we considered a first scenario in which the missing data were distributed between fetal chromosomal anomalies and CPM according to the ratio observed in those cases where additional data were available: 75 out of the 143 were thus assumed to be fetal chromosomal anomalies and 68 were CPM. This estimate is supported by the fact that in at least half of the cases, data were considered ‘missing’ according to the criteria of the current study but were assumed to represent fetal anomalies with the clinical consequences thereof in the various centres concerned. On this basis, the incidence of fetal chromosomal anomalies in the control group increased, so that the difference with the IVF/ICSI group was no longer significant (IVF/ICSI group 4.3%, controls 2.4%, odds ratio 1.81, 95% CI 0.95–3.42). Applying this scenario, the incidence of CPM also increased in the control group but the difference with that found in the IVF–ICSI group still failed to reach significance (IVF/ICSI group 1.3%, controls 2.2%, odds ratio 0.59, 95% CI 0.19–1.85). To test the robustness of this conclusion, a second scenario was considered in which all missing data cases were assumed to represent cases of CPM. The incidence of CPM in the control group increased accordingly but once again not enough to reach statistical significance (IVF/ICSI group 1.3%, controls 2.5%, odds ratio 0.5, 95% CI 0.16–1.57).
In summary, a non-significant trend towards an increased incidence of fetal chromosomal anomalies in IVF/ICSI compared with spontaneous conceptions was observed. No statistical difference was observed in the incidence of CPM in the IVF/ICSI group compared with the control populations (1.3% versus 1.8%, OR 0.59, 95% CI 0.19–1.85).
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Discussion |
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The present study aimed to address two pressing issues in the field of reproductive medicine: the uncertain clinical importance of the high rate of chromosomal mosaicism observed in early IVF embryos and the lack of explanation for the adverse perinatal outcomes observed in IVF singletons. We hypothesized that these two issues might be linked. Mosaicism in the embryo could lead to adverse perinatal outcomes if it were found to persist in a localized form in the placenta throughout gestation. To test this hypothesis, we conducted the largest study to date on the occurrence of CPM in IVF pregnancies. The principal findings are that CPM does not occur more frequently in IVF pregnancies than in spontaneous conceptions, although there is a non-significant trend towards an increased incidence of fetal chromosomal anomalies at this stage of gestation in IVF pregnancies.
The frequency of fetal chromosomal anomalies was found to be approximately twice as high in the IVF–ICSI group as in the control group (4.3% versus 2.1% or 2.4%, depending on the treatment of the missing data). This is in agreement with earlier studies which have found incidences in IVF or ICSI pregnancies above 4% at CVS (In't Veld et al., 1995; Loft et al., 1999). After accounting for the missing data, however, this difference was not statistically significant.
The most important finding of this study was the demonstration that the incidence of CPM is not significantly different in IVF pregnancies compared with that in spontaneous conceptions. This robust finding, which was not affected by missing data, is in contrast with the only other study of similar design (In't Veld et al., 1995) which reported a significantly higher rate of CPM in IVF pregnancies. The rate of chromosomal anomalies found at CVS was much higher than in our study: 13.8%: divided between fetal chromosomal anomalies, 7.5%, and CPM, 6.2%. They also compared the rate of chromosomal anomalies found using amniocentesis for similar indications but found no difference between IVF and spontaneous conceptions in that case. The causes for the differences observed between this study and ours are not obvious given the similarity in design. The discrepancy between the rates of anomalies found by In't Veld et al. at CVS and using amniocentesis could suggest a possible bias in the selection of patients for one of the procedures. The smaller size of the IVF group, 80 in the study by In't Veld et al. versus 235 in the current study, is another possible explanation for these differences. However, since the confidence intervals in both studies intersect, the differences may not be significant.
The retrospective, multi-centre, design of the present study carries the inherent risk of dealing with incomplete datasets and differing policies regarding the use of CVS or amniocentesis and criteria for defining CPM. The policies on the use of CVS or amniocentesis were reviewed per centre to identify possible differences between how they were applied to IVF–ICSI pregnancies and spontaneous conceptions. The counselling offered regarding the choice of CVS or amniocentesis was in most cases either similar in both groups or based on the risks or advantages of the procedure itself and not on its outcome. Specific counselling for IVF–ICSI pregnancies was offered in only about one-fifth of pregnancies in this group. This limits the possibility that a referral bias would significantly distort the analysis. Moreover, the results of CVS procedures from all centres were analysed using the same criteria. The presence of missing data did not affect the validity of our main conclusion that there is no significant difference in incidence of CPM between IVF and non-IVF pregnancies. Moreover, the incidence of both CPM and fetal chromosomal anomalies found in spontaneous conceptions are within the range reported in other studies (Lippman et al., 1992; Pittalis et al., 1994; In't Veld et al., 1995; Hahnemann and Vejerslev, 1997a).
In conclusion, the present study indicates that the incidence of CPM is not increased in IVF pregnancies compared with spontaneous conceptions. This would imply that early mosaicism in IVF embryos is not translated into localized chromosomal anomalies in the placenta and that CPM itself cannot account for the adverse perinatal outcomes observed in IVF singletons. Early mosaicism is more likely to be a phenomenon restricted to the first stages of embryogenesis (Baart et al., 2006) with little clinical significance beyond the peri-implantation period or for perinatal outcomes.
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Funding |
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The study was funded by the Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, The Netherlands.
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Footnotes |
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IVF – CPM Study Group: R.S.G.M. Bots (Department of Obstetrics and Gynaecology, St Elisabeth Hospital, Tilburg, The Netherlands), B.J. Cohlen (Department of Gynaecology, Isala Hospital, Zwolle, The Netherlands), P. van Dop (Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, The Netherlands), B.H.V. Faas (Department of Clinical Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands), M. Goddijn (Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Amsterdam Medical Centre, Amsterdam, The Netherlands), M.J.V. Hoffer (Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands), W.G. van Inzen (Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, The Netherlands), A.C. Knegt (Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, The Netherlands), J.A.M. Kremer (Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands), J.A. Land (Department of Obstetrics and Gynaecology, Ùniversity Medical Centre Groningen, Groningen, The Netherlands), M.V.E. Macville (Department of Clinical Genetics, Academic Hospital Masstricht, Maastricht, The Netherlands), N. Muntjewerff (Department of Obstetrics and Gynaecology, Academic Hospital Masstricht, Maastricht, The Netherlands), A.W.M. Nieuwint (Department of Clinical Genetics, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands), R. Schats (Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands), B. Sikkema-Raddatz (Department of Clinical Genetics, Ùniversity Medical Centre Groningen, Groningen, The Netherlands), H.J. Verburg (Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands). 
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Submitted on August 28, 2007; resubmitted on December 20, 2007; accepted on January 7, 2008.
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