ABSTRACT
Modern techniques in assisted reproduction have become a common and accepted form
of clinical care benefiting an estimated 1 in 10 people of reproductive age who are
subfertile or infertile. The success of these technologies relies, to large extent,
on the remarkable tolerance of mammalian gametes and the preimplantation embryo to
physical manipulations and alterations to their chemical environment. Recent reports
from both human and animal studies, however, suggest that our faith in the ability
of these “germ cells” to accurately recapitulate the normal process of early development
under such conditions may be misplaced. While acknowledging the recognized risk factors
of increased maternal age and infertility in human assisted reproductive technology
(ART) subjects and the transfer of supernumerary embryos, evidence from animal studies
indicates that ART procedures can directly contribute to the variable perinatal outcomes
observed and imprinting disorders recently recognized. Controversy surrounds the specific
nature and extent of these contributions; however, ovarian stimulation, in vitro maturation
and embryo culture, intracytoplasmic sperm injection, and gamete/embryo cryopreservation
have all been implicated. These issues are considered in detail in this article, which
evaluates the insights that can be gained from studies with animals.
KEYWORDS
Human - assisted reproduction - large offspring syndrome - genomic imprinting
REFERENCES
- 1
Reddy U M, Wapner R J, Rebar R W, Tasca R J.
Infertility, assisted reproductive technology, and adverse pregnancy outcomes.
Obstet Gynecol.
2007;
109
967-977
- 2
El Toukhy T, Khalaf Y, Braude P.
IVF results: optimize not maximize.
Am J Obstet Gynecol.
2006;
322-331
- 3
Olivennes F, Fanchin R, Ledee N, Righini C, Kadoch I J, Frydman R.
Perinatal outcome and developmental studies on children born after IVF.
Hum Reprod Update.
2002;
8
117-128
- 4 Thibier M, Humblot P, Guerin B.
Role of reproductive biotechnologies: global perspective, current methods and success
rates. In: Simm G, Villanueva B, Sinclair KD, Townsend S Farm Animal Genetic Resources.
BSAS publication no. 30. Nottingham, UK; Nottingham University Press 2004: 177-189
- 5
Young L E, Sinclair K D, Wilmut I.
Large offspring syndrome in cattle and sheep.
Rev Reprod.
1998;
3
155-163
- 6
Sinclair K D, Young L E, Wilmut I, McEvoy T G.
In-utero overgrowth in ruminants following embryo culture: lessons from mice and a
warning to men.
Hum Reprod.
2000;
15(Suppl 5)
68-86
- 7
Young L E, Fernandes K, McEvoy T G et al..
Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo
culture.
Nat Genet.
2001;
27
153-154
- 8
Edwards R G, 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
131-138
- 9
Niemitz E L, Feinberg A P.
Epigenetics and assisted reproductive technology: a call for investigation.
Am J Hum Genet.
2004;
74
599-609
- 10
Baird D T, Collins J, Egozcue J et al..
Fertility and ageing. ESHRE Capri Workshop Group.
Hum Reprod Update.
2005;
11
261-276
- 11
Sauer M V.
The impact of age on reproductive potential: lessons learned from oocyte donation.
Maturitas.
1998;
30
221-225
- 12
Hassold T, Hunt P.
To err (meiotically) is human: the genesis of human aneuploidy.
Nat Rev Genet.
2001;
2
280-291
- 13
Hassold T, Chiu D.
Maternal age-specific rates of numerical chromosome abnormalities with special reference
to trisomy.
Hum Genet.
1985;
70
11-17
- 14
Lamb N E, Freeman S B, Savage-Austin A et al..
Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction
in both maternal meiosis I and meiosis II.
Nat Genet.
1996;
14
400-405
- 15
Simon C, Rubio C, Vidal F et al..
Increased chromosome abnormalities in human preimplantation embryos after in-vitro
fertilization in patients with recurrent miscarriage.
Reprod Fertil Dev.
1998;
10
87-92
- 16
Ruangvutilert P, Delhanty J D, Serhal P, Simopoulou M, Rodeck C H, Harper J C.
FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos.
Prenat Diagn.
2000;
20
552-560
- 17
Mastenbroek S, Twisk M, van Echten-Arends J et al..
In vitro fertilization with preimplantation genetic screening.
N Engl J Med.
2007;
357
9-17
- 18
Braude P, Flinter F.
Use and misuse of preimplantation genetic testing.
BMJ.
2007;
335
752-754
- 19
Munné S, Sanalinas M, Escudero T, Marquez C, Cohen J.
Chromosome mosaicism in cleavage-stage human embryos: evidence of a maternal age effect.
Reprod Biomed Online.
2002;
4
223-232
- 20
Daphnis D D, Delhanty J DA, Jerkovic S, Geyer J, Craft I, Harper J C.
Detailed FISH analysis of day 5 human embryos reveals the mechanisms leading to mosaic
aneuploidy.
Hum Reprod.
2005;
20
129-137
- 21
Bielanska M, Shaoguang J, Bernier M, Tan S L, Ao A.
Diploid-aneuploid mosaicism in human embryos cultured to the blastocyst stage.
Fertil Steril.
2005;
84
336-342
- 22
Bean C J, Hunt P A, Millie E A, Hassold T J.
Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage
divisions of the mammalian embryo are non-disjunction-prone.
Hum Mol Genet.
2001;
10
963-972
- 23
Viuff D, Hendriksen P J, Vos P L et al..
Chromosomal abnormalities and developmental kinetics in in vivo-developed cattle embryos
at days 2 to 5 after ovulation.
Biol Reprod.
2001;
65
204-208
- 24
Bean C J, Hassold T J, Judis L, Hunt P A.
Fertilization in vitro increases non-disjunction during early cleavage divisions in
a mouse model system.
Hum Reprod.
2002;
17
2362-2367
- 25
Draper E S, Kurinczuk J J, Abrams K R, Clarke M.
Assessment of separate contributions to perinatal mortality of infertility history
and treatment: a case-control analysis.
Lancet.
1999;
353
1746-1749
- 26
Gaudoin M, Dobbie R, Finlayson A, Chalmers J, Cameron I T, Fleming R.
Ovulation induction/intrauterine insemination in infertile couples is associated with
low-birth-weight infants.
Am J Obstet Gynecol.
2003;
188
611-616
- 27
Pandian Z, Bhattacharya S, Templeton A.
Review of unexplained infertility and obstetric outcome: a 10 year review.
Hum Reprod.
2001;
16
2593-2597
- 28
Serafini P.
Outcome and follow-up of children born after IVF-surrogacy.
Hum Reprod Update.
2001;
7
23-27
- 29
Olivennes F, Rufat P, Andre B, Pourade A, Quiros M C, Frydman R.
The increased risk of complication observed in singleton pregnancies resulting from
in-vitro fertilization (IVF) does not seem to be related to the IVF method itself.
Hum Reprod.
1993;
8
1297-1300
- 30
Brinton L A, Scoccia B, Moghissi K S et al..
Breast cancer risk associated with ovulation-stimulating drugs.
Hum Reprod.
2004;
19
2005-2013
- 31
Källén B, Otterblad Olausson P, Nygren K G.
Neonatal outcome in pregnancies from ovarian stimulation.
Obstet Gynecol.
2002;
100
414-419
- 32
Kapiteijn K, de Bruijn C S, deBoer E et al..
Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian
hyperstimulation?.
Hum Reprod.
2006;
21
3228-3234
- 33
Oktay K, Berkowitz P, Berkus M, Schenken R S, Brzyski R G.
The re-incarnation of an old question-clomid effect on oocyte and embryo?.
Fertil Steril.
2000;
74
422-423
- 34
London S N, Young D, Caldito G, Mailhes J B.
Clomiphene citrate-induced perturbations during meiotic maturation and cytogenetic
abnormalities in mouse oocytes in vivo and in vitro.
Fertil Steril.
2000;
73
620-626
- 35
Van der Auwera I, Pijnenborg R, Koninckx P R.
The influence of in-vitro culture versus stimulated and untreated oviductal environment
on mouse embryo development and implantation.
Hum Reprod.
1999;
14
2570-2574
- 36
Van der Auwera I, D'Hooghe T.
Superovulation of female mice delays embryonic and fetal development.
Hum Reprod.
2001;
16
1237-1243
- 37
Ertzeid G, Storeng R.
The impact of ovarian stimulation on implantation and fetal development in mice.
Hum Reprod.
2001;
16
221-225
- 38
Shi W, Haaf T.
Aberrant methylation patterns at the two-cell stage as an indicator of early developmental
failure.
Mol Reprod Dev.
2002;
63
329-334
- 39
Sato A, Otsu E, Negishi H, Utsunnomiya T, Arima T.
Aberrant DNA methylation of imprinted loci in superovulated oocytes.
Hum Reprod.
2007;
22
26-35
- 40
Maxfield E K, Sinclair K D, Dunne L D et al..
Temporary exposure of ovine embryos to an advanced uterine environment does not affect
fetal weight but alters fetal muscle development.
Biol Reprod.
1998;
59
321-325
- 41
Jurema M W, Nogueira D.
In vitro maturation of human oocytes for assisted reproduction.
Fertil Steril.
2006;
86
1277-1291
- 42
Andersen A N, Goosens V, Gianaroli L, Felberbaum R, de Mouzon J, Nygren K G.
Assisted reproductive technology in Europe, 2003. Results generated from European
registers by ESHRE.
Hum Reprod.
2007;
22
1523-1525
- 43
Söderström-Anttila V, Salokorpi T, Pihlaja M, Sereniou-Sirve S, Suikkari A M.
Obstetric and perinatal outcome and preliminary results of development of children
born after in vitro maturation of oocytes.
Hum Reprod.
2006;
21
1508-1513
- 44
Hardy K, Wright C S, Franks S, Winston R M.
In vitro maturation of oocytes.
Br Med Bull.
2000;
56
588-602
- 45
Merton J S, de Roos A P, Mullaart E et al..
Factors affecting oocyte quality and quantity in commercial application of embryo
technologies in the cattle breeding industry.
Theriogenology.
2003;
59
651-674
- 46
El Shourbagy S H, Spikings E C, Freitas M, St John J C.
Mitochondria directly influence fertilisation outcome in the pig.
Reproduction.
2006;
131
233-245
- 47
Spikings E C, Alderson J, St John J C.
Regulated mitochondrial DNA replication during oocyte maturation is essential for
successful porcine embryo development.
Biol Reprod.
2007;
76
327-335
- 48
Wallace D C.
Mitochondrial diseases in man and mouse.
Science.
1999;
283
1482-1488
- 49
Keefe D L, Niven-Fairchild T, Buradagunta S.
Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive ageing in
women.
Fertil Steril.
1995;
64
577-583
- 50
Barritt J, Willadsen S, Brenner C, Cohen J.
Cytoplasmic transfer in assisted reproduction.
Hum Reprod Update.
2001;
7
428-435
- 51
St. John J C.
The need to investigate the transmission of mitochondrial DNA following cytoplasmic
transfer.
Hum Reprod.
2002;
17
1954-1958
- 52
Andersen A N, Gianaroli L, Felberbaum R, de Mouzon J, Nygren K G.
for the European IVF-Monitoring Programme (EIM) for the European Society of Human
Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2002.
Results generated from European registers by ESHRE.
Hum Reprod.
2006;
21
1680-1697
- 53
Yanagimachi R.
Gamete manipulation for development: new methods for conception.
Reprod Fertil Dev.
2001;
13
3-14
- 54
Hewitson L, Takahashi D, Dominko T, Simerly C, Schatten G.
Fertilization and embryo development to blastocysts after intracytoplasmic sperm injection
in the rhesus monkey.
Hum Reprod.
1998;
13
3449-3455
- 55
Ramalho-Santos J, Sutovsky P, Simerly C et al..
ICSI choreography: fate of sperm structures after monospermic rhesus ICSI and first
cell cycle implications.
Hum Reprod.
2000;
15
2610-2620
- 56
Wall R J.
New gene transfer methods.
Theriogenology.
2002;
57
189-201
- 57
Bonduelle M, Liebaers I, Deketelaere V et al..
Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995
infants born after IVF (1983-1999).
Hum Reprod.
2002;
17
671-694
- 58
Egozcue S, Blanco J, Vendrell J M et al..
Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa
and recurrent abortion.
Hum Reprod Update.
2000;
6
93-105
- 59
Rubio C, Gil-Salom M, Simon C et al..
Incidence of sperm chromosomal abnormalities in a risk population: relationship with
sperm quality and ICSI outcome.
Hum Reprod.
2001;
16
2084-2092
- 60
Vendrell J M, Aran B, Veiga A et al..
Spermatogenic patterns and early embryo development after intracytoplasmic sperm injection
in severe oligoasthenozoospermia.
J Assist Reprod Genet.
2003;
20
106-112
- 61
Menezo Y J, Hamamah S, Hazout A, Dale B.
Time to switch from co-culture to sequential defined media for transfer at the blastocyst
stage.
Hum Reprod.
1998;
13
2043-2044
- 62
Quinn P.
The development and impact of culture media for assisted reproductive technologies.
Fertil Steril.
2004;
81
27-29
- 63
Khosla S, Dean W, Brown D, Reik W, Feil R.
Culture of preimplantation mouse embryos affects fetal development and the expression
of imprinted genes.
Biol Reprod.
2001;
64
918-926
- 64
Fernandez-Gonzalez R, Moreira P, Bilbao A et al..
Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression
of imprinting genes, development, and behavior.
Proc Natl Acad Sci USA.
2004;
101
5880-5885
- 65
Powell K, Rooke J A, McEvoy T G et al..
Zygote donor nitrogen metabolism and in vitro embryo culture perturbs in utero development
and IGF2R expression in ovine fetal tissues.
Theriogenology.
2006;
66
1901-1912
- 66
Rooke J A, McEvoy T G, Ashworth C J et al..
Ovine fetal development is more sensitive to perturbation by presence of serum in
embryo culture before rather than after compaction.
Theriogenology.
2007;
67
639-647
- 67
Sinclair K D, McEvoy T G, Maxfield E K et al..
Aberrant fetal growth and development after in vitro culture of sheep zygotes.
J Reprod Fertil.
1999;
116
177-186
- 68
Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M.
Differential effects of culture on imprinted H19 expression in the preimplantation
mouse embryo.
Biol Reprod.
2000;
62
1526-1535
- 69
Lane M, Gardner D K.
Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene
expression and subsequently alters fetal development in the mouse.
Biol Reprod.
2003;
69
1109-1117
- 70
Sinawat S, Hsaio W C, Flockhart J H, Kaufman M H, Keith J, West J D.
Fetal abnormalities produced after preimplantation exposure of mouse embryos to ammonium
chloride.
Hum Reprod.
2003;
18
2157-2165
- 71
Luna M, Duke M, Copperman A, Grunfield L, Sandler B, Barritt J.
Blastocyst embryo transfer is associated with a sex-ration imbalance in favor of male
offspring.
Fertil Steril.
2007;
87
519-523
- 72
Sills E S, Tucker M J, Palermo G D.
Assisted reproductive technologies and monozygous twins: implications for future study
and clinical practice.
Twin Res.
2000;
3
217-223
- 73
da Costa A LA, Abdelmassih S, de Oliveira F G et al..
Monozygotic twins and transfer at the blastocyst stage after ICSI.
Hum Reprod.
2001;
16
333-336
- 74
Milki A A, Jun S H, Hinckley M D, Behr B, Giudice L C, Westphal L M.
Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage
transfer.
Fertil Steril.
2003;
79
503-506
- 75
Gutiérrez-Adán A, Pintado J GB, De La Fuente J.
Influence of glucose on the sex ratio of bovine IVM/IVF embryos cultured in vitro.
Reprod Fertil Dev.
2001;
13
361-365
- 76
Tarlatzis B C, Qublan H S, Sanopoulou T, Zepiridis L, Grimbizis G, Bontis J.
Increase in the monozygotic twinning rate after intracytoplasmic sperm injection and
blastocyst stage embryo transfer.
Fertil Steril.
2002;
77
196-198
- 77
Hershlag A, Paine T, Cooper G W, Scholl G M, Rawlinson K, Kvapil G.
Monozygotic twinning associated with mechanical assisted hatching.
Fertil Steril.
1999;
71
144-146
- 78
Gardner D K, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft W B.
Single blastocyst transfer: a prospective randomized trial.
Fertil Steril.
2004;
81
551-555
- 79
Jain J K, Boostanfar R, Slater C C, Francis M M, Paulson R J.
Monozygotic twins and triplets in association with blastocyst transfer.
J Assist Reprod Genet.
2004;
21
103-107
- 80
Botchan A, Hauser R, Gamzu R, Yogev L, Paz G, Yavetz H.
Results of 6139 artificial insemination cycles with donor spermatozoa.
Hum Reprod.
2001;
16
2298-2304
- 81
Gorrill M J, Burry K A, Patton P E.
Pregnancy outcomes using donor sperm insemination after failed in vitro fertilization
with intracytoplasmic sperm injection cycles in couples with complex infertility disorders.
Fertil Steril.
2003;
80
936-938
- 82
Lansac J, Royere D.
Follow-up studies of children born after frozen sperm donation.
Hum Reprod Update.
2001;
7
33-37
- 83 Holt W V, Watson P F.
Role of new and current methods in semen technology for genetic resource conservation. In: Simm G, Villanueva B, Sinclair KD, Townsend S Farm Animal Genetic Resources.
BSAS publication no. 30. Nottingham, UK; Nottingham University Press 2004: 191-205
- 84
Morris G J.
A new development in the cryopreservation of sperm.
Hum Fertil (Camb).
2002;
5
23-29
- 85
Seli E, Gardner D K, Schoolcraft W B, Moffatt O, Sakkas D.
Extent of nuclear DNA damage in ejaculated spermatozoa impacts on blastocyst development
after in vitro fertilization.
Fertil Steril.
2004;
82
378-383
- 86
Thompson-Cree M E, McClure N, Donnelly E T, Steele K E, Lewis S E.
Effects of cryopreservation on testicular sperm nuclear DNA fragmentation and its
relationship with assisted conception outcome following ICSI with testicular spermatozoa.
Reprod Biomed Online.
2003;
7
449-455
- 87
Park Y S, Lee S H, Song S J, Jun J H, Koong M K, Seo J T.
Influence of motility on the outcome of in vitro fertilization/intracytoplasmic sperm
injection with fresh vs. frozen testicular sperm from men with obstructive azoospermia.
Fertil Steril.
2003;
80
526-530
- 88
Ramos L, De Boer P, Meuleman E J, Braat D D, Wetzels A M.
Evaluation of ICSI-selected epididymal sperm samples of obstructive azoospermic males
by the CKIA system.
J Androl.
2004;
25
406-411
- 89
Wennerholm U B, Bergh C, Hamberger L, Westlander G, Wikland M, Wood M.
Obstetric outcome of pregnancies following ICSI, classified according to sperm origin
and quality.
Hum Reprod.
2000;
15
1189-1194
- 90
Kolibianakis E M, Zikopoulos K, Devroey P.
Implantation potential and clinical impact of cryopreservation-a review.
Placenta.
2003;
24(Suppl B)
S27-S33
- 91
Winston R M, Hardy K.
Are we ignoring potential dangers of in vitro fertilization and related treatments?.
Nat Cell Biol.
2002;
4(Suppl)
s14-s18
- 92
Paynter S J.
Current status of the cryopreservation of human unfertilized oocytes.
Hum Reprod Update.
2000;
6
449-456
- 93
Mandelbaum J, Anastasiou O, Levy R, Guerin J F, de Larouzière V, Antoine J M.
Effects of cryopreservation on the meiotic spindle of human oocytes.
Eur J Obstet Gynecol Reprod Biol.
2004;
113(Suppl 1)
S17-S23
- 94
Jones A, Van Blerkom J, Davis P, Toledo A A.
Cryopreservation of metaphase II human oocytes effects mitochondrial membrane potential:
implications for developmental competence.
Hum Reprod.
2004;
19
1861-1866
- 95
Coticchio G, Bonu M A, Borini A, Flamigni C.
Oocyte cryopreservation: a biological perspective.
Eur J Obstet Gynecol Reprod Biol.
2004;
115(Suppl 1)
S2-S7
- 96
Mavrides A, Morroll D.
Cryopreservation of bovine oocytes: is cryoloop vitrification the future to preserving
the female gamete?.
Reprod Nutr Dev.
2002;
42
73-80
- 97
Liebermann J, Tucker M J, Sills E S.
Cryoloop vitrification in assisted reproduction: analysis of survival rates in > 1000
human oocytes after ultra-rapid cooling with polymer augmented cryoprotectants.
Clin Exp Obstet Gynecol.
2003;
30
125-129
- 98
Auroux M.
Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation.
Hum Reprod Update.
2000;
6
550-556
- 99
Sinclair K D, Singh R.
Modelling the developmental origins of adult disease in the early embryo.
Theriogenology.
2007;
67
43-53
Kevin D SinclairPh.D.
School of Biosciences, University of Nottingham, Sutton Bonington Campus
Leicestershire LE12 5RD, UK
Email: kevin.sinclair@nottingham.ac.uk