Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 1, pp 121–138 | Cite as

Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality

  • Barbara LukeEmail author
  • Morton B. Brown
  • Ethan Wantman
  • David B. Seifer
  • Amy T. Sparks
  • Paul C. Lin
  • Kevin J. Doody
  • Bradley J. Van Voorhis
  • Logan G. Spector
Assisted Reproduction Technologies



To evaluate the risk of prematurity and infant mortality by maternal fertility status, and for in vitro fertilization (IVF) pregnancies, by oocyte source and embryo state combinations.


Women in 14 States who had IVF-conceived live births during 2004–13 were linked to their infant’s birth and death certificates; a 10:1 sample of non-IVF births was selected for comparison; those with an indication of infertility treatment on the birth certificate were categorized as subfertile, all others were categorized as fertile. Risks were modeled separately for the fertile/subfertile/IVF (autologous-fresh only) group and for the IVF group by oocyte source-embryo state combinations, using logistic regression, and reported as adjusted odds ratios (AORs) and 95% confidence intervals (CI).


The study population included 2,474,195 pregnancies. Placental complications (placenta previa, abruptio placenta, and other excessive bleeding) and prematurity were both increased with pregestational and gestational diabetes and hypertension, among subfertile and IVF groups, and in IVF pregnancies using donor oocytes. Both subfertile and IVF pregnancies were at risk for prematurity and NICU admission; IVF infants were also at risk for small-for-gestation birthweight, and subfertile infants had greater risks for neonatal and infant death. Within the IVF group, pregnancies with donor oocytes and/or thawed embryos were at greater risk of large-for-gestation birthweight, and pregnancies with thawed embryos were at greater risk of neonatal and infant death.


Prematurity was associated with placental complications, diabetes and hypertension, subfertility and IVF groups, and in IVF pregnancies, donor oocytes and/or thawed embryos.


Embryo state Fertility status Infant morbidity Infant mortality Oocyte source Placental complications Prematurity 



The authors wish to thank SART and all of its members for providing clinical information to the SART CORS database for use by patients and researchers. Without the efforts of their members, this research would not have been possible.

The authors also gratefully acknowledge the following State agencies for their assistance in conducting this study:

California Department of Public Health, Office of Health Information and Research

Colorado Department of Public Health and Environment

Connecticut Department of Public Health

Florida Department of Health

Illinois Department of Public Health

Massachusetts Department of Public Health

Michigan Department of Health and Human Services, Division for Vital Records and Health Statistics

New Jersey Department of Health

New York City Department of Health and Mental Hygiene, Bureau of Vital Statistics

New York State Department of Health, Bureau of Health Informatics, Vital Statistics Unit

North Carolina Department of Health

Ohio Department of Health, Bureau of Vital Statistics

Pennsylvania Department of Health, Bureau of Health Statistics and Research

Texas Department of State Health Services, Center for Health Statistics

Virginia Department of Health.

Source of funding

The project described was supported by grant R01CA151973 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health, nor any of the State Departments of Health which contributed data.

Compliance with ethical standards

Conflict of interest

Barbara Luke is a research consultant to the Society for Assisted Reproductive Technology; all other authors report no conflict of interest.


  1. 1.
    Martin JA, Hamilton BE, Ventura SJ, Menacker F, Park MM. Births: final data for 2000. Natl Vital Stat Rep. 2002;50(5):1–102.Google Scholar
  2. 2.
    Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Mathews TJ. Births: final data for 2015. Natl Vital Stat Rep. 2017;66(1):1–70.Google Scholar
  3. 3.
    Toner J, Coddington CC, Doody K, van Voorhis B, Seifer D, Ball GD, Luke B, Wantman E. SART & ART in the US: a 2016 update. Fertil Steril 2016 Sep 1; 106 (3):541–546.Google Scholar
  4. 4.
    Center for Disease Control and Prevention, American Society for Reproductive Medicine, and Society for Assisted Reproductive Technology. 2015 Assisted reproductive technology success rates: national summary report. Atlanta (GA): US Dept. of Health and Human Services; 2017.Google Scholar
  5. 5.
    Basso O, Olsen J. Subfecundity and neonatal mortality: longitudinal study within the Danish National Birth Cohort. BMJ. 2005;330:393–4.CrossRefGoogle Scholar
  6. 6.
    Helmerhorst FM, Perquin DAM, Donker D, Keirse JNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328:261–6.CrossRefGoogle Scholar
  7. 7.
    Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004;103:551–63.CrossRefGoogle Scholar
  8. 8.
    McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A, et al. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol. 2009;146:138–48.CrossRefGoogle Scholar
  9. 9.
    Källén B, Finnström O, Lindam A, Nilsson E, Nygren K-G, Olausson PO. Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years. Hum Reprod. 2010;25:1026–34.CrossRefGoogle Scholar
  10. 10.
    Yang X, Li Y, Li C, Zhang W. Current overview of pregnancy complications and live-birth outcome of assisted reproductive technology in mainland China. Fertil Steril. 2014;101:385–91.CrossRefGoogle Scholar
  11. 11.
    Zhu JL, Obel C, Bech BH, Olsen J, Basso O. Infertility, infertility treatment, and fetal growth restriction. Obstet Gynecol. 2007;110:1326–34.CrossRefGoogle Scholar
  12. 12.
    Raatikainen K, Kuivasaari-Pirinen P, Hippeläinen M, Heinonen S. Comparison of the pregnancy outcomes of subfertile women after infertility treatment and in naturally conceived pregnancies. Hum Reprod. 2012;27:1162–9.CrossRefGoogle Scholar
  13. 13.
    Edwards RG, Ludwig M. Are major defects in children conceived in vitro due to innate problems in patients or to induced genetic damage? Reprod BioMed Online. 2003;7:131–8.CrossRefGoogle 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.CrossRefGoogle Scholar
  15. 15.
    Buckett WM, Tan SL. Congenital abnormalities in children born after assisted reproductive techniques: how much is associated with the presence of infertility and how much with its treatment? Fertil Steril. 2005;84:1318–9.CrossRefGoogle Scholar
  16. 16.
    Sutcliffe AG, Ludwig M. Outcome of assisted reproduction. Lancet. 2007;370:351–9.CrossRefGoogle Scholar
  17. 17.
    Kondapalli LA, Perales-Puchalt A. Low birth weight: is it related to assisted reproductive technology or underlying infertility? Fertil Steril. 2013;99:303–10.CrossRefGoogle Scholar
  18. 18.
    Parrish KM, Holt VL, Connell FA, Williams B, LoGerfo JP. Variations in the accuracy of obstetric procedures and diagnoses on birth records in Washington State, 1989. Am J Epidemiol. 1993;138:119–27.CrossRefGoogle Scholar
  19. 19.
    Buescher PA, Taylor KP, Davis MH, Bowling JM. The quality of the new birth certificate data: a validation study in North Carolina. Am J Public Health. 1993;83:1163–5.CrossRefGoogle Scholar
  20. 20.
    Piper JM, Mitchel EF, Snowden M, Hall C, Adams M, Taylor P. Validation of 1989 Tennessee birth certificate using maternal and newborn hospital records. Am J Epidemiol. 1993;137:758–68.CrossRefGoogle Scholar
  21. 21.
    Woolbright LA, Harshberger DS. The revised standard certificate of live birth: analysis of medical risk factor data from birth certificates in Alabama, 1988-92. Public Health Rep. 1995;110:59–63.Google Scholar
  22. 22.
    Clark K, Chun-Mei F, Burnett C. Accuracy of birth certificate data regarding the amount, timing, and adequacy of prenatal care using prenatal medical records as referents. Am J Epidemiol. 1997;145:68–71.CrossRefGoogle Scholar
  23. 23.
    Dobie SA, Baldwin L-M, Rosenblatt RA, Fordyce MA, Andrilla CH, Hart LG. How well do birth certificates describe the pregnancies they report? The Washington State experience with low-risk pregnancies. Matern Child Health J. 1998;2:145–54.CrossRefGoogle Scholar
  24. 24.
    Reichman NE, Hade EM. Validation of birth certificate data: a study of women in New Jersey’s healthy start program. Ann Epidemiol. 2001;11:186–93.CrossRefGoogle Scholar
  25. 25.
    Roohan PJ, Josberger RE, Acar J, Dabir P, Feder HM, Gagliano PJ. Validation of birth certificate data in New York State. J Community Health. 2003;28:335–46.CrossRefGoogle Scholar
  26. 26.
    Dietz P, Bombard J, Mulready-Ward C, Gauthier J, Sackoff J, Brozicevic P, et al. Validation of selected items on the 2003 US Standard Certificate of Live Birth: New York City and Vermont. Public Health Rep. 2015;130:60–70.CrossRefGoogle Scholar
  27. 27.
    Martin JA, Wilson EC, Osterman MJK, Saadi EW, Sutton SR, Hamilton BE. Assessing the quality of medical and health data from the 2003 birth certificate revision: results from two states. Natl Vital Stat Rep. 2013;62(2):1–20.Google Scholar
  28. 28.
    Heron M. Deaths: leading causes for 2016. Natl Vital Stat Rep. 2018;67(6):1–77.Google Scholar
  29. 29.
    Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected for implausible gestational age estimates. Pediatrics. 2014;133:844–53.CrossRefGoogle Scholar
  30. 30.
    Land JA. How should we report on perinatal outcome? Hum Reprod. 2006;21:2638–9.CrossRefGoogle Scholar
  31. 31.
    Luke B, Gopal D, Cabral H, Stern JE, Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am J Obstet Gynecol. 2017;217:327.e1–14.CrossRefGoogle Scholar
  32. 32.
    Luke B, Gopal D, Cabral H, Stern JE, Diop H. Adverse pregnancy, birth, and infant outcomes in twins: effects of maternal fertility status and infant gender combinations; the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am J Obstet Gynecol. 2017;217:330.e1–15.CrossRefGoogle Scholar
  33. 33.
    Albrecht SS, Kuklina EV, Bansil P, Jamieson DJ, Whiteman MK, Kourtis AP, et al. Diabetes trends among delivery hospitalizations in the US, 1994-2004. Diabetes Care. 2010;33:768–73.CrossRefGoogle Scholar
  34. 34.
    Bateman BT, Shaw KM, Kuklina EV, Callaghan WM, Seely EW. Hypertension in women of reproductive age in the United States: NHANES 1999-2008. PLoS One. 2012;7:e36171. Scholar
  35. 35.
    Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe obstetric morbidity in the United States. Obstet Gynecol. 2009;113:1299–306.CrossRefGoogle Scholar
  36. 36.
    Bateman BT, Bansil P, Hernandez-Diaz S, Mhyre JM, Callaghan WM, Kuklina EV. Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admissions. Am J Obstet Gynecol. 2012;206:134.e1–8.CrossRefGoogle Scholar
  37. 37.
    Berg CJ, MacKay AP, Qin C, Callaghan WM. Overview of maternal morbidity during hospitalization for labor and delivery in the United States, 1993–1997 and 2001–2005. Obstet Gynecol 2009; 113:1075–1081.Google Scholar
  38. 38.
    Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol. 2010;116:1302–9.CrossRefGoogle Scholar
  39. 39.
    Kuklina EV, Callaghan WM. Chronic heart disease and severe maternal morbidity among hospitalizations for pregnancy in the USA: 1995-2006. Br J Obstet Gynecol. 2011;118:345–52.CrossRefGoogle Scholar
  40. 40.
    Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM. Pregnancy-related mortality in the United States, 2006-2010. Obstet Gynecol. 2015;125:5–12.CrossRefGoogle Scholar
  41. 41.
    Romundstad LB, Romundstad PR, Sunde A, von Düring V, Skjærven R, 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; 21:2353–2358.Google Scholar
  42. 42.
    Luke B, Stern JE, Kotelchuck M, Declercq E, Cohen B, Diop H. Birth outcomes by infertility diagnosis: analyses of the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART). J Reprod Med. 2015;60:480–90.Google Scholar
  43. 43.
    Luke B, Stern JE, Hornstein MD, Kotelchuck M, Diop H, Cabral H, et al. Is the wrong question being asked in infertility research? J Assist Reprod Genet. 2016;33(1):3–8.CrossRefGoogle Scholar
  44. 44.
    Schachter M, Tovbin Y, Arieli S, Friedler S, Ron-El R, Sherman D. In vitro fertilization is a risk factor for vasa previa. Fertil Steril. 2002;78:642–3.CrossRefGoogle Scholar
  45. 45.
    Sheiner E, Shoham-Vardi I, Hallak M, Hershkowitz R, Katz M, Mazor M. Placenta previa: obstetric risk factors and pregnancy outcome. J Matern Fetal Med. 2001;10:414–9.CrossRefGoogle Scholar
  46. 46.
    Ebbing C, Kiserud T, Johnsen SL, Albrechtsen S, Rasmussen S. Prevalence, risk factors and outcomes of velamentous and marginal cord insertions: a population-based study of 634,741 pregnancies. PLoS One. 2013;8:e70380. Scholar
  47. 47.
    Rosenberg T, Pariente G, Serienko R, Wiznitzer A, Sheiner E. Critical analysis of risk factors and outcome of placenta previa. Arch Gynecol Obstet. 2011;284:47–51.CrossRefGoogle Scholar
  48. 48.
    Joy J, Gannon C, McClure N, Cooke I. Is assisted reproduction associated with abnormal placentation? Pediatr Dev Pathol. 2012;15:306–14.CrossRefGoogle Scholar
  49. 49.
    Nelissen ECM, Dumoulin JCM, Daunay A, Evers JLH, Tost J, van Montfort APA. Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions. Hum Reprod. 2013;28:1117–26.CrossRefGoogle Scholar
  50. 50.
    Nakamura Y, Yaguchi C, Itoh H, Sakamoto R, Kimura T, Furuta N, et al. Morphologic characteristics of the placental basal plate in in vitro fertilization pregnancies: a possible association with the amount of bleeding in delivery. Hum Pathol. 2015;46:1171–9.CrossRefGoogle Scholar
  51. 51.
    Sakian S, Louie K, Wong EC, Havelock J, Kashyap S, Rowe T, et al. Altered gene expression of H19 and IGF2 in placentas from ART pregnancies. Placenta. 2015;36:1100–5.CrossRefGoogle Scholar
  52. 52.
    Catov JM, Wu CS, Olsen J, Sutton-Tyrrell K, Li J, Nohr EA. Early or recurrent preterm birth and maternal cardiovascular disease risk. Ann Epidemiol. 2010;20:604–9.CrossRefGoogle Scholar
  53. 53.
    Arias F, Rodriguez L, Raayne SC, Kraus FT. Maternal placental vasculopathy and infection: two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol. 1993;168:585–91.CrossRefGoogle Scholar
  54. 54.
    Germain A, Carvajal J, Sanchez M, Valenzuela G, Tsunekawa H, Chuaqui B. Preterm labor: placental pathology and clinical correlation. Obstet Gynecol. 1999;94:284–9.Google Scholar
  55. 55.
    Kato O, Kawasaki N, Bodri D, Kuroda T, Kawachiya S, Kato K, et al. Neonatal outcome and birth defects in 6,623 singletons born following minimal ovarian stimulation and vitrified versus fresh single embryo transfer. Eur J Obstet Gyencol Reprod Biol. 2012;161:46–50.CrossRefGoogle Scholar
  56. 56.
    Weinerman R, Mainigi M. Why we should transfer frozen instead of fresh embryos: the translational rationale. Fertil Steril. 2014;102:10–8.CrossRefGoogle Scholar
  57. 57.
    Barnhart KT. Introduction: are we ready to eliminate the transfer of fresh embryos in in vitro fertilization? Fertil Steril. 2014;102:1–2.CrossRefGoogle Scholar
  58. 58.
    Shapiro BS, Daneshmand 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.CrossRefGoogle Scholar
  59. 59.
    Shapiro BS, Daneshmand ST, De Leon L, Garner FC, Aguirre M, Hudson C. Frozen-thawed embryo transfer is associated with a significantly reduced incidence of ectopic pregnancy. Fertil Steril. 2012;98:1490–4.CrossRefGoogle Scholar
  60. 60.
    Santos MA, Kuijk EW, Macklon NS. The impact of ovarian stimulation for IVF on the developing embryo. Reproduction. 2010;139:23–34.CrossRefGoogle Scholar
  61. 61.
    Pinborg A, Loft A, Henningsen A-KA, Rasmussen S, Andersen AN. Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995-2006. Fertil Steril. 2010;94:1320–7.CrossRefGoogle Scholar
  62. 62.
    Ishihara O, Araki R, Kuwahara A, Itakura A, Saito H, Adamson GD. Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan. Fertil Steril. 2014;101:128–33.CrossRefGoogle Scholar
  63. 63.
    Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Hum Reprod. 1995;10:3332–7.CrossRefGoogle Scholar
  64. 64.
    Belva F, Henriet S, Van den Abbeel E, Camus M, Devroey P, Van der Elst J, et al. Neonatal outcome of 937 children born after transfer of cryopreserved embryos obtained by ICSI and IVF and comparison with outcome data of fresh ICSI and IVF cycles. Hum Reprod. 2008;23:2227–38.CrossRefGoogle Scholar
  65. 65.
    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.CrossRefGoogle Scholar
  66. 66.
    Murakami M, Egashira A, Murakami K, Araki Y, Kuramoto T. Perinatal outcome of twice-frozen-thawed embryo transfers: a clinical follow-up study. Fertil Steril. 2011;95:2648–50.CrossRefGoogle Scholar
  67. 67.
    Wennerholm U-B, Henningsen A-KA, 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.CrossRefGoogle Scholar
  68. 68.
    Luke B, Brown MB, Wantman E, Stern JE, Toner J, Coddington CC. Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles. J Assist Reprod Genet. 2017;34:191–200.CrossRefGoogle Scholar
  69. 69.
    Luke B, Brown MB, Spector LG. Validation of infertility treatment and assisted reproductive technology use on the birth certificate in eight States. (Research Letter) Am J Obstet Gynecol 2016; 215:126–7. PMID:26945609, 127.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Barbara Luke
    • 1
    Email author
  • Morton B. Brown
    • 2
  • Ethan Wantman
    • 3
  • David B. Seifer
    • 4
  • Amy T. Sparks
    • 5
  • Paul C. Lin
    • 6
  • Kevin J. Doody
    • 7
  • Bradley J. Van Voorhis
    • 5
  • Logan G. Spector
    • 8
  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, Inc.New YorkUSA
  4. 4.Yale Fertility, Yale School of MedicineNew HavenUSA
  5. 5.Department of Obstetrics and GynecologyUniversity of IowaIowa CityUSA
  6. 6.Seattle Reproductive MedicineSeattleUSA
  7. 7.Center for Assisted ReproductionBedfordUSA
  8. 8.Department of PediatricsUniversity of MinnesotaMinneapolisUSA

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