Elder K. Human preimplantation embryo selection
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INDEX
blastocysts (Contd.)
with IVF vs ICSI 329
and sperm quality 329
formation and chromosome abnormalities 215–17
embryo survival to blastocyst stage 216
fragments 13
hatching 2, 10, 12, 13
problems 16
implantation potential 84
inner cell mass (ICM) assessment 109
morphology 108–9
analysis 81
effect of score on pregnancy outcome 84
scoring system 81, 82–4
normal 10
E-cadherin distribution 65
after ICSI 13
in vivo maturation 102
physiology analysis 81, 84, 85
respiration 281
blastocyst transfer
advantages 79, 79, 84, 117
disadvantages 117
single 118–19
blastomeres
asymmetry
blastomere size during cleavage 96
and chromosomal abnormalities 212
lysis in cryopreservation 129–30
morphometric analysis 93–7
sampling, preimplantation 205
size
asymmetric blastomeres 96, 212
cell size cut-off limits 96
and fragmentation 93–6, 95, 97
total cytoplasmic volume 95, 95–6
multinucleation 96–7
variations in size/cell generations 94
blastulation 52
impact of fragmentation 59,59
patterns 60
bone morphogenic protein (Bmp) genes 264, 265
BORIS 238
BRCA1 gene 268, 270, 293
calcium-calmodulin in NO production 169–70
calcium oscillations 21
capillary electrophoresis (CE) 249
carbohydrate metabolism 181–5
glucose 184
lactate 185
pyruvate 183–4
Carnoy’s fixation method 221
CCCTC-binding factor protein (CTCF) 237–8
cell cycle regulation 170–1, 172
checkpoints 171
in oocytes 268
cell type/number analyzed in PGD 218–21
centrin 343
centrioles
absence in oocytes 347
see also sperm centriole structure
centrosomes
definition 337
embryo development, effect on 337–53
female
absence in meiotic spindles 347
anomalies in 345–7
future research 350–1
inheritance 337, 338, 339
male 6, 24
centrosome function assays 342–3
dysfunction and infertility 340–2
during fertilization 339–40
during nuclear transfer 348–50
phenotypic expression in bulls 341–2
reconstitution during fertilization 342
zygotic centrosome formation 342
centrosome function assays 342–3
centrosome microinjection therapy 343
CGH see comparative genome hybridization (CGH)
checkpoints 171, 173–4
during meiosis 266–8
in oocytes 267
cholesterol synthesis 193, 194
chromatin, nucleolar–associated 6
alignment 6, 6,24
rotation and pronuclear scoring 32
chromosomal abnormalities
in ART embryos
causes 210–11
prevalence of 288
and asymmetric blastomeres 212
and blastocyst formation 215–17
and cytoplasmic irregularities 213
and dysmorphism 212–13
and elongated embryo shape 213
of embryos 14
survival to blastocyst stage 216
and fragmentation 212
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frequency in cleavage stage 209
and giant oocytes 212–13
and implantation failure 208
and maternal age 245
morphological selection against 212–13
and multinucleation 212
in oocytes 302
of polar bodies 201–7
detection rate 203
embryos, relationship with 204–6
frequency/types 202–4
postmeiotic 209, 215
pronuclear morphology 213
self-correction (balancing) 204
and structural defects 58
study requirements 209
in unselected blastocyst studies 215–16, 216
in XO female mice 203
see also specific conditions
chromosomal status
of embryos 209–33
of MNEs 44–8
and multinucleation severity 47–8
of non-MNEs 46–7
and pronuclear morphology 38–9
cleavage
rate
and Qa-2/HLA-G levels 161
and sHLA-G levels 152
vs fragmentation 214–15
stage 156
and chromosomal abnormalities 213–15
in morphometric analysis 93
patterns
haploidy 217
monosomies 217
mosaicism 216
polyploidy 217
trisomies 216–17
timing
early cleavage 103–4
assessment 104, 110, 113
and embryo competence 98
cloning
experiments in mice 239
nuclear transfer 350–1
therapeutic 350
COH
see also controlled ovarian hyperstimulation (COH)
cohesins 267–8
compaction 2, 179
morphology analysis 107
regional (partial) and fragmentation 60
comparative genome hybridization (CGH) 209–10,
289–92, 290
difficulties of application 291–2
microarray CGH 292
competence related determinants 313–15
cortisol:cortisone ratio 313–14
protein growth factors 314–15
computational biology 247–8
computer-assisted embryo assessment 90
controlled ovarian hyperstimulation (COH) 302
Doppler blood flow assessment 305–9
‘good beginners’ vs ‘bad beginners’ 307–8
repeated cycles and fertility potential 319
corona radiata 2
corrected embryo score 109, 110–12, 115
cortical granules 2
and cryopreservation–induced damage 126
postmature (aging) oocytes 5
cortisol:cortisone ratio 313–14
cryopreservation 123–34
8-cell embryos 129
cleavage-stage embryos 129
cooling 124, 131
embryo morphology, effects on 123
and embryo transfer timing 117–18
fragments/lysed cells, removal of 140–1
plunging/vitrification 124
pre-equilibration 124, 131
seeding 124, 131
sensitivity of in vitro produced cells 125
slow cooling 124, 130, 131
thawing/rehydration 124, 131–2
theory 124
cryopreservation–induced damage
causes 130–2
cellular metabolism 130
consequences 123–4
cortical granules in 126
and embryo origin 124–5
embryo quality 129–30
embryo ultrastructure 127–9
intra/interspecies differences 125–6
and intracellular lipids 125
meiotic spindle in 126–7
types of damage 124–7
cryoprotectants 124
impermeable 131
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cryoprotectants (Contd.)
permeable 131
toxicity 131
culture conditions and multinucleation 42–3, 43
culture, extended see blastocyst transfer
culture media
amino acids in 197–8
ammonium ions in 197
development 181, 191
embryo ‘plasticity’ 199
sequential media 199
culture system and embryo metabolism 191–2
culture techniques 199
cumulus cell assessment 297
cyclic guanosine 3´,5´–monophosphate (cGMP) 173
cyclin-CDK complexes 171
cyclin-dependent kinases (CDKs) 171
cyclins 171, 173–4, 268
cytasters 339
cytokinesis
and fragmentation 71–3
and multinucleation 95–6, 97
cytoplasm
cytoplasmic halo 32–3
cytoplasmic rotation 24
distribution of types 279–80
irregularities 302–3
and chromosomal abnormalities 213
in spermatozoa 326
oocyte 302–3
cytoplasmic microtubule asters 339
cytosine methylation 237
cytoskeleton
anomalies in spermatozoa 326
and fragmentation 69–73
cytostatic factor (CSF) 265
cytotoxic T lymphocytes 158
Dazla gene 264
development see embryo development; oocyte develop-
ment; preimplantation development
diandric triploidy 345
dietary status of patient 79
differentiation and effect of fragmentation 59
digital image analysis
multilevel system 90–1, 91, 92, 95
single image system 90
dimethylsulfoxide (DMSO) 124, 125
and cortical granules 126
dispermy 345, 346
dispermic embryos 6–7, 11, 12
‘dispermy hypothesis’ 343, 345
DNA
damage 268, 268
mitochondrial 276
organization
in inseminated oocytes 339
in polyspermy/parthenogenesis 340
repair 326–7
synthesis, post-fertilization 23
see also sperm DNA
DNA fragmentation index (DFI) 330–1
DNA precursors 198
Doppler blood flow assessment
for abnormalities in natural menstrual cycle 309
in controlled ovarian hyperstimulation 305–9
Doppler ultrasonography 305–9
cost vs benefits 310–11
follicle images 306
higher resolution 308
in ‘poor responders’ 309
and treatment options 306
double stranded DNA breaks (DSBs) 268
dysmorphism
asymmetric blastomeres 212
and chromosomal abnormalities 212–13
cytoplasmic irregularities 213
elongated embryo shape 213
fragmentation 212
and giant oocytes 212–13
multinucleation 212
E-cadherin distribution 64, 65
early embryonic wastage 245
electrophoretic sperm isolation 332
elongated embryo shape 213
embryos 1
abnormalities, early 9, 9
arrested 8
degenerating 9, 12
assessment 8–10, 12, 14
grading for embryo transfer in laboratory 8, 8
preimplantation development 8
without blastomere biopsy 295–7
chimeric aggregates 63, 64
chromosome abnormalities in 14
chromosome status 209–33
computer-assisted assessment 90
dispermic 6–7, 11, 12
early stages 2
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fragmented 10, 11, 12
morphology
preimplantation development 58–60
and structural defects 58
and viability 58
morphology analysis 103–8
2-cell embryos 103–4
4-cell embryos 104, 106
8-cell embryos 106–7
cell number 106–7
compaction 107
fragmentation 107
symmetry 107
cumulative scoring
day 3 grading 107–8
multiday assessments 109, 115–16
day 3 grading 107–8
viability assessment 287–8
zygote stage 103
morphometric analysis 89–99
multinucleated 11
normal 9
1-cell to morula 10
2-cell 10
cleavage stage 9
day 2–8 8
proteomic analysis 295
quality 107–8, 116
and cryopreservation–induced damage 129–30
and single embryo transfer 118
‘top quality’ 107–8, 116
and single embryo transfer 118
ultrastructure and cryopreservation-induced damage
127–9
viability see viability
embryo biopsy 141–2
avoidance 297
comparison with cryopreservation 220
technique in PGD 221
vs polar body biopsy 218–20
zona opening techniques 137
see also preimplantation genetic diagnosis
embryo development
atypical 51, 52
after cell loss 220
developmental rate, normal timeline of 101–3
early, kinetics of 97–8
fragmentation, impact of 66
immunological aspects 155–68
manipulation of 135–44
history 135
see also assisted hatching (AH) technique;
embryo biopsy
normal 51, 52
sequential testing 205–6
slow rate, advantages of 162–3
and sperm quality 329
timeline of events 102, 103
embryo development rate (EDR) 104
embryo selection
and chromosomal abnormalities of oocytes 302
criteria 275, 282
developmental selection, impact of 217
ideal methods 101
importance of 245
by metabolomic profiling 245–61
metabolomics-based 252
morphology analysis 288
non-invasive methods 245
sHLA-G levels for 151, 152
embryo transfer
day 2 vs day 3 117
day 3 101
number of embryos 118–19
numbers, proscription of 305
optimum timing 116–18
sHLA-G levels for selection 151, 152
single 118
technique 224–5
see also multiple embryo transfer
embryonic cleavage
evaluation 26
and pronuclear scoring 33
embryonic wastage 268
empty follicle syndrome 315–16
endothelial NOS (eNOS) 169–70
expression in embryos 174–5
immunocytochemistry 174
epigenetics 235–44
and ART 235
problems, evidence for 238–41
animal experiments 238–40
human population studies 240–1
and ART offspring 240–1
basic concepts 235–7
consequences/future prospects 241–3
definitions 235–6
male germ cell in 326
mechanistic concepts 237–8
origin 236
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estrogen and embryo NO production 172
extravillous cytotrophoblasts (EVTs) 145, 147, 148
factor in germline alpha (FIGLA) 264
fertility
potential 319
rate, and maternal age 316
screens, potential 342
see also infertility
fertilization 2
assessment 5–7
and centrosome inheritance 337, 338
early events 5–6
failed sperm incorporation 7, 8
failure see infertility
rates, and oocyte size 92–3
silent 7
sperm-derived centrosomes 339–40
start 5
fertilized ovum
abnormally fertilized
digyny in ICSI 7
dispermy in IVF 6–7
normally fertilized
after 3 hours 6
after 12–14 hours 6
FertiMorph 90, 94
‘first in, first out’ theory 317
FISH 201
fixation
loss of micronuclei 223
method in PGD 221–2
fluorescence in situ hybridization (FISH) 201
with CGH 291, 292
in chromosome abnormality detection 209
errors
minimization 222–3
technical sources 223
rescue 223–4
in multinucleation studies 41
probes in PGD 222
hybridization, unsuitable 223
sequential testing 209
signal overlaps 223
stretched signals/double chromosomes 223
fluorescent mitochondrial measurement 282–3
folic acid in vitro 198
follicles
aging, biological and chronological 303
antral (tertiary) (Graafian) 302
and maternal age 317
chemistry/physiology studies 304–5
and maternal age 317–18
non-invasive assessment 301
clinical parameters 304
defect detectability 303–4
pre-antral 301
follicle stimulating hormone (FSH) 210, 301, 302
follicular biochemistry 311–13
follicular biology and maternal age/lifestyle 316–19
follicular development, clinical parameters of 301–5
follicular fluid
angiogenic factors in 311–13
anti-Mullerian hormone in 314–15
biochemical composition 304
competence determinants in 313–15
components 313
cortisol:cortisone ratio in 313–14
inhibins in 314–15
follicular markers, search for 301–23
folliculogenesis 301
gene expression during 263–5
Fourier Transform infrared (FTIR) spectroscopy 249,
252
fragmentation 51–77, 52, 72–3
‘aberrant cytokinesis’ model 71–3
and aneuploidy 57–8
animal models, relevance of 73
blastomeres, impact on
fragmenting blastomere 60
sister blastomeres 60–2
blastulation, impact on 59, 59, 60
causes
apoptosis
in human embryos 67–8
in non-human eggs/embryos 66–7
metabolic/genetic defects 68–9
cell cycle phases 69–71
and cell division 53, 56, 56, 57
and chromosomal abnormalities 212
classification 52–4, 56
and cytoskeleton 69–73
‘damaged chromosome’ model 72
and differentiation 59
events 51–2
initial 52
extensive 52
fragment disappearance 52
fragment removal 61, 63
future studies 73–4
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impact on preimplantation development 58
and implantation/pregnancy rates 55, 55–7, 57
in IVF 51
mechanisms 69–73
in meiosis II 71, 72
microtubule status 69–70, 70, 72–3
in mitosis I 71
morphology analysis 106, 107
morphometric analysis 93–6
total cytoplasmic volume 95–6
and mosaicism 68
and neonatal outcome 57–8
patterns 53, 53–5, 56
and cell division 56
frequency/fragmentation degree 54,55
impact on blastula/blastocyte formation 60
prevalence 51
and regional (partial) compaction 60
spindles in 73
and telomere length 69
‘toxicity’ of fragments 52, 61
and viability 51, 55, 57, 61
freezing, blastocysts after 84
frozen-thawed embryos 61
fructose metabolism 192
functional genomics 251
gamete selection by metabolomic profiling 245–61
gas chromatography (GC) 248, 252
Gdf-9 gene 264–5
gene expression
and embryo viability 292–5
embryonic 22, 268
control, shift from maternal to embryonic 170, 170
downstream effects 247
during folliculogenesis 263–5
oocytes vs embryos 266
during preimplantation development 268–70
gene expression analysis 263–73, 293–5, 294
as diagnostic tool 270
genome activation 179
genomic imprinting 235, 236
maternal 236–7
paternal 236
in spermatozoa 326–7
genomics, functional 251
germinal vesicle breakdown (GVBD) 1
signaling after 266
giant oocytes 93
and chromosomal abnormalities 212–13
glucose, excess 192–3, 193
glucose metabolism 180, 181–3, 184, 192, 192–3
catabolic pathways 181–3, 182
optimal glucose level 192
species variation 192
glutamine degradation 197
glutathione 192
glycine 193–4
glycolysis 181–2, 182
gonadotropin releasing hormone agonist (GnRH-a)
210, 211
graduated embryo score (GES) 110–14, 115, 115
granulocyte macrophage colony stimulating factor GM-
CSF 198
granulosa cell layer
development 301–2
zona proteins 15
growth differentiation factor (Gdf-9) gene 264–5
growth factors 198–9
and preimplantation development 199
GVBD see germinal vesicle breakdown (GVBD)
gynogenetic embryos 236, 239
H19 genes 237, 239–40
half-embryo development 62
haploidy 217
HELLP syndrome 150
hierarchical cluster analysis 294, 296
high performance liquid chromatography (HPLC)
248–9, 252
highly DNA stainable cells (HDSs) 330, 331
histone protein methylation 237
HLA-G see human leukocyte antigen G (HLA-G)
Hoffman modulation contrast optics 25
homocysteine 196
host-pathogen interactions 251
human chorionic gonadotropin (hCG) 186
in cortisol:cortisone ratio 313
in empty follicle syndrome 316
human leukocyte antigens 145, 146
human leukocyte antigen G (HLA-G) 146
and ART 151–2
assessment in human embryos 145–54
characterization 146–7
cytotrophoblast protection 150
effect of presence/absence 162–3
function 145
and implantation 147–51
inhibition of NK cells 146, 147, 148, 150–1
localization of expression 145
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human leukocyte antigen G (HLA-G) (Contd.)
membrane bound, in pregnancy 147
and PED gene 162–3
polymorphism 147
on preimplantation embryos 160–1
as signaling molecule 162
tissue distribution 147
see also soluble human leukocyte antigen G (sHLA-G)
human serum albumin (HSA) and multinucleation 42
11?-hydroxysteroid dehydrogenase (11?-HSD) 313
hypoxia inducible factor (HIF-1) pathway 311–12
ICSI see intracytoplasmic sperm injection (ICSI)
Igf2 expression in imprinting 236–7, 239
immune system
overview 155–6
and preimplantation development 156–61
immunocytochemistry of NO synthase 174
implantation 145
and high ovarian response 211
and immune system 145
and impact of PGD on multiple pregnancies 288–9
implantation rates
with assisted hatching 137
and immunosuppression 158
and biopsy type 220–1
and embryo transfer timing 117
and fragmentation 55, 55–7, 57
improvement with PGD 226–7
and multiday embryo scoring 112, 114
and multinucleation 48–9
and numbers of embryos for biopsy 227
and sHLA-G levels 151–2
imprinting 235, 236
maternal 236–7
paternal 236
in spermatozoa 326–7
imprinting control regions (ICRs) 237
in vitro environment see culture system
in vitro fertilization (IVF)
abnormal fertilization
dispermy 6–7, 11
failed sperm incorporation 7, 8
chromosome abnormalities 208
culture system
media composition 80–1
oxygen content 81
prescreening 80
dietary status of patient and 79
embryonic wastage 268
holistic analysis 79, 80
‘IVF dilemma’ 245
repeated cycles 319
and SCSA values 330–1
and sperm damage 331
timeline of events 101
in vitro produced cells and cryopreservation 125
in vivo embryo maturation 101, 102
inducible NOS (iNOS) 170
expression in embryos 174–5
immunocytochemistry 174
infertility
and centrosome dysfunction 340–2
and centrosome function assays 342–3
see also fertility
inhibins 315
innate immune system 155, 156
inner cell mass (ICM)
assessment 109
in cryopreservation 128
formation 270
ICM-specific markers 270
Institute for Reproductive Medicine and Science (IRMS)
41
insulin 198
intracellular pH (pHi) 310
intracytoplasmic sperm injection (ICSI)
digyny 7
and imprinting 240
and SCSA values 330–1
and sperm damage 331
and sperm DNA breaks 325
intrafollicular oxygen regulation 305–9
IVF see in vitro fertilization
karyokinesis 95–6, 97
kinesin motors 347, 349
N-omega-nitro-L-arginine methyl ester (L-NAME) 172
lactate production 180, 181, 185, 193
laser, assisted hatching with 137, 140
leucine 186, 195
lipid metabolism 193
lipids, intracellular 125, 126
luteinizing hormone (LH) 302
in cortisol:cortisone ratio 313
macromolecules 198–9
magnetic sperm sorting 332
major histocompatability complex (MHC) 159–61
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class I proteins on preimplantation embryos 160
membrane-bound vs soluble 160–1
human vs mouse MHC 159, 159
and immune rejection 159–60
in implantation 145
inheritance 160
Nobel prize research 159
markers
of ART outcome 16–17
follicular, search for 301–23
oxidative stress biomarkers 245–61
search for 270
viability 179, 186
mass spectrometry (MS) 249, 295
maternal age
and centrosome anomalies 345
and chromosomal abnormalities 245, 288
and follicular biology/oocyte competence 316–19
influence on genes 266
and meiosis rescue 204
and mitochondrial activity 281
and multinucleation 42, 43
and oocyte competence 303
PB1 testing 201
see also older females
maternal effect genes 268
maternal-zygotic transfer (MZT) 195, 292
and embryo metabolism 191
maturation promoting factor (MPF) 265
maturational status of oocytes 1–2
meiosis
chromosome abnormalities in 201
male/female differences 347
testing for errors 205
see also blastomeres, sampling; polar bodies, FISH
analysis
meiosis II
fragmentation in 71, 72
mitochondrial morphology 277
meiosis rescue (balancing) 204
meiotic spindle
aging of 346
and cryopreservation–induced damage 126–7
messenger RNA (mRNA)
during oogenesis 265–6
transcript quantification 293
metabolism
cleavage stage vs postcompaction 180
CO2 production 180–1
precompaction 180
preimplantation embryos 179–80
species variation 180
and in vitro environment 191–200
metabolism measurement techniques 180–1
metabolite uptake/release 179–89
amino acid metabolism 185–6
carbohydrate metabolism 181–5
glucose 184
lactate 185
pyruvate 183–4
human chorionic gonadotropin (hCG) 186
oxygen consumption 186
as viability marker 179
metabolome 246
metabolomic profile/fingerprint 253
metabolomics 245–7
analytical techniques 248–9
detection methods 249
separation methods 248–9
applications
in ART 252–60
current 252
key 250–1
case for 246–7
definition 246
definitions 246
history 247
indications
in other fields 259–60
in reproductive health 259–60
studies
Metabolomics Study Group for ART 253–8
other 259
metabolomics-based embryo selection 252
Metabolomics Study Group for ART 253–8
Bayesian probability model 258
instrumentation 254, 254
metabolomic profiling of OS biomarkers 255
results
near infrared spectroscopy 257
Raman spectral signature 255, 256
study aims 253
study conclusion 257–8
study design 254–5, 255
study results 255–7
technology platform 253, 253
metabonomics 246
metaphase I mitochondrial morphology 277
methionine 195–7, 196
microarray CGH 292
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microdrops 199
microfluorescence assays 181
micromanipulation 135
importance of skills 143
micronucleated blastomeres 47–8
microtubule asters 339, 340
microtubule motors 347–8
microtubule organization
abnormal, after nuclear transfer 349
in fertilization failures 341
in inseminated oocytes 339
in polyspermy/parthenogenesis 340
without MTOCs 347
microtubule-organizing centers (MTOCs) 24, 337
absence 347
in fragmentation 69–70, 72–3
importance of 351
microtubule status in fragmentation 69–70, 70
mineral oil in culture medium 199
misdiagnosis in PGD 224, 225, 225
mitochondria 275–6
activity
and embryo development 280–2
oocytes 280–1
in embryo selection 282–3
and localization 279
and maternal age 281
measurement in embryos 282–3
and fragmentation 68–9
localization and embryo development 278, 279–80
matrix 276
morphology
and developmental characteristics 278, 279
in embryo selection 282
in embryos 278
in oocytes 281
germinal vesicle stage 277–9
immature 277
mature 277
in zygotes 278, 278
in oocytes/embryos 276–9
cleavage stage 281
after fertilization 278, 281
in reproduction 275–85
role of 275–6
mitochondrial ‘bottleneck’ theory 276
mitochondrial DNA 276
mitosis
modulation by NO 173–4
spindle formation
in dispermy 346
faulty, in aneuploidy 350
in parthenogenesis 348
MNEs see multinucleated embryos (MNEs)
molecular biometrics 253, 260
molecular diagnostics 250
monosomies 217
monozygotic twinning 141
morphological abnormalities 96, 212–13
pronuclear 213
relation to chromosomal abnormalities 213
morphological selection
against chromosome abnormalities 212–13
impact of 217
morphology analysis
blastocysts 81
effect of score on pregnancy outcome 84
scoring system 81, 82–4
embryos 103–8
2-cell embryos 103–4
4-cell embryos 104, 106
8-cell embryos 106–7
cell number 106, 106–7
compaction 107
fragmentation 106, 107
symmetry 106, 107
cumulative scoring
day 3 characteristics 107–8
multiday assessments 109, 110–14, 115–16
day 2 characteristics 104, 105, 106, 111
day 3 characteristics 107–8, 111, 113
zygote stage 103
and scoring systems 103–8
morphometric analysis
advantages 89–90
blastomere size during cleavage 93–7
asymmetric blastomeres 96
cell size cut-off limits 96
and fragmentation 93–6, 95, 97
total cytoplasmic volume 95, 95–6
multinucleation 96–7
variations in size/cell generations 94
digital image analysis
multilevel system 90–1, 91, 92, 95
single image system 90
embryos 89–99
kinetics of early development 97–8
nuclei, size of 96–7
oocyte size 92–3
technique 90
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time-lapse monitoring 91
zygote size 92–3
morula 2, 156
E-cadherin localization 65
mosaicism
cleavage stage patterns 215, 216
and fragmentation 68
and multinucleation 45–6, 46,47
and PGD misdiagnosis 224, 225, 225
and polar body chromosome abnormalities 204–5
pronuclei in 24, 25, 38
in unselected blastocyst studies 215–16
multiday embryo scoring 109, 115–16
novel method 116
studies
prospective 113–14
retrospective 110–12
multinucleated blastomeres (MNBs) 41, 44, 52
and chromosomal abnormalities 210, 211
morphometric analysis 95–6, 97
multinucleated embryos (MNEs) 41
multinucleation 47–8
in 4-cell embryo assessment 106
chromosomal status of embryos 44–8
MNEs 44–8
and severity of multinucleation 46, 47–8
non-MNEs 46, 46–7
and chromosome abnormalities 212
clinical outcomes 41, 44, 48, 48–9
day of multinucleation 48–9
and culture conditions 42–3
definition 41
frequency of 41–3
impact on embryo morphology 41, 44, 45
and maternal age 42
mechanisms 43–4, 45
morphometric analysis 96–7
and mosaicism 45–6, 46,47
and repetition of IVF cycles 42–3, 43
types of 41, 42
multiple embryo transfer 245, 269
legal controls 305
outcomes 305
multiple pregnancies
implantation, impact of PGD on 288–9
ovarian stimulation 287
reducing 287
natural killer (NK) cells
in implantation 148
inhibition by HLA-G 146, 147, 148, 150–1
near infrared (NIR) spectroscopy 249
follicular fluid 259
Metabolomics Study Group for ART 257
from seminal plasma 258
neonatal outcome with fragmentation 57–8
neuronal NOS (nNOS) 169–70
expression in embryos 174, 175
immunocytochemistry 174
newborn ovary homeobox (Nobox) gene 265
nitric oxide inhibitors 172
nitric oxide (NO) 169–70
induction of excessive levels 172
regulation of preimplantation embryos 169–78
signal transduction modulation 173–4
multiple mechanisms 175–6
nitric oxide synthase (NOS) 169
expression in embryos 174–6
see also endothelial NOS (eNOS); inducible NOS
(iNOS); neuronal NOS (nNOS)
nitric oxide synthase knockout mice 175–6
NG-nitro-L-arginine (NLA) 172
NO see nitric oxide (NO)
Nobox gene 265
nuclear envelope formation 22, 23
nuclear magnetic resonance (NMR) spectroscopy 249
nuclear transfer (NT)
abnormal microtubule patterns 348, 349
centrosomes during 348–50
in mammals 348
nuclear transfer cloning 350–1
nucleolar precursor bodies (NPBs) 23, 23
alignment and pronuclear scoring 32
and RNA synthesis 25
size/distribution 26
visualization 25
nucleus size in morphometric analysis 96–7
nutrigenomics 251
older females
endogenous amino acid pool 197
see also maternal age
oocytes 1
activated 2
activation 21–2
aneuploidy/dysmorphism development 303
assessment 1–5
maturational status 1–2
mature egg, structure of 2–5, 3
without blastomere biopsy 295–7
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