Rates of genetic defects following IVF-ICSI.

1. Dr Antima Rathore,
Consultant (IVF Specialist),
Institute of Human Reproduction (IHR),
Kolkata
1

2. 2

3. The Spark
3

4. Intra Cytoplasmic Sperm Injection
(1992)
4
Gianpiero Palermo

5. RISKS INVOLVED
 Physical disturbance of ooplasm
or the meiotic spindle
 Injection of biochemical
contaminants
 Injection of sperm-associated
exogenous DNA
Matthew G et al. Is intracytoplasmic sperm injection safe? Fertil Steril 2003;80:851–9. 5
ICSI procedure-dependent risks

6. Risks involved
 Injection of sperm carrying a chromosomal anomaly
 Fertilization of anomalous female gamete
 Potential for incorporating sperm mitochondrial DNA
Matthew G et al. Is intracytoplasmic sperm injection safe? Fertil Steril 2003;80:851–9. 6
ICSI procedure-independent risks

7. Fear
7
Normal
morphology
May have DNA
fragmentation
DNA damage is promutagenic

8. Genetic abnormalities
8
de novo
Inherited Autosomal
Sex chromosomal
Imprinting
disorders

9. Inherited Genetic Disorders
Linked To Male Infertility
9
Klinefelter’s
syndrome
Spermatozoal
Aneuploidy
Y-chromosome
microdeletions
Cystic fibrosis

10. Inherited Genetic Disorders
 3%–15% of men with severe
oligospermia
Matthew G et al. Is intracytoplasmic sperm injection safe? Fertil Steril 2003;80:851–9. 10
Y chromosome microdeletion
100 %
Autosomal
Chromosomal
Abnormalities
1 %

11. de-novo Mutations
AUTOSOMAL
 no increased risk (0.2%)
SEX CHROMOSOMAL
 Increased risk – 0.8 - 1%
(general – 0.2%)
BALANCED TRANSLOCATIONS
 Increased (0.36%)
(general - 0.07%)
Genetic considerations related to intracytoplasmic sperm injection (ICSI). The Practice Committee of the American
Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive
Technology. Fertil Steril 2008;90:S182–4. 11

12. Imprinting disorders
 Increased incidences
• Beckwith–Wiedemann syndrome (1:12,000 to 1:15,000)
• Angelman syndrome (1 in 300,000)
(Chang, Moley, Wangler, Feinberg, & Debaun, 2005; Sutcliffe et al., 2006)
 increased up to 4 times after ART
(DeBaun, Neimitx, & Feinberg, 2003; Maher et al., 2003)
12
Vermeiden JPW et al. Are imprinting disorders more prevalent after human in vitro fertilization or
intracytoplasmic sperm injection? Fertil Steril 2013;99:642–51.
Allen C, Reardon W. Assisted reproduction technology and defect of genomi imprinting. BJOG. December
2005, Vol. 112, pp. 1589–1594.

13. Mechanism of imprinting defect in ICSI
 Unknown
 Elimination of natural
selection
 Removal of cumulus cells
 Abnormal oocyte activation
 Mechanical disruption of
the oocyte
 Culture conditions of the
ovum
 Embryo culture
 Subfertility and
superovulation
Allen C, Reardon W. Assisted reproduction technology and defect of genomi imprinting. BJOG.
December 2005, Vol. 112, pp. 1589–1594. 13

14. IVF vs ICSI
14
Vermeiden JPW et al. Are imprinting disorders more prevalent after human in vitro fertilization or
intracytoplasmic sperm injection? Fertil Steril 2013;99:642–51.
Munne´ S et al. Chromosome abnormalities in embryos obtained after conventional in vitro
fertilization and intracytoplasmic sperm injection. Fertility And Sterility Vol. 69, No. 5, May 1998
CONVENTIONAL
IVF
IVF-ICSI

15. Trinucleotide polymorphism in Androgen
Receptor Gene
CAG microsatellite repeats in Androgen Receptor (AR)
gene
 Enhanced androgen action
at lower repeat lengths
 Decreased function at
longer lengths
Katagiri Y et al, Trinucleotide polymorphism in the androgen receptor gene of ICSI offspring with de novo gonosomal abnormalities.
Fertelity & sterility. September 2004. Volume 82, Supplement 2, Pages S7–S8. 15

16. Trinucleotide polymorphism in
Androgen Receptor Gene
Katagiri Y et al, 2004. 16
Androgen Receptor
Gene
Fertility potential may be maintained
defect

17. DNA mismatch repair
 Childhood malignancies - retinoblastoma
 DNA mismatch repair defects → non-obstructive azoospermia
Do ART conceived offspring have a higher incidence of
malignancy due to DNA repair defects?
17
Vermeiden JPW et al. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic
sperm injection? Fertil Steril 2013;99:642–51.
Maduro MR et al. Microsatellite instability and defects in mismatch repair proteins: a new aetiology for Sertoli cell-only
syndrome. Mol Hum Reprod. 2003 Feb;9(2):61-8.
NO

18. Congenital malformations
 An increased malformation rate in the
male genitalia after ICSI
(Bonduelle et al., 2005)
 Undescended Testes
 Subtle impairment of Leydig function
Wen J et al. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a
meta-analysis. Fertil Steril 2012;97:1331–7. 18
CURRENT EVIDENCE INCONCLUSIVE

19. Congenital Abnormalities
Risk of major congenital malformations
4.2 %
19
Genetic considerations related to intracytoplasmic sperm injection (ICSI). The Practice Committee of
the American Society for Reproductive Medicine and the Practice Committee of the Society for
Assisted Reproductive Technology. Fertil Steril 2008;90:S182–4.

20. Genetic abnormalities in abortus
Aneuploidy rates and sex chromosome anomalies
vs
21
Bingol B et al. Comparison of chromosomal abnormality rates in ICSI for non-male factor and spontaneous conception. J
Assist Reprod Genet (2012) 29:25-30.
Ma S et al. Frequency of chromosomal abnormalities in spontaneous abortions derived from intracytoplasmic sperm
injection compared with those from in vitro Fertilization. Fertil Steril 2006;85:236 –9.
ICSI for
non-male factor
Natural
Conception
SIMILAR

21. Pitfalls
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very rare
disorders
absence of
control data
circumstantial
observations
statistical
misinterpretation
retrospective
trials
unexpected over-
representation of
ART conceptions

22. Pitfalls
23
lack of
standardized
reporting
parental age
genetic associated
infertility etiologies
multiple
gestation
lack of
standardized
methodologies
animal studies

23. • SUMMARY AND RECOMMENDATIONS
2008 24
ICSI appears to be a safe and effective therapy for
the treatment of male factor infertility
Certain conditions may carry an increased risk for
transmission of genetic abnormalities to offspring via
ICSI

24. • SUMMARY AND RECOMMENDATIONS
2008 25
Whether the increased prevalence of genetic
abnormalities observed in ICSI offspring relates
to the procedure itself, or to the characteristics
of couples who require ICSI to conceive, is
UNCLEAR

25. • SUMMARY AND RECOMMENDATIONS
2008 26
When specific genetic abnormalities (e.g., abnormal
karyotypes, Y chromosome microdeletions, CF
mutations) are identified, affected couples should
receive appropriate genetic counseling before
proceeding with treatment
Only those fully apprised of risk for transmitting
a genetic defect and its potential effect on their
offspring should be offered ICSI

26. • SUMMARY AND RECOMMENDATIONS
2008 27
Couples with male factor infertility considering ICSI
should be counseled about the associated potential
risks
Other genetic testing before embryo transfer
(preimplantation genetic diagnosis) or during early
pregnancy (amniocentesis or chorionic villus
sampling) may be appropriate in selected cases

27. Thank You
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