Vanishing embryo syndrome in IVF/ICSI
Dorte Hvidtjørn1,5,
Jakob Grove1,
Diana Schendel1,2,
Michael Væth3,
Erik Ernst4,
Lene Nielsen1 and
Poul Thorsen1
1 NANEA, Department of Epidemiology, Institute of Public Health, University of Aarhus, Paludan-Müllers Vej 17, DK-8000 Aarhus C, Denmark, 2 Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, USA, 3 Department of Biostatistics, Institute of Public Health, University of Aarhus and 4 Fertility Section, Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark
5 To whom correspondence should be addressed. Email: dh{at}soci.au.dk
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Abstract
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BACKGROUND: In a Danish population-based cohort study assessing the risk of cerebral palsy in children born after IVF, we made some interesting observations regarding vanishing co-embryos. METHODS and RESULTS: All live-born children born in Denmark from 1 January 1995 to 31 December 2000 were included in this analysis. The children conceived by IVF/ICSI (9444) were identified through the IVF Register, the children conceived without IVF/ICSI (395 025) were identified through The Danish Medical Birth Register. Main outcome measure was the incidence of cerebral palsy. Within the IVF/ICSI children we found indications of an increased risk of cerebral palsy in those children resulting from pregnancies, where the number of embryos transferred was higher than the number of children born. CONCLUSIONS: The association between vanishing embryo syndrome and incidence of cerebral palsy following IVF requires further investigation in larger, adequately powered, studies.
Key words:
cerebral palsy/IVF/vanishing embryo syndrome
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Introduction
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Some pregnancies begin with twins or higher gestations, but conclude with a lower number of live birthsthe vanishing embryo syndrome. How common this is and what impact it has on the surviving fetus is largely unknown (Landy and Keith, 1998
).
In the application of assisted reproductive technologies, the likelihood of a vanishing embryo may be higher than in spontaneous pregnancies. During IVF, commonly two or more embryos are transferred with a potential risk of losing co-embryos in early pregnancy. Furthermore, in assisted reproductive technologies an iatrogenic vanishing embryo is introduced in some pregnancies, when selective fetal reduction is performed to reduce the number of gestations in order to improve the chances of the remaining fetuses.
Schieve et al. (2002)
found that infants conceived with assisted reproductive technologies were more likely to be of low birthweight in pregnancies with vanishing embryos. Dickey et al. (2002)
found that the length of gestation in pregnancies was inversely related to the initial numbers of gestational sacs in singletons and twins. It has also been hypothesized that cerebral palsy (CP) of unknown aetiology could be the result of the vanishing embryo syndrome (Pharoah and Cooke, 1997
).
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Materials and methods
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Permission to conduct this study was achieved through The Danish Data Protection Agency and The Regional Ethics Committee in Aarhus. A Danish cohort study of CP in children born after IVF comprised all liveborn children born between 1995 and 2000, identified through The Danish Medical Birth Register. Data on IVF exposure were obtained through the IVF Register and children diagnosed with CP were identified through the National Register of Hospital Discharges based on hospital discharge diagnoses and outpatient diagnoses. Reporting to these national registers is mandatory, and data were recorded prospectively independent of outcome. Children were followed up to 31 December 2001. As the follow-up period was from 1 to 7 years of age, some children may not have received the diagnosis of CP by the end of follow-up and the prevalence of CP in this cohort may be underestimated. Also, since the number of IVF treatments increased over the study period, a disproportionate number of IVF children had a shorter follow-up time than non-IVF children. The diversity in follow-up time was handled using the Cox regression model, estimating the relative incidence by the hazard rate ratio (HRR) with 95% confidence intervals. The proportional hazards assumption was met. An analysis using robust estimates of variance, to account for siblings (both singletons and twins) not being entirely independent, was applied. STATA version 8 was used in the analyses.
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Results
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Overall, we observed an increased incidence of CP in 41 out of 9444 children born after IVF (0.43%) compared to 1016 children out of 395 025 non-IVF children (0.26%) with a crude HRR of 1.79 [confidence interval (CI) 1.302.47]. But within the IVF children the proportion with CP was higher in pregnancies where the number of gestations at delivery was less than the number of embryos originally transferred. Specifically, no child was diagnosed with CP in the group of children born after transfer of a single embryo; the proportion with CP was 3.9/1000 (CI 2.25.5/1000) births in singletons born after transfer of more than one embryo, similar to the proportion among twins born after transfer of two embryos 4.4/1000 (CI 1.96.9), but the proportion with CP among twins born after transfer of more than two embryos was more than doubled at 9.5/1000 (CI 3.016/1000). A similar pattern was observed in specific gestational age groups, as shown in Table I. No variability across time was detected.
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Table I. The number of IVF children classified according to gestations at delivery, number of embryos transferred, and cerebral palsy (CP): all Danish births, 19952000
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A Cox regression analysis including the covariates: number of gestations at delivery, gestational age, maternal age, sex, parity and education, showed an increased risk of cerebral palsy in pregnancies where the number of gestations at delivery was less than the number of embryos originally transferred compared to pregnancies where the number of gestations at delivery was the same as the number of embryos transferred [HRR 2.30 (CI 0.99; 5.32)].
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Discussion
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Some limitations of this study should be noted. Only the number of embryos transferred is known, not the number of embryos implanted or the gestational age at the time of loss of a co-embryo. The risk of CP in surviving co-embryos has primarily been associated with monochorionicity (Pharoah and Cooke, 1997
), but unfortunately information on chorionicity was not available. We included several crucial covariates in the Cox analysis, yet unmeasured explanations for number of embryos transferred might confound the result, such as ovarian response of the mother, or embryo grade or availability. No children in the single embryo transfer group were diagnosed with CP; however, this may be due to chance as only 492 children were born after single embryo transfer.
The association between vanishing embryos and an increased risk of CP was not statistically significant. However, this may be due to lack of power, and borderline statistically significant results like these call for replication in larger study populations with adequate power, especially in prospective studies monitoring the number of embryos by frequent ultrasound scans in the early pregnancy. A confirmation of the hypothesis would necessitate reconsideration of clinical practice in assisted reproduction.
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Acknowledgements
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Funding for this study was provided by: Centers for Disease Control and Prevention, Atlanta, USA, Ludvig and Sara Elsass Fund, Aase and Ejnar Danielsens Fund, Else and Mogens Wedell-Wedellsborgs Fund.
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References
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Dickey RP, Taylor SN, Lu PY, Sartor BM, Storment JM, Rye PH, Pelletier WD, Zender JL and Matulich EM (2002) Spontaneous reduction of multiple pregnancy: incidence and effect on outcome. Am J Obstet Gynecol 186, 7783.[CrossRef][ISI][Medline]
Landy HJ and Keith LG (1998) The vanishing twin: a review. Hum Reprod Update 4, 177183.[Abstract/Free Full Text]
Pharoah POD and Cooke RWI (1997) A hypothesis for the aetiology of spastic cerebral palsythe vanishing twin. Dev Med Child Neurol 39, 292296.[ISI][Medline]
Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng GJ and Wilcox LS (2002) Low and very low birth weight in infants conceived with use of assisted reproductive technology. New Engl J Med 346, 731737.[Abstract/Free Full Text]
Submitted on February 24, 2005;
resubmitted on April 7, 2005;
accepted on April 22, 2005.