Journal of Assisted Reproduction and Genetics

, Volume 34, Issue 2, pp 191–200 | Cite as

Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles

  • Barbara LukeEmail author
  • Morton B. Brown
  • Ethan Wantman
  • Judy E. Stern
  • James P. Toner
  • Charles C. CoddingtonIII
Assisted Reproduction Technologies



Children born from fresh in vitro fertilization (IVF) cycles are at greater risk of being born smaller and earlier, even when limited to singletons; those born from frozen cycles have an increased risk of large-for-gestational age (LGA) birthweight (z-score ≥1.28). This analysis sought to overcome limitations in other studies by using pairs of siblings, and accounting for prior cycle outcomes, maternal characteristics, and embryo state and stage.


Pairs of singleton births conceived with IVF and born between 2004 and 2013 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database, matched for embryo stage (blastocyst versus non-blastocyst) and infant gender, categorized by embryo state (fresh versus frozen) in 1st and 2nd births (four groups).


The data included 7795 singleton pairs. Birthweight z-scores were 0.00–0.04 and 0.24–0.26 in 1st and 2nd births in fresh cycles, and 0.25–0.34 and 0.50–0.55 in frozen cycles, respectively. LGA was 9.2–9.8 and 14.2–15.4% in 1st and 2nd births in fresh cycles, and 13.1–15.8 and 20.8–21.0% in 1st and 2nd births in frozen cycles. The risk of LGA was increased in frozen cycles (1st births, adjusted odds ratios (AOR) 1.74, 95% CI 1.45, 2.08; and in 2nd births when the 1st birth was not LGA, AOR 1.70, 95% CI 1.46, 1.98 for fresh/frozen and 1.40, 1.11, 1.78 for frozen/frozen).


Our results with siblings indicate that frozen embryo state is associated with an increased risk for LGA. The implications of these findings for childhood health and risk of obesity are unclear, and warrant further investigation.


Assisted reproductive technology Siblings Fresh and thawed cycles Birth outcomes 


Authors’ roles

BL and MBB contributed to the conception and design of the study, drafted the manuscript, and revised it. MBB performed the statistical analyses. BL, JE, and EW linked IVF cycles in the SART CORS database. All the authors contributed to the interpretation of the data and approved the final version of the manuscript.

Compliance with ethical standards

This study was approved by the Committees for the Protection of Human Subjects at the Dartmouth College, Michigan State University, and University of Michigan.

Conflict of interest

BL is a research consultant to the Society for Assisted Reproductive Technology (SART). EW is under contract with SART to maintain the SART CORS database. MBB, JES, JPT, and CCC have no conflicts to declare.


  1. 1.
    Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:485–503.CrossRefPubMedGoogle Scholar
  2. 2.
    Pinborg A, Wennerholm UB, Romundstad LB, Loft A, Aittomaki K, Söderström-Anttila V, et al. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Hum Reprod Update. 2013;19:87–104.CrossRefPubMedGoogle Scholar
  3. 3.
    Qin J, Liu X, Sheng X, Wang H, Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril. 2016;105:73–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL, et al. Factors affecting low birthweight after assisted reproduction technology: difference between transfer of fresh and cryopreserved embryos suggests an adverse effect of oocyte collection. Hum Reprod. 2008;23:1644–53.CrossRefPubMedGoogle Scholar
  5. 5.
    Pelkonen S, Koivunen R, Gissler M, Nuojua-Huttunen S, Suikkari A-M, Hydén-Granskog C, et al. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006. Hum Reprod. 2010;25:914–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Henningsen A-KA, Pinborg A, Lidegaard Ø, Vestergaard C, Forman JL, Andersen AN. Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study. Fertil Steril. 2011;95:959–63.CrossRefPubMedGoogle Scholar
  7. 7.
    Sazonova A, Källen K, Thurin-Kjellberg A, Wennerholm U-B, Bergh C. Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos. Hum Reprod. 2012;27:1343–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Nakashima A, Araki R, Tani H, Ishihara O, Kuwahara A, Irahara M, et al. Implications of assisted reproductive technologies on term singleton birth weight: an analysis of 25,777 children in the national assisted reproduction registry of Japan. Fertil Steril. 2013;99:450–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Wennerholm UB, Henningsen AK, Romundstad LB, Bergh C, Pinborg A, Skjaerven R, et al. Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group. Hum Reprod. 2013;28:2545–53.CrossRefPubMedGoogle Scholar
  10. 10.
    Pinborg A, Henningsen AA, Loft A, Malchau SS, Forman J, Nyboe AA. Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? Hum Reprod. 2014;29:618–27.CrossRefPubMedGoogle Scholar
  11. 11.
    Marino JL, Moore VM, Willson KJ, Rumbold A, Whitrow MJ, Giles LC, et al. Perinatal outcomes by mode of assisted conception and sub-fertility in an Australian data linkage cohort. PLoS ONE. 2014;9:e80398. doi: 10.1371/journal.pone.0080398.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Korosec S, Frangez HB, Steblovnik L, Verdenik I, Bokal EV. Independent factors influencing large-for-gestation birth weight in singletons born after in vitro fertilization. J Assist Reprod Genet. 2016;33:9–17.CrossRefPubMedGoogle Scholar
  13. 13.
    Mäkinen S, Söderström-Anttila V, Vainio J, Suikkari AM, Tuuri T. Does long in vitro culture promote large for gestational age babies? Hum Reprod. 2013;28:828–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Buck Louis GM, Schisterman EF, Dukic VM, Schieve LA. Research hurdles complicating the analysis of infertility treatment and child health. Hum Reprod. 2005;20:12–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Declercq E, Luke B, Belanoff C, Cabral H, Diop H, Gopal D, et al. Perinatal outcomes associated with assisted reproductive technology: the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART). Fertil Steril. 2015;103:888–95.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Stern JE, Luke B, Tobias M, Gopal D, Hornstein MD, Diop H. Adverse pregnancy and birth outcomes by infertility diagnoses with and without ART treatment. Fertil Steril. 2015;103:1438–45.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Romundstad LB, Romundstad PR, Sunde A, von Düring V, Skjærven R, Gunnell D, et al. Effects of technology or maternal factors on perinatal outcome after assisted fertilization: a population-based cohort study. Lancet. 2008;372:737–43.CrossRefPubMedGoogle Scholar
  18. 18.
    Seggers J, Pontesilli M, Ravelli ACJ, Painter RC, Hadders-Algra M, Heineman MJ, et al. Effects of in vitro fertilization and maternal characteristics on perinatal outcomes: a population-based study using siblings. Fertil Steril. 2016;105:590–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Galliano D, Garrido N, Serra-Serra V, Pellicer A. Difference in birth weight of consecutive sibling singletons is not found in oocyte donation when comparing fresh versus frozen embryo replacements. Fertil Steril. 2015;104:1411–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Opdahl S, Henningsen AA, Tiitinen A, Bergh C, Pinborg A, Romundstad PR, et al. Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group. Hum Reprod. 2015;30:1724–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Center for Disease Control and Prevention, American Society for Reproductive Medicine, and Society for Assisted Reproductive Technology. Assisted reproductive technology success rates: national summary and fertility clinic reports. Washington, DC: US Dept. of Health and Human Services; 2012. p. 2014.Google Scholar
  22. 22.
    Bakketeig LS, Hoffman HJ, Harley EE. The tendency to repeat gestational age and birthweight in successive births. Am J Obstet Gynecol. 1979;135:1086–103.CrossRefPubMedGoogle Scholar
  23. 23.
    Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected for implausible gestational age estimates. Pediatrics. 2014;133:844–53.CrossRefPubMedGoogle Scholar
  24. 24.
    Land JA. How should we report on perinatal outcome? Hum Reprod. 2006;21:2638–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes. 2001;25:1175–82.CrossRefGoogle Scholar
  26. 26.
    Institute of Medicine. Weight gain during pregnancy: reexamining the guidelines. Washington, DC: National Academies Press; 2009.Google Scholar
  27. 27.
    Luke B, Brown MB, Grainger DA, Stern JE, Klein N, Cedars M. The effect of early fetal losses on singleton assisted-conception pregnancy outcomes. Fertil Steril. 2009;91:2578–85.CrossRefPubMedGoogle Scholar
  28. 28.
    de Zegher F, Devlieger H, Eeckels R. Fetal growth: boys before girls. Horm Res. 1999;51:258–9.PubMedGoogle Scholar
  29. 29.
    de Zegher F, Francois I, Boehmer ALM, Saggese G, Muller J, Hiort O, et al. Androgens and fetal growth. Horm Res. 1998;50:243–4.PubMedGoogle Scholar
  30. 30.
    Pedersen JF. Ultrasound evidence of sexual difference in fetal size in first trimester. Br Med J. 1980;281:1253.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zeilmaker GH, Alberda AT, van Gent I, Rijkmans CM, Drogendijk AC. Two pregnancies following transfer of intact frozen-thawed embryos. Fertil Steril. 1984;42:293–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Maheshwari A, Bhattacharya S. Elective frozen replacement cycles for all: ready for prime time? Hum Reprod. 2013;28:6–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Shapiro BS, Daneshman ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril. 2014;102:3–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Weinerman R, Mainigi M. Why we should transfer frozen instead of fresh embryos: the translational rationale. Fertil Steril. 2014;102:10–8.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wong KM, Mastenbroek S, Repping S. Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril. 2014;102:19–26.CrossRefPubMedGoogle Scholar
  36. 36.
    Hu X-L, Feng C, Lin X-H, Zhong Z-X, Zhu Y-M, Lv P-P, et al. High maternal serum estradiol environment in the 1st trimester is associated with the increased risk of small-for-gestational-age birth. J Clin Endocrinol Metab. 2014;99:2217–24.CrossRefPubMedGoogle Scholar
  37. 37.
    Rallis A, Tremellen K. Controlled ovarian hyper-stimulation during IVF treatment does not increase the risk of preterm delivery compared to the transfer of frozen-thawed embryos in a natural cycle. Aust N Z J Obstet Gynaecol. 2013;53:165–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Yeh JS, Steward RG, Dude AM, Shah AA, Goldfarb JM, Muasher SJ. Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology. Fertil Steril. 2014;102:399–404.CrossRefPubMedGoogle Scholar
  39. 39.
    Wennerholm U-B, Söderström-Anttila V, Bergh C, Aittomäki K, Hazekamp J, Nygren K-G, et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data. Hum Reprod. 2009;24:2158–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Roque M, Lattes K, Serra S, Solà I, Geber S, Carreras R, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril. 2013;99:156–62.CrossRefPubMedGoogle Scholar
  41. 41.
    Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2012;98:368–77.CrossRefPubMedGoogle Scholar
  42. 42.
    Pinborg A, Loft A, Henningsen AKA, Rasmussen S, Nyboe AA. Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995–2006. Fertil Steril. 2010;94:1320–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Healy DL, Breheny S, Halliday J, Jaques A, Rushford D, Garrett C, et al. Prevalence and risk factors for obstetric haemorrhage in 6,730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod. 2010;25:265–74.CrossRefPubMedGoogle Scholar
  44. 44.
    Luke B, Gopal D, Stern JE, Declercq E, Hoang L, Kotelchuck M, et al. Maternal pregnancy and birth complications by fertility status: the Massachusetts outcomes study of assisted reproductive technologies. Fertil Steril. 2015;104:e15.CrossRefGoogle Scholar
  45. 45.
    Belanoff C, Declercq ER, Diop H, Gopal D, Kotelchuck M, Luke B, et al. Severe maternal morbidity and the use of assisted reproductive technology in Massachusetts. Obstet Gynecol. 2016;127:527–34.CrossRefPubMedGoogle Scholar
  46. 46.
    Korosec S, Frangez HB, Verdenik I, Kladnik U, Kotar V, Virant-Klun I, Bokal EV. Singleton pregnancy outcomes after in vitro fertilization with fresh or frozen-thawed embryo transfer and incidence of placenta previa. BioMed Res Int. 2014; article ID 431797. 10.1155/2014/431797.
  47. 47.
    Luke B, Stern JE, Kotelchuck M, Declercq E, Anderka M, Diop H. Birth outcomes by infertility treatment: analyses of the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART). J Reprod Med. 2016;61:114–27.PubMedGoogle Scholar
  48. 48.
    Vatten LJ, Skjaerven R. Is pre-eclampsia more than one disease? Br J Obstet Gynaecol. 2004;111:298–302.CrossRefGoogle Scholar
  49. 49.
    Pinborg A, Loft A, Noergaard L, Henningsen AA, Rasmussen S, Nyboe Andersen A. Singletons born after frozen embryo transfer (FET) have an increased risk of being large of gestational age—Danish national controlled cohort study of 15,078 singletons. [abstract] Human Reprod. 2011 (suppl. 1): O-230.Google Scholar
  50. 50.
    Pinborg A. To transfer fresh or thawed embryos? Seminars Reprod Med. 2012;30:230–5.CrossRefGoogle Scholar
  51. 51.
    Henningsen A-K A, Pinborg A. Birth and perinatal outcomes and complications for babies conceived following ART. Seminars Fetal Neonatal Med. 2014;19:234–8.CrossRefGoogle Scholar
  52. 52.
    Weissmann-Brenner A, Simchen MJ, Zilberberg E, Kalter A, Weisz B, Achiron R, et al. Maternal and neonatal outcomes of large for gestational age pregnancies. Acta Obstet Gynecol Scand. 2012;91:844–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Eyzaguirre F, Bancalari R, Romàn R, Silva R, Youlton R, Urquidi C, et al. Prevalence of components of the metabolic syndrome according to birthweight among overweight and obese children and adolescents. J Pediatr Endocrinol Metab. 2012;25:51–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Parsons TJ, Power C, Logan S, Summerbell CD. Childhood predictors of adult obesity: a systematic review. Int J Obes. 1999;23(Supplement 8):S1–107.Google Scholar
  55. 55.
    Eriksson J, Forsén T, Tuomilehto J, Osmond C, Barker D. Size at birth, childhood growth and obesity in adult. Int J Obes. 2001;25:735–40.CrossRefGoogle Scholar
  56. 56.
    Giapros V, Evagelidou E, Challa A, Kiortrios D, Drougia A, Andronikou S. Serum adiponectin and leptin levels and insulin resistance in children born large for gestational age are affected by the degree of overweight. Clin Endocrinol. 2007;66:353–9.CrossRefGoogle Scholar
  57. 57.
    Moore GS, Kneitel AW, Walker CK, Gilbert WM, Xing G. Autism risk in small- and large-for-gestational-age infants. Am J Obstet Gynecol. 2012;206:314.e1–9.CrossRefGoogle Scholar
  58. 58.
    O’Neill KA, Murphy MFG, Bunch KJ, Puumala SE, Carozza SE, Chow EJ, et al. Infant birthweight and risk of childhood cancer: International population-based case control studies of 40,000 cases. Int J Epidemiol. 2015;44:153–68.CrossRefPubMedGoogle Scholar
  59. 59.
    Olivennes F, Schneider Z, Remy V, Blanchet V, Kerbrat V, Fanchin R, et al. Perinatal outcome and follow-up of 82 children aged 1–9 years old conceived from cryopreserved embryos. Hum Reprod. 1996;11:1665–8.Google Scholar
  60. 60.
    Wennerholm UB, Albertsson-Wikland K, Bergh C, Hamberger L, Niklasson A, Nilsson L, et al. Postnatal growth and health in children born after cryopreservation as embryos. Lancet. 1998;351:1085–90.CrossRefPubMedGoogle Scholar
  61. 61.
    Nakajo Y, Fukunaga N, Fuchinoue K, Yagi A, Chiba S, Takeda M, et al. Physical and mental development of children after in vitro fertilization and embryo transfer. Reprod Med Biol. 2004;3:63–7.CrossRefGoogle Scholar
  62. 62.
    Green MP, Mouat F, Miles HL, Pleasants AB, Henderson HV, Hofman PL, et al. The phenotype of an IVF child is associated with peri-conception measures of follicular characteristics and embryo quality. Hum Reprod. 2014;29:2583–91.CrossRefPubMedGoogle Scholar
  63. 63.
    Romundstad LB, Romundstad PR, Sunde A, von Düring V, Vatten LJ. Increased risk of placenta previa in pregnancies following IVF/ICSI; a comparison of ART and non-ART pregnancies in the same mother. Hum Reprod. 2006;21:2353–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Grace KS, Sinclair KD. Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. Semin Reprod Med. 2009;27:409–16.CrossRefPubMedGoogle Scholar
  65. 65.
    Shufaro Y, Laufer N. Epigenetic concerns in assisted reproduction: update and critical review of the current literature. Fertil Steril. 2013;99:605–6.CrossRefPubMedGoogle Scholar
  66. 66.
    Kopeika J, Thornhill A, Khalaf Y. The effect of cryopreservation on the genome of gametes and embryos: principles of cryobiology and critical appraisal of the evidence. Hum Reprod Update. 2015;21:209–27.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human MedicineMichigan State UniversityEast LansingUSA
  2. 2.Department of Biostatistics, School of Public HealthUniversity of MichiganAnn ArborUSA
  3. 3.Redshift Technologies, IncNew YorkUSA
  4. 4.Department of Obstetrics and GynecologyGeisel School of Medicine at DartmouthLebanonUSA
  5. 5.Atlanta Center for Reproductive MedicineAtlantaUSA
  6. 6.Division of Reproductive Endocrinology and InfertilityMayo ClinicRochesterUSA

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