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Clustering of monozygotic twinning in IVF

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The aim of this analysis was to study whether monozygotic twinning (MZT) events occur in clusters after IVF and, if so, to explore possible explanations for this clustering.

Methods

This is a retrospective cohort study carried out in a single, large university-affiliated reproductive medicine practice. Medical records of all patients who had undergone fresh IVF cycles, resulting in a viable clinical pregnancy, from Jan 2002 to Dec 2013 were reviewed. The incidence of MZT in 6-month intervals and the association with independent risk factors such as maternal age, extended embryo culture, PGD/intracytoplasmic sperm injection (ICSI)/assisted hatching performed were analyzed.

Results

Over the 12-year study period, 25,502 fresh IVF cycles were performed, resulting in 8598 clinical pregnancies. Ninety-five cycles (1.1 %) resulted in MZ twins. The percentage of MZT was >2 standard deviations (SD) higher than the overall percentage of MZT in 4 of the 24 6-month intervals. PGD, extended embryo culture (≥4 days), and more recent cycles (2005 or later) were independent risk factors for MZT. The use of multivariable logistic regression modeling to control for risk factors for MZT did not correct for this clustering effect, with both high-risk interval (clustering) and extended embryo culture remaining significant.

Conclusion

This study supports our hypothesis that MZT occurs in clusters and that this clustering effect could not be explained by demographics and cycle characteristics alone. Although we are unable to explain the clustering phenomenon, this study is important as it highlights high-risk intervals for MZT and opens the door to performing a more detailed investigation, to identify the mechanisms responsible for the spikes of MZT incidence.

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References

  1. Martin JA, Hamilton BE, Osterman MJK. Three decades of twin births in the United States, 1980–2009. NCHS data brief, no 80. Hyattsville: National Center for Health Statistics; 2012.

  2. The ESHRE Capri Workshop Group. Multiple gestation pregnancy. Hum Reprod. 2000;15(8):1856–64.

    Article  Google Scholar 

  3. Sebire NJ, Snijders RJ, Hughes K, et al. The hidden mortality of monochorionic twin pregnancies. Br J Obstet Gynaecol. 1997;104:1203.

    Article  PubMed  CAS  Google Scholar 

  4. Glinianaia SV, Obeysekera MA, Sturgiss S, Bell R. Stillbirth and neonatal mortality in monochorionic and dichorionic twins: a population based study. Hum Reprod. 2011;26:2549.

    Article  PubMed  Google Scholar 

  5. Maier RF, Bailobreski B, Gross A, Vogel M, Dudenhausen JW, Obladen M. Acute and chronic fetal hypoxia in monochorionic and dichorionic twins. Obstet Gynecol. 1995;86:973–7.

    Article  PubMed  CAS  Google Scholar 

  6. Honma Y, Minakami H, Eguchi Y, Uchida A, Izumi A, Sato I. Relation between hemoglobin discordance and adverse outcome in monochorionic twins. Acta Obstet Gynecol Scand. 1999;78:207–11.

    Article  PubMed  CAS  Google Scholar 

  7. Harkness UF, Crombleholme TM. Twin-twin transfusion syndrome: where do we go from here? Semin Perinatol. 2005;29:296–304.

    Article  PubMed  Google Scholar 

  8. Kalra SK, Molinaro TA. The association of in vitro fertilization and perinatal morbidity. Semin Reprod Med. 2008;26:423–35.

    Article  PubMed  Google Scholar 

  9. Vitthala S, Gelbaya TA, Brison DR, Fitzgerald CT, Nardo LG. The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis. Hum Reprod. 2009;15:45–55.

    Article  CAS  Google Scholar 

  10. Knopman JM, Krey LC, Oh C, Lee J, McCaffrey C, Noyes N. What makes them split? Identifying risk factors that lead to monozygotic twins after in vitro fertilization. Fertil Steril. 2014;102(1):82–9.

    Article  PubMed  Google Scholar 

  11. Aston KL, Peterson CM, Carrell DT. Monozygotic twinning associated with assisted reproductive technologies: a review. Reproduction. 2008;136:377–86.

    Article  PubMed  CAS  Google Scholar 

  12. Kawachiya S, Bodri D, Shimada N, Kato K, Takehara Y, Kato O. Blastocyst culture is associated with an elevated incidence of monozygotic twinning after single embryo transfer. Fertil Steril. 2011;95:2140–2.

    Article  PubMed  Google Scholar 

  13. Knopman J, Krey LC, Lee J, Fino ME, Novetsky AP, Noyes N. Monozygotic twinning: an eight-year experience at a large IVF center. Fertil Steril. 2010;94:502–10.

    Article  PubMed  Google Scholar 

  14. Sills ES, Moomjy M, Zaninovic N, Veeck LL, McGee M, Palermo GD, et al. Human zona pellucida micromanipulation and monozygotic twinning frequency after IVF. Hum Reprod. 2000;15(4):890–5.

    Article  PubMed  CAS  Google Scholar 

  15. Papanikolaou EF, Fatemu H, Venetis C, Donoso P, Kolibianakis E, Tournaye H, et al. Monozygotic twinning is not increased after single blastocyst transfer compared with singe cleavage-stage embryo transfer. Fertil Steril. 2010;93:592–7.

    Article  PubMed  Google Scholar 

  16. Franasiak JM, Dondik Y, Molinaro TA, Hong KH, Forman EJ, Werner MD, et al. Blastocyst transfer is not associated with increased rates of monozygotic twins when controlling for embryo cohort quality. Fertil Steril. 2015;103:95–100.

    Article  PubMed  Google Scholar 

  17. Menezo YJR, Sakkas D. Monozygotic twins: is it related to apoptosis in the embryo? Hum Reprod. 2002;17:247–51.

    Article  PubMed  Google Scholar 

  18. Sobek Jr A, Zbořilová B, Procházka M, Šilhánová E, Koutná O, Klásková E, et al. High incidence of monozygotic twinning after assisted reproduction is related to genetic information, but not to assisted reproduction technology itself. Fertil Steril. 2015;103(3):756–60.

    Article  PubMed  Google Scholar 

  19. Osianlis T, Rombauts L, Gabbe M, Motteram C, Vollenhoven B. Incidence and zygosity of twin births following transfers using a single fresh or frozen embryo. Hum Reprod. 2014;29:1438–43.

    Article  PubMed  CAS  Google Scholar 

  20. Hillman SC, Morris RK, Kilby MD. Co-twin prognosis after single fetal death: a systematic review and meta-analysis. Obstet Gynecol. 2011;118:928–40.

    Article  PubMed  Google Scholar 

  21. Evans MI, Berkowitz RL, Wapner RJ, Carpenter RJ, Goldberg JD, Ayoub MA, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol. 2001;184:97–103.

    Article  PubMed  CAS  Google Scholar 

  22. Guilherme R, Drunat S, Delezoide AL, Le Ray C, Oury JF, Luton D. Zygosity and chorionicity in triplet pregnancies: new data. Hum Reprod. 2009;24:100–5.

    Article  PubMed  Google Scholar 

  23. Thun MJ, Sinks T. Understanding cancer clusters. CA Cancer J Clin. 2004;54(5):273–80.

    Article  PubMed  Google Scholar 

  24. Edwards RG, Mettler L, Walters DE. Identical twins and in vitro fertilization. J In Vitro Fert Embryo Transf. 1986;3:114–7.

    Article  PubMed  CAS  Google Scholar 

  25. Frankfurter D, Hackett R, Meng L, Keefe DL. Complete removal of the zona pellucida by pronase digestion prior to blastocyst embryo transfer does not eliminate monozygotic pregnancies following IVF. Fertil Steril. 2001;76:S144.

    Article  Google Scholar 

  26. Alikani M, Noyes N, Cohen J, Rosenwaks Z. Monozygotic twinning in the human is associated with the zona pellucida architecture. Hum Reprod. 1994;9:1318–21.

    PubMed  CAS  Google Scholar 

  27. Kissin DM, Kawwass KF, Monsour M, Boulet SL, Session DR, Jamieson DJ, et al. Assisted hatching: trends and pregnancy outcomes, United States, 2000-2010. Fertil Steril. 2014;102(3):795–801.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Garside WT, De Mola J, Bucci JA, Tureck W, Heyner S. Sequential analysis of zona thickness during in vitro culture of human zygote: correlation with embryo quality, age, and implantation. Mol Reprod Dev. 1997;47:99–104.

    Article  PubMed  CAS  Google Scholar 

  29. Machin G. Familial monozygotic twinning: a report of seven pedigrees. Am J Med Genet. 2009;151C:152–4.

    Article  PubMed  Google Scholar 

  30. Eskild A, Monkerud L, Tanbo T. Birthweight and placental weight: do changes in culture media used for IVF matter? Comparisons with spontaneous pregnancies in the corresponding time periods. Hum Reprod. 2013;28(12):3207–14.

    Article  PubMed  Google Scholar 

  31. Zhu J, Li M, Chen L, Liu P, Qiao J. The protein source in embryo culture media influences birthweight: a comparative study between G1 v5 and G1-PLUS v5. Hum Reprod. 2014;29(7):1387–92.

    Article  PubMed  CAS  Google Scholar 

  32. Menezo Y, Sakkas D. Monozygotic twinning: is it related to apoptosis in the embryo? Hum Reprod. 2002;17(1):247–8.

    Article  PubMed  Google Scholar 

  33. Eaton JL, Hacker MR, Harris D, Thornton KL, Penzias AS. Assessment of day-3 morphology and euploidy for individual chromosomes in embryos that develop to the blastocyst stage. Fertil Steril. 2009;91:2432–6.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA

    Denis A. Vaughan & Errol R. Norwitz

  2. Research Design Center/ Biostatistics Research Center, Tufts Clinical and Translational Science Institute, Boston MA and Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University, 35 Kneeland St, 7th–11th Floors, Boston, MA, 02111, USA

    Robin Ruthazer

  3. Boston IVF, 130 Second Avenue, Waltham, MA, 02451, USA

    Alan S. Penzias & Denny Sakkas

  4. Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA

    Alan S. Penzias

Authors
  1. Denis A. Vaughan
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  2. Robin Ruthazer
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  3. Alan S. Penzias
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  4. Errol R. Norwitz
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  5. Denny Sakkas
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Corresponding author

Correspondence to Denis A. Vaughan.

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Funding

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Conflict of interest

Ms. Ruthazer’s institution (Tufts Clinical and Translational Science Institute, Tufts University) was reimbursed for statistical support. Dr Penzias is a paid consultant for OvaScience and receives payment for lectures including service on speaker bureaus for Ferring Pharmaceuticals.

Additional information

Capsule This study supports our hypothesis that MZT occurs in clusters and that this clustering effect could not be explained by demographics and cycle characteristics alone.

Electronic supplementary material

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Supplemental figure 1

Bar chart denoting MZT events based on interval (days) between events. 68% of MZT events had an interval <46.2 days apart, which would be the expected interval if MZT events were uniformly distributed and 50% should have occurred. The “p value” for the z-test against a null of 50% is 0.0003. (GIF 77 kb)

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Vaughan, D.A., Ruthazer, R., Penzias, A.S. et al. Clustering of monozygotic twinning in IVF. J Assist Reprod Genet 33, 19–26 (2016). https://doi.org/10.1007/s10815-015-0616-x

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  • DOI: https://doi.org/10.1007/s10815-015-0616-x

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