Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Strategies to control the rate of high order multiple gestation

Wendy Kuohung, MD
Elizabeth S Ginsburg, MD
Catherine Racowsky, PhD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kristen Eckler, MD, FACOG


The incidence of multiple gestation has risen significantly over several decades, primarily due to increased use of fertility drugs for ovulation induction, superovulation, and assisted reproductive technologies (ART), such as in vitro fertilization (IVF) [1]. In 1960, before the commercial availability of drugs for treatment of infertility, there were approximately 4.3 million births in the United States, with 1244 triplets and higher order multiples [2]. In 2011, the total number of births was slightly lower (3.9 million), but there were 5417 triplet and higher order multiples; these numbers do not include those high order multiple gestations (ie, pregnancies with at least three fetuses) reduced naturally or iatrogenically [3]. Approximately 20 percent of high order multiple births are naturally conceived, 39 to 67 percent are related to ovulation induction/superovulation, and 13 to 44 percent are associated with ART [4].

Among women undergoing IVF with fresh nondonor embryos in 2009, the rates of singleton, twin, and triplets-or-more pregnancies were 61.7, 28.5, and 3.1 percent, respectively (6.7 percent undetermined at early miscarriage) [5]. By comparison, in 2011, 3.5 percent of all live births in the United States were multiple gestations (twins 3.3 percent, triplets or more 0.14 percent) [3].

The lack of insurance coverage for ART in most of the United States, as well as competition among ART programs, has generated pressure to achieve success in a minimal number of cycles [6,7]. One strategy has been to increase the number of embryos transferred per IVF procedure. An analysis of 1998 Society of Assisted Reproductive Technology (SART) data demonstrated that providers in states without insurance coverage for IVF transferred more embryos per cycle, had a higher percentage of cycles resulting in pregnancy, and encountered an increased frequency of high order gestations compared to providers in states with IVF insurance coverage [6].

Infertility patients often consider the birth of twins acceptable, or even desirable, since it may result in a completed family after (sometimes) years of infertility [8-12]. Nevertheless, there is a need for effective methods to reduce the frequency of multiple gestation, particularly high order pregnancies. Multiple gestations are at significantly increased risk of fetal, neonatal, and maternal complications, as well as complete pregnancy loss, when compared to singleton pregnancies (table 1) [4]. As an example, in one review, the risk of delivery <32 weeks of gestation for singleton, twin, triplet, and quadruplet pregnancies was 2, 8, 26, and >95 percent, respectively [4]. In another study that compared twin pregnancy outcome with outcome of two successive singleton pregnancies delivered by the same mother, adverse pregnancy and neonatal outcomes were significantly increased for IVF twins compared with two successive IVF singleton pregnancies [13].

The economic and psychological impact on families raising children of a multiple gestation is also important [14-17]. In one study, for example, 22 percent of mothers of multiples had Parenting Stress Index scores indicating severe parenting stress, compared with 5 percent of mothers of IVF singletons and 9 percent of mothers of naturally conceived singletons [16]. Another study found that each additional child more than tripled the odds of not being able to meet basic material needs and doubled the odds of a lowered quality of life for the family [17]. (See "Neonatal complications, outcome, and management of multiple births", section on 'Family support'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 21, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013; 369:2218.
  2. Dickey RP. Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril 2009; 91:1.
  3. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2011. Natl Vital Stat Rep 2013; 62:1.
  4. Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril 2012; 97:825.
  5. 2009 SART http://www.cdc.gov/ART/ART2009 (Accessed on February 23, 2012).
  6. Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med 2002; 347:661.
  7. Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril 2003; 80:16.
  8. Ryan GL, Zhang SH, Dokras A, et al. The desire of infertile patients for multiple births. Fertil Steril 2004; 81:500.
  9. Gleicher N, Campbell DP, Chan CL, et al. The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 1995; 10:1079.
  10. Pinborg A, Loft A, Schmidt L, Andersen AN. Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer. Hum Reprod 2003; 18:621.
  11. Child TJ, Henderson AM, Tan SL. The desire for multiple pregnancy in male and female infertility patients. Hum Reprod 2004; 19:558.
  12. Gleicher N, Barad D. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril 2009; 91:2426.
  13. Sazonova A, Källen K, Thurin-Kjellberg A, et al. Neonatal and maternal outcomes comparing women undergoing two in vitro fertilization (IVF) singleton pregnancies and women undergoing one IVF twin pregnancy. Fertil Steril 2013; 99:731.
  14. Multiple gestation pregnancy. The ESHRE Capri Workshop Group. Hum Reprod 2000; 15:1856.
  15. Thorpe K, Golding J, MacGillivray I, Greenwood R. Comparison of prevalence of depression in mothers of twins and mothers of singletons. BMJ 1991; 302:875.
  16. Glazebrook C, Sheard C, Cox S, et al. Parenting stress in first-time mothers of twins and triplets conceived after in vitro fertilization. Fertil Steril 2004; 81:505.
  17. Ellison MA, Hotamisligil S, Lee H, et al. Psychosocial risks associated with multiple births resulting from assisted reproduction. Fertil Steril 2005; 83:1422.
  18. Nygren KG, Andersen AN, European IVF-monitoring programme (EIM). Assisted reproductive technology in Europe, 1998. Results generated from European registers by ESHRE. European Society of Human Reproduction and Embryology. Hum Reprod 2001; 16:2459.
  19. CDC/SART Registry, 2001.
  20. American Society for Reproductive Medicine. Guidelines on Number of Embryos Transferred. American Society for Reproductive Medicine, Birmingham, Ala 1998.
  21. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Practice Committee of the Society for Assisted Reproductive Technology. Guidance on the limits to the number of embryos to transfer: a committee opinion. Fertil Steril 2017; 107:901.
  22. Dickey RP. The relative contribution of assisted reproductive technologies and ovulation induction to multiple births in the United States 5 years after the Society for Assisted Reproductive Technology/American Society for Reproductive Medicine recommendation to limit the number of embryos transferred. Fertil Steril 2007; 88:1554.
  23. Jain T, Missmer SA, Hornstein MD. Trends in embryo-transfer practice and in outcomes of the use of assisted reproductive technology in the United States. N Engl J Med 2004; 350:1639.
  24. Stern JE, Cedars MI, Jain T, et al. Assisted reproductive technology practice patterns and the impact of embryo transfer guidelines in the United States. Fertil Steril 2007; 88:275.
  25. Sunderam S, Kissin DM, Crawford SB, et al. Assisted Reproductive Technology Surveillance — United States, 2012. MMWR Surveill Summ 2015; 64:1.
  26. Sunderam S, Kissin DM, Crawford SB, et al. Assisted Reproductive Technology Surveillance - United States, 2014. MMWR Surveill Summ 2017; 66:1.
  27. Sunderam S, Chang J, Flowers L, et al. Assisted reproductive technology surveillance--United States, 2006. MMWR Surveill Summ 2009; 58:1.
  28. Racowsky C, Vernon M, Mayer J, et al. Standardization of grading embryo morphology. Fertil Steril 2010; 94:1152.
  29. Brison DR, Houghton FD, Falconer D, et al. Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover. Hum Reprod 2004; 19:2319.
  30. Seli E, Vergouw CG, Morita H, et al. Noninvasive metabolomic profiling as an adjunct to morphology for noninvasive embryo assessment in women undergoing single embryo transfer. Fertil Steril 2010; 94:535.
  31. Katz-Jaffe MG, Gardner DK, Schoolcraft WB. Proteomic analysis of individual human embryos to identify novel biomarkers of development and viability. Fertil Steril 2006; 85:101.
  32. Scott, RT, Miller, KA, Olivares, R, et al. Microarray based 24 chromosome preimplantation genetic diagnosis (mPGD) is highly predictive of the reproductive potential of human embryos: a prospective blinded non-selection trial. Fertil Steril 2008; 90:S22.
  33. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998; 339:573.
  34. Erenus M, Zouves C, Rajamahendran P, et al. The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization. Fertil Steril 1991; 56:707.
  35. Testart J. Cleavage stage of human embryos two days after fertilization in vitro and their developmental ability after transfer into the uterus. Hum Reprod 1986; 1:29.
  36. Shulman A, Ben-Nun I, Ghetler Y, et al. Relationship between embryo morphology and implantation rate after in vitro fertilization treatment in conception cycles. Fertil Steril 1993; 60:123.
  37. Staessen C, Janssenswillen C, Van den Abbeel E, et al. Avoidance of triplet pregnancies by elective transfer of two good quality embryos. Hum Reprod 1993; 8:1650.
  38. Ziebe S, Petersen K, Lindenberg S, et al. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum Reprod 1997; 12:1545.
  39. Giorgetti C, Terriou P, Auquier P, et al. Embryo score to predict implantation after in-vitro fertilization: based on 957 single embryo transfers. Hum Reprod 1995; 10:2427.
  40. Alikani M, Cohen J, Tomkin G, et al. Human embryo fragmentation in vitro and its implications for pregnancy and implantation. Fertil Steril 1999; 71:836.
  41. Ebner T, Yaman C, Moser M, et al. Prognostic value of first polar body morphology on fertilization rate and embryo quality in intracytoplasmic sperm injection. Hum Reprod 2000; 15:427.
  42. Garello C, Baker H, Rai J, et al. Pronuclear orientation, polar body placement, and embryo quality after intracytoplasmic sperm injection and in-vitro fertilization: further evidence for polarity in human oocytes? Hum Reprod 1999; 14:2588.
  43. Ludwig M, Schöpper B, Al-Hasani S, Diedrich K. Clinical use of a pronuclear stage score following intracytoplasmic sperm injection: impact on pregnancy rates under the conditions of the German embryo protection law. Hum Reprod 2000; 15:325.
  44. Scott LA, Smith S. The successful use of pronuclear embryo transfers the day following oocyte retrieval. Hum Reprod 1998; 13:1003.
  45. Tesarik J, Greco E. The probability of abnormal preimplantation development can be predicted by a single static observation on pronuclear stage morphology. Hum Reprod 1999; 14:1318.
  46. Sakkas D, Shoukir Y, Chardonnens D, et al. Early cleavage of human embryos to the two-cell stage after intracytoplasmic sperm injection as an indicator of embryo viability. Hum Reprod 1998; 13:182.
  47. Shoukir Y, Campana A, Farley T, Sakkas D. Early cleavage of in-vitro fertilized human embryos to the 2-cell stage: a novel indicator of embryo quality and viability. Hum Reprod 1997; 12:1531.
  48. Jackson KV, Ginsburg ES, Hornstein MD, et al. Multinucleation in normally fertilized embryos is associated with an accelerated ovulation induction response and lower implantation and pregnancy rates in in vitro fertilization-embryo transfer cycles. Fertil Steril 1998; 70:60.
  49. Skiadas, CC, Racowsky, C. Developmental rate, cumulative scoring, and embryonic viability. In: Human Preimplantation Embryo Selection, K, Elder, J Cohen (Eds), Informa Healthcare, UK Ltd.
  50. Racowsky C, Ohno-Machado L, Kim J, Biggers JD. Is there an advantage in scoring early embryos on more than one day? Hum Reprod 2009; 24:2104.
  51. Sakkas, D. Evaluation of embryo quality: A strategy for sequential analysis of embryo development with the aim of single embryo transfer. In: Laboratory and Clinical Perspectives, Gardner D, Weissman A, Howles C, Shoham Z (Eds), Martin Dunitz Press, London 2001 p. 223.
  52. Basile N, Nogales Mdel C, Bronet F, et al. Increasing the probability of selecting chromosomally normal embryos by time-lapse morphokinetics analysis. Fertil Steril 2014; 101:699.
  53. Harper J, Coonen E, De Rycke M, et al. What next for preimplantation genetic screening (PGS)? A position statement from the ESHRE PGD Consortium Steering Committee. Hum Reprod 2010; 25:821.
  54. ACOG Committee Opinion No. 430: preimplantation genetic screening for aneuploidy. Obstet Gynecol 2009; 113:766.
  55. Racowsky C. High rates of embryonic loss, yet high incidence of multiple births in human ART: is this paradoxical? Theriogenology 2002; 57:87.
  56. Shen S, Rosen MP, Dobson AT, et al. Day 2 transfer improves pregnancy outcome in in vitro fertilization cycles with few available embryos. Fertil Steril 2006; 86:44.
  57. Gardner DK, Lane M. Culture of viable human blastocysts in defined sequential serum-free media. Hum Reprod 1998; 13 Suppl 3:148.
  58. Braude P, Bolton V, Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 1988; 332:459.
  59. Wilson M, Hartke K, Kiehl M, et al. Transfer of blastocysts and morulae on day 5. Fertil Steril 2004; 82:327.
  60. Practice Committee of American Society for Reproductive Medicine, Practice Committee of Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction. Fertil Steril 2008; 90:S174.
  61. Harton GL, Munné S, Surrey M, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril 2013; 100:1695.
  62. Marek D, Langley M, Gardner DK, et al. Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertil Steril 1999; 72:1035.
  63. Abdelmassih V, Balmaceda JP, Nagy ZP, et al. ICSI and day 5 embryo transfers: higher implantation rates and lower rate of multiple pregnancy with prolonged culture. Reprod Biomed Online 2001; 3:216.
  64. Gardner DK, Surrey E, Minjarez D, et al. Single blastocyst transfer: a prospective randomized trial. Fertil Steril 2004; 81:551.
  65. Criniti A, Thyer A, Chow G, et al. Elective single blastocyst transfer reduces twin rates without compromising pregnancy rates. Fertil Steril 2005; 84:1613.
  66. Henman M, Catt JW, Wood T, et al. Elective transfer of single fresh blastocysts and later transfer of cryostored blastocysts reduces the twin pregnancy rate and can improve the in vitro fertilization live birth rate in younger women. Fertil Steril 2005; 84:1620.
  67. Kissin DM, Kulkarni AD, Mneimneh A, et al. Embryo transfer practices and multiple births resulting from assisted reproductive technology: an opportunity for prevention. Fertil Steril 2015; 103:954.
  68. Chang HJ, Lee JR, Jee BC, et al. Impact of blastocyst transfer on offspring sex ratio and the monozygotic twinning rate: a systematic review and meta-analysis. Fertil Steril 2009; 91:2381.
  69. Skiadas CC, Missmer SA, Benson CB, et al. Risk factors associated with pregnancies containing a monochorionic pair following assisted reproductive technologies. Hum Reprod 2008; 23:1366.
  70. Dar S, Lazer T, Shah PS, Librach CL. Neonatal outcomes among singleton births after blastocyst versus cleavage stage embryo transfer: a systematic review and meta-analysis. Hum Reprod Update 2014; 20:439.
  71. Fernando D, Halliday JL, Breheny S, Healy DL. Outcomes of singleton births after blastocyst versus nonblastocyst transfer in assisted reproductive technology. Fertil Steril 2012; 97:579.
  72. Oron G, Sokal-Arnon T, Son WY, et al. Extended embryo culture is not associated with increased adverse obstetric or perinatal outcome. Am J Obstet Gynecol 2014; 211:165.e1.
  73. Papanikolaou EG, Kolibianakis EM, Tournaye H, et al. Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in IVF. A systematic review and meta-analysis. Hum Reprod 2008; 23:91.
  74. Racowsky C, Jackson KV, Cekleniak NA, et al. The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer. Fertil Steril 2000; 73:558.
  75. Cruz JR, Dubey AK, Patel J, et al. Is blastocyst transfer useful as an alternative treatment for patients with multiple in vitro fertilization failures? Fertil Steril 1999; 72:218.
  76. Milki AA, Hinckley MD, Fisch JD, et al. Comparison of blastocyst transfer with day 3 embryo transfer in similar patient populations. Fertil Steril 2000; 73:126.
  77. Schoolcraft WB, Gardner DK. Blastocyst culture and transfer increases the efficiency of oocyte donation. Fertil Steril 2000; 74:482.
  78. Balaban B, Urman B, Alatas C, et al. Blastocyst-stage transfer of poor-quality cleavage-stage embryos results in higher implantation rates. Fertil Steril 2001; 75:514.
  79. Wilson M, Hartke K, Kiehl M, et al. Integration of blastocyst transfer for all patients. Fertil Steril 2002; 77:693.
  80. Kissin DM, Schieve LA, Reynolds MA. Multiple-birth risk associated with IVF and extended embryo culture: USA, 2001. Hum Reprod 2005; 20:2215.
  81. Karaki RZ, Samarraie SS, Younis NA, et al. Blastocyst culture and transfer: a step toward improved in vitro fertilization outcome. Fertil Steril 2002; 77:114.
  82. Scholtes MC, Zeilmaker GH. A prospective, randomized study of embryo transfer results after 3 or 5 days of embryo culture in in vitro fertilization. Fertil Steril 1996; 65:1245.
  83. Gardner DK, Schoolcraft WB, Wagley L, et al. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod 1998; 13:3434.
  84. Coskun S, Hollanders J, Al-Hassan S, et al. Day 5 versus day 3 embryo transfer: a controlled randomized trial. Hum Reprod 2000; 15:1947.
  85. Huisman GJ, Fauser BC, Eijkemans MJ, Pieters MH. Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture. Fertil Steril 2000; 73:117.
  86. Levron J, Shulman A, Bider D, et al. A prospective randomized study comparing day 3 with blastocyst-stage embryo transfer. Fertil Steril 2002; 77:1300.
  87. Rienzi L, Ubaldi F, Iacobelli M, et al. Day 3 embryo transfer with combined evaluation at the pronuclear and cleavage stages compares favourably with day 5 blastocyst transfer. Hum Reprod 2002; 17:1852.
  88. Utsunomiya T, Naitou T, Nagaki M. A prospective trial of blastocyst culture and transfer. Hum Reprod 2002; 17:1846.
  89. Levitas E, Lunenfeld E, Har-Vardi I, et al. Blastocyst-stage embryo transfer in patients who failed to conceive in three or more day 2-3 embryo transfer cycles: a prospective, randomized study. Fertil Steril 2004; 81:567.
  90. Practice Committee of Society for Assisted Reproductive Technology, Practice Committee of American Society for Reproductive Medicine. Elective single-embryo transfer. Fertil Steril 2012; 97:835.
  91. Pandian Z, Marjoribanks J, Ozturk O, et al. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2013; :CD003416.
  92. Kjellberg AT, Carlsson P, Bergh C. Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis. Hum Reprod 2006; 21:210.
  93. Heijnen EM, Eijkemans MJ, De Klerk C, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007; 369:743.
  94. Vitthala S, Gelbaya TA, Brison DR, et al. The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis. Hum Reprod Update 2009; 15:45.
  95. Papanikolaou EG, Camus M, Kolibianakis EM, et al. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med 2006; 354:1139.
  96. van Peperstraten A, Nelen W, Grol R, et al. The effect of a multifaceted empowerment strategy on decision making about the number of embryos transferred in in vitro fertilisation: randomised controlled trial. BMJ 2010; 341:c2501.
  97. Grady R, Alavi N, Vale R, et al. Elective single embryo transfer and perinatal outcomes: a systematic review and meta-analysis. Fertil Steril 2012; 97:324.
  98. Chaabane S, Sheehy O, Monnier P, et al. Association between ovarian stimulators with or without intrauterine insemination, and assisted reproductive technologies on multiple births. Am J Obstet Gynecol 2015; 213:511.e1.
  99. Jones HW. Multiple births: how are we doing? Fertil Steril 2003; 79:17.
  100. Gleicher N, Oleske DM, Tur-Kaspa I, et al. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000; 343:2.
  101. Dickey RP, Taylor SN, Lu PY, et al. Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertil Steril 2005; 83:671.
  102. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999; 5:493.
  103. Wang JX, Kwan M, Davies MJ, et al. Risk of multiple pregnancy when infertility is treated with ovulation induction by gonadotropins. Fertil Steril 2003; 80:664.
  104. Albano C, Platteau P, Nogueira D, et al. Avoidance of multiple pregnancies after ovulation induction by supernumerary preovulatory follicular reduction. Fertil Steril 2001; 76:820.
  105. ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002; 99:347.
  106. Royal College of Obstetricians and Gynaecologists. The initial investigation and management of the infertile couple. Evidence-based clinical guideline no. 2. Royal College of Obstetricians and Gynaecologists. 1998.
  107. Dickey RP, Taylor SN, Lu PY, et al. Spontaneous reduction of multiple pregnancy: incidence and effect on outcome. Am J Obstet Gynecol 2002; 186:77.