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Semin Reprod Med 2018; 36(03/04): 195-203
DOI: 10.1055/s-0038-1677048
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Assisted Reproductive Technology and Origins of Disease: The Clinical Realities and Implications

Scott J. Morin
1   Reproductive Medicine Associates of Northern California, San Francisco, California
,
Emre Seli
2   Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey
3   Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
› Author Affiliations
Further Information

Publication History

Publication Date:
13 March 2019 (online)

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Abstract

The majority of offspring born following assisted reproductive technology (ART) achieve equivalent development milestones and demonstrate comparable health as spontaneously conceived children. Yet, multiple studies have suggested offspring conceived with ART have slightly increased risk of metabolic derangements, cardiovascular disease, and malignancy. However, the associations observed in these studies often inadequately control for a variety of confounding variables, such as multiple gestation, premature birth, and low birth weight. Furthermore, many studies fail to account for the increased risk of many of these pathologies in the offspring of subfertile women in general. Lastly, the absolute risk of most of the ailments studied is extremely low. In nearly all examples, the number of women who would need to be treated to observe one additional diagnosis is substantially high. When compared with the number of couples who would have remained childless due to severe male factor infertility or would have been exposed to the risk of passing on a severe monogenic disorder, the general increased risks to ART-exposed children is very small.

Keywords

assisted reproductive technologies - embryo culture - IVF offspring - multiple gestations - single embryo transfer
 

  • References

  • 1 European Society of Human Reproduction and Embryology. More than 8 million babies born from IVF since the world's first in 1978: European IVF pregnancy rates now steady at around 36 percent, according to ESHRE monitoring. ScienceDaily. Available at: www.sciencedaily.com/releases/2018/07/180703084127.htm . Accessed July 3, 2018
    PubMedGoogle Scholar
  • 2 Sunderam S, Kissin DM, Crawford SB. , et al. Assisted reproductive technology surveillance - United States, 2014. MMWR Surveill Summ 2017; 66 (06) 1-24
    PubMedGoogle Scholar
  • 3 Saito H, Jwa SC, Kuwahara A. , et al. Assisted reproductive technology in Japan: a summary report for 2015 by The Ethics Committee of The Japan Society of Obstetrics and Gynecology. Reprod Med Biol 2017; 17 (01) 20-28
    PubMedGoogle Scholar
  • 4 de Mouzon J, Lancaster P, Nygren KG. , et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART). World Collaborative Rep Assist Reproduct Tech; 2002. Hum Reprod 2009; 24 (09) 2310-2320
    CrossrefPubMedGoogle Scholar
  • 5 Strong C. Too many twins, triplets, quadruplets, and so on: a call for new priorities. J Law Med Ethics 2003; 31 (02) 272-282
    CrossrefPubMedGoogle Scholar
  • 6 Grifo JA, Hodes-Wertz B, Lee HL, Amperloquio E, Clarke-Williams M, Adler A. Single thawed euploid embryo transfer improves IVF pregnancy, miscarriage, and multiple gestation outcomes and has similar implantation rates as egg donation. J Assist Reprod Genet 2013; 30 (02) 259-264
    CrossrefPubMedGoogle Scholar
  • 7 Scott Jr RT, Franasiak JM, Forman EJ. Comprehensive chromosome screening with synchronous blastocyst transfer: time for a paradigm shift. Fertil Steril 2014; 102 (03) 660-661
    CrossrefPubMedGoogle Scholar
  • 8 Kulkarni AD, Jamieson DJ, Jones Jr HW. , et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013; 369 (23) 2218-2225
    CrossrefPubMedGoogle Scholar
  • 9 Forman EJ, Hong KH, Franasiak JM, Scott Jr RT. Obstetrical and neonatal outcomes from the BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates. Am J Obstet Gynecol 2014; 210 (02) 157.e1-157.e6
    CrossrefPubMedGoogle Scholar
  • 10 Fleming TP, Velazquez MA, Eckert JJ, Lucas ES, Watkins AJ. Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring. Anim Reprod Sci 2012; 130 (3-4): 193-197
    CrossrefPubMedGoogle Scholar
  • 11 Fleming TP, Lucas ES, Watkins AJ, Eckert JJ. Adaptive responses of the embryo to maternal diet and consequences for post-implantation development. Reprod Fertil Dev 2011; 24 (01) 35-44
    PubMedGoogle Scholar
  • 12 Whitten WK. Culture of tubal mouse ova. Nature 1956; 177 (4498): 96
    PubMedGoogle Scholar
  • 13 De Kretzer D, Dennis P, Hudson B. , et al. Transfer of a human zygote. Lancet 1973; 2 (7831): 728-729
    PubMedGoogle Scholar
  • 14 Wiemer KE, Cohen J, Amborski GF. , et al. In-vitro development and implantation of human embryos following culture on fetal bovine uterine fibroblast cells. Hum Reprod 1989; 4 (05) 595-600
    CrossrefPubMedGoogle Scholar
  • 15 Tucker MJ, Kort HI, Toledo AA. , et al. Effect of coculture on subsequent survival and implantation of cryopreserved human embryos. J Assist Reprod Genet 1995; 12 (10) 689-692
    CrossrefPubMedGoogle Scholar
  • 16 Gardner DK. The impact of physiological oxygen during culture, and vitrification for cryopreservation, on the outcome of extended culture in human IVF. Reprod Biomed Online 2016; 32 (02) 137-141
    CrossrefPubMedGoogle Scholar
  • 17 Morin SJ. Oxygen tension in embryo culture: does a shift to 2% O2 in extended culture represent the most physiologic system?. J Assist Reprod Genet 2017; 34 (03) 309-314
    CrossrefPubMedGoogle Scholar
  • 18 Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: final data for 2016. Natl Vital Stat Rep 2018; 67 (01) 1-55
    PubMedGoogle Scholar
  • 19 National Collaborating Centre for Women's and Children's Health (UK). Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press; 2011
    Google Scholar
  • 20 Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA. Infant and childhood growth patterns, insulin sensitivity, and blood pressure in prematurely born young adults. Pediatrics 2008; 122 (02) 313-321
    CrossrefPubMedGoogle Scholar
  • 21 Morrison KM, Ramsingh L, Gunn E. , et al. Cardiometabolic health in adults born premature with extremely low birth weight. Pediatrics 2016; 138 (04) e20160515
    CrossrefPubMedGoogle Scholar
  • 22 Larroque B, Bréart G, Kaminski M. , et al; Epipage Study Group. Survival of very preterm infants: Epipage, a population based cohort study. Arch Dis Child Fetal Neonatal Ed 2004; 89 (02) F139-F144
    CrossrefPubMedGoogle Scholar
  • 23 Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993; 307 (6914): 1239-1243
    CrossrefPubMedGoogle Scholar
  • 24 Schwartz DB, Daoud Y, Zazula P. , et al. Gestational diabetes mellitus: metabolic and blood glucose parameters in singleton versus twin pregnancies. Am J Obstet Gynecol 1999; 181 (04) 912-914
    CrossrefPubMedGoogle Scholar
  • 25 Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. ; Kaiser Permanente of Colorado GDM Screening Program. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005; 28 (03) 579-584
    CrossrefPubMedGoogle Scholar
  • 26 Damm P, Houshmand-Oeregaard A, Kelstrup L, Lauenborg J, Mathiesen ER, Clausen TD. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia 2016; 59 (07) 1396-1399
    CrossrefPubMedGoogle Scholar
  • 27 Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009; 201 (03) 269.e1-269.e10
    CrossrefPubMedGoogle Scholar
  • 28 Halliday J, Wilson C, Hammarberg K. , et al. Comparing indicators of health and development of singleton young adults conceived with and without assisted reproductive technology. Fertil Steril 2014; 101 (04) 1055-1063
    CrossrefPubMedGoogle Scholar
  • 29 Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004; 328 (7434): 261
    CrossrefPubMedGoogle Scholar
  • 30 Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004; 103 (03) 551-563
    CrossrefPubMedGoogle Scholar
  • 31 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 (05) 485-503
    CrossrefPubMedGoogle Scholar
  • 32 Basso O, Baird DD. Infertility and preterm delivery, birthweight, and caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18 (11) 2478-2484
    CrossrefPubMedGoogle Scholar
  • 33 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 (04) 1162-1169
    CrossrefPubMedGoogle Scholar
  • 34 Allen VM, Wilson RD, Cheung A. ; Genetics Committee; Reproductive Endocrinology and Infertility Committee. Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can 2006; 28 (03) 220-233
    CrossrefPubMedGoogle Scholar
  • 35 Martin AS, Chang J, Zhang Y. , et al; States Monitoring Assisted Reproductive Technology (SMART) Collaborative. Perinatal outcomes among singletons after assisted reproductive technology with single-embryo or double-embryo transfer versus no assisted reproductive technology. Fertil Steril 2017; 107 (04) 954-960
    CrossrefPubMedGoogle Scholar
  • 36 Sullivan EA, Wang YA, Hayward I. , et al. Single embryo transfer reduces the risk of perinatal mortality, a population study. Hum Reprod 2012; 27 (12) 3609-3615
    CrossrefPubMedGoogle Scholar
  • 37 Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN. Consequences of vanishing twins in IVF/ICSI pregnancies. Hum Reprod 2005; 20 (10) 2821-2829
    CrossrefPubMedGoogle Scholar
  • 38 Pinborg A, Lidegaard O, Andersen AN. The vanishing twin: a major determinant of infant outcome in IVF singleton births. Br J Hosp Med (Lond) 2006; 67 (08) 417-420
    CrossrefPubMedGoogle Scholar
  • 39 Heisey AS, Bell EM, Herdt-Losavio ML, Druschel C. Surveillance of congenital malformations in infants conceived through assisted reproductive technology or other fertility treatments. Birth Defects Res A Clin Mol Teratol 2015; 103 (02) 119-126
    CrossrefPubMedGoogle Scholar
  • 40 Hwang SS, Dukhovny D, Gopal D. , et al. Health of infants after ART-treated, subfertile, and fertile deliveries. Pediatrics 2018; 142 (02) 1-11 . Doi: 10.1542/peds.2017-4069. [Epub July 3, 2018]
    CrossrefPubMedGoogle Scholar
  • 41 Wen J, Jiang J, Ding C. , et al. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril 2012; 97 (06) 1331-7.e1 , 4
    CrossrefPubMedGoogle Scholar
  • 42 Davies MJ, Moore VM, Willson KJ. , et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012; 366 (19) 1803-1813
    CrossrefPubMedGoogle Scholar
  • 43 Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment: Part I--General health outcomes. Hum Reprod Update 2013; 19 (03) 232-243
    CrossrefPubMedGoogle Scholar
  • 44 Hargreave M, Jensen A, Toender A, Andersen KK, Kjaer SK. Fertility treatment and childhood cancer risk: a systematic meta-analysis. Fertil Steril 2013; 100 (01) 150-161
    CrossrefPubMedGoogle Scholar
  • 45 Källén B, Finnström O, Nygren KG, Olausson PO. In vitro fertilization in Sweden: child morbidity including cancer risk. Fertil Steril 2005; 84 (03) 605-610
    CrossrefPubMedGoogle Scholar
  • 46 Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome?. Fertil Steril 2010; 94 (05) 1680-1683
    CrossrefPubMedGoogle Scholar
  • 47 Moll AC, Imhof SM, Cruysberg JR, Schouten-van Meeteren AY, Boers M, van Leeuwen FE. Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet 2003; 361 (9354): 309-310
    CrossrefPubMedGoogle Scholar
  • 48 Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H. Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 2001; 81 (01) 77-82
    PubMedGoogle Scholar
  • 49 Winston RM, Hardy K. Are we ignoring potential dangers of in vitro fertilization and related treatments?. Nat Cell Biol 2002; 4 (Suppl): s14-s18
    CrossrefPubMedGoogle Scholar
  • 50 Anteby I, Cohen E, Anteby E, BenEzra D. Ocular manifestations in children born after in vitro fertilization. Arch Ophthalmol 2001; 119 (10) 1525-1529
    CrossrefPubMedGoogle Scholar
  • 51 Viot GB, Epelboin S, Olivennes F. Epigenetic risks in assisted reproductive technologies (ART): results from a French cohort composed of 15,162 children conceived by in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril 2010; 94 (4, Suppl): s22
    PubMedGoogle Scholar
  • 52 Dommering CJ, van der Hout AH, Meijers-Heijboer H, Marees T, Moll AC. IVF and retinoblastoma revisited. Fertil Steril 2012; 97 (01) 79-81
    CrossrefPubMedGoogle Scholar
  • 53 Stolk L, Perry JR, Chasman DI. , et al; LifeLines Cohort Study. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012; 44 (03) 260-268
    CrossrefPubMedGoogle Scholar
  • 54 AlAsiri S, Basit S, Wood-Trageser MA. , et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 2015; 125 (01) 258-262
    CrossrefPubMedGoogle Scholar
  • 55 Desai S, Wood-Trageser M, Matic J. , et al. MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab 2017; 102 (02) 576-582
    PubMedGoogle Scholar
  • 56 Bay B, Mortensen EL, Kesmodel US. Assisted reproduction and child neurodevelopmental outcomes: a systematic review. Fertil Steril 2013; 100 (03) 844-853
    CrossrefPubMedGoogle Scholar
  • 57 Leslie GI, Gibson FL, McMahon C, Cohen J, Saunders DM, Tennant C. Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age. Hum Reprod 2003; 18 (10) 2067-2072
    CrossrefPubMedGoogle Scholar
  • 58 Leunens L, Celestin-Westreich S, Bonduelle M, Liebaers I, Ponjaert-Kristoffersen I. Cognitive and motor development of 8-year-old children born after ICSI compared to spontaneously conceived children. Hum Reprod 2006; 21 (11) 2922-2929
    CrossrefPubMedGoogle Scholar
  • 59 Mains L, Zimmerman M, Blaine J. , et al. Achievement test performance in children conceived by IVF. Hum Reprod 2010; 25 (10) 2605-2611
    CrossrefPubMedGoogle Scholar
  • 60 Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab 2008; 93 (05) 1682-1688
    CrossrefPubMedGoogle Scholar
  • 61 Zhu JL, Obel C, Basso O. , et al. Infertility, infertility treatment and behavioural problems in the offspring. Paediatr Perinat Epidemiol 2011; 25 (05) 466-477
    CrossrefPubMedGoogle Scholar
  • 62 Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment. Part II--Mental health and development outcomes. Hum Reprod Update 2013; 19 (03) 244-250
    CrossrefPubMedGoogle Scholar
  • 63 Ceelen M, van Weissenbruch MM, Roos JC, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Body composition in children and adolescents born after in vitro fertilization or spontaneous conception. J Clin Endocrinol Metab 2007; 92 (09) 3417-3423
    CrossrefPubMedGoogle Scholar
  • 64 Ceelen M, van Weissenbruch MM, Prein J. , et al. Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8-18 years of IVF children and spontaneously conceived controls born to subfertile parents. Hum Reprod 2009; 24 (11) 2788-2795
    CrossrefPubMedGoogle Scholar
  • 65 Belva F, Painter R, Bonduelle M, Roelants M, Devroey P, De Schepper J. Are ICSI adolescents at risk for increased adiposity?. Hum Reprod 2012; 27 (01) 257-264
    CrossrefPubMedGoogle Scholar
  • 66 Pelkonen S, Koivunen R, Gissler M. , et al. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995-2006. Hum Reprod 2010; 25 (04) 914-923
    CrossrefPubMedGoogle Scholar
  • 67 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 (01) 128-133
    CrossrefPubMedGoogle Scholar
  • 68 Pinborg A, Henningsen AA, Loft A, Malchau SS, Forman J, Andersen AN. Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?. Hum Reprod 2014; 29 (03) 618-627
    CrossrefPubMedGoogle Scholar
  • 69 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 (02) 368-77.e1 , 9
    CrossrefPubMedGoogle Scholar
  • 70 Lidegaard O, Pinborg A, Andersen AN. Imprinting diseases and IVF: Danish National IVF cohort study. Hum Reprod 2005; 20 (04) 950-954
    CrossrefPubMedGoogle Scholar
  • 71 Kallen B, Finnstrom O, Lindam A. , et al. Congenital malformations in infants born after in vitro fertilization in Sweden 2010 birth defects. Res A Clin Mol Teratol 2010; 88 (03) 137-143
    PubMedGoogle Scholar
  • 72 Fruchter E, Beck-Fruchter R, Hourvitz A. , et al. Health and functioning of adolescents conceived by assisted reproductive technology. Fertil Steril 2017; 107 (03) 774-780
    CrossrefPubMedGoogle Scholar
  • 73 ESHRE PGD Consortium Steering Committee. ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001). Hum Reprod 2002; 17 (01) 233-246
    CrossrefPubMedGoogle Scholar
  • 74 Harper JC, Wilton L, Traeger-Synodinos J. , et al; The ESHRE PGD Consortium. The ESHRE PGD Consortium: 10 years of data collection. Hum Reprod Update 2012; 18 (03) 234-247
    CrossrefPubMedGoogle Scholar
  • 75 De Rycke M, Belva F, Goossens V. , et al. ESHRE PGD Consortium data collection XIII: cycles from January to December 2010 with pregnancy follow-up to October 2011. Hum Reprod 2015; 30 (08) 1763-1789
    CrossrefPubMedGoogle Scholar
  • 76 De Rycke M, Goossens V, Kokkali G, Meijer-Hoogeveen M, Coonen E, Moutou C. ESHRE PGD Consortium data collection XIV-XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013. Hum Reprod 2017; 32 (10) 1974-1994
    CrossrefPubMedGoogle Scholar
  • 77 Levy R. Male infertility and surgical sperm retrieval/ICSI. Paper presented at the European Society of Human Reproduction and Embryology. May 27, 2010. Available at: https://www.eshre.eu/~/media/sitecore-files/SIGs/Reproductive.../Levy2.pdf?la=en . Accessed July 30, 2018
    PubMedGoogle Scholar