4. •PGD requires excellence in
–Fertility Medicine
–Clinical Genetics
–Embryology
–Molecular analysis
–Embryo vitrification
–Clinical support systems
–Funding
–IVF is the foundation stone of PGD
5. •Improve health& wellbeing of offspring
•Minimiserisk of inheriting serious disability
•Typically fertile couples
•Adjunct to IVF
•Euploidvitrified embryo selectionmay:
•Increase clinical pregnancy rate per embryo transfer
•Reduce miscarriage rate
•ReduceriskofIVF-relatedbirthdefects
•Infertility may alter threshold for PGD
•Disease predispositions
8. Laser-assisted hatching
Day 3 embryo: 1-2 cells
(out of 4-8 cells)
OR
D5 embryo (blastocyst)
3-5trophectodermcells from
(future placenta)
Inner cell mass (embryo) untouched
10. DNA extraction & amplificationPCRpolymerase chain reaction
Genetic analysis done on site or remotely (transport PGD)
Blastocystvitrificationawaiting DNA test results
11. Array CGH testing
http://www.nature.com/scitable/topicpage/microarray-based-comparative-genomic- hybridization-acgh-45432Figure1
Source: Fertility and Sterility 2011; 95:953-958(DOI:10.1016/j.fertnstert.2010.09.010 )
+19/-22
-10/-16
46, XX
16. •absence of the mutated gene
May be a failure of DNA amplification
Occurs in 5-10% of PGD testing
x
17. Linkage analysis is best practice in PGD testing
•Polymorphic short tandem repeats (STRs) that flank the mutation/disease locus
•Determine phasing by family study in PGD work-up
•Highly accurate, highly reproducible: primary test in PGDGENE
Marker 1
Marker 2
Marker 3
Marker 4
Mutation
x
26. Initial PGD cycle may incur >10k out-of-pocket costs
~6-9k for subsequent cycles
27.
28.
29.
30. •IVF 30 year history
–2-3 million babies. Many are now parents
–1-2% Australian babiespa are conceived by IVF
•PGD 15 year history
•>1,000 Australian PGD babies
31.
32. •An excess risk of birth defects in IVF and ICSI infants is biologically plausible.
•Factors associated that may increase the risk of birth defects include
–the underlying causes of infertility in the couples
–factors associated with the IVF/ICSI procedures
–egfreezing and thawing of embryos
–delayed fertilization of oocytes
–culture media composition
–medications used to induce ovulation or for lutealphase support
–Endometrial milieu
33. The risk of major birth defects after intracytoplasmicsperm injection and in vitro fertilisationHansen et al NEJM 2002;346 (10):725-730
Methods
•Data obtained from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997.
•Assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmicsperm injection or in vitro fertilization.
Results
•Twenty-six of the 301 infants conceived with intracytoplasmicsperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception)
.
•As compared with natural conception, the odds ratio for a major birth defect by one year of age, was2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmicsperm injection, and 2.0(95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization.
•Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects.
34. •Systematic review all papers published by March 2003 with data relating to the prevalence of birth defects in infants conceived following IVF and/or ICSI compared with spontaneously conceived infants
•Twenty-five studies were identified for review.Two-thirds of these showed a 25% or greater increased risk of birth defects in ART infants.
•Size of ART group in each study ranged from 32-9111 infants
•Additionally results of meta-analyses of the seven reviewer-selected studies and of all 25 studies suggest a statistically significant 30–40% increased risk of birth defects associated with ART.
•Pooled results from all suitable published studies suggested that children born following ART are at increased risk of birth defects compared with spontaneous conceptions
•1.3-fold risk
35. •Data analysed from the National Birth Defects Prevention Study, a population-based, multicenter, case– control study of birth defects.
•NBDPS;10 states, investigates environmental and genetic risk factors for 30 major birth defects
•Included mothers of fetusesor live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997–December 2003.
•Study compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions.
•4792 control infants, 9584 case infants.
•ART was reported by 51 (1.1% ) of all control mothers and 230 (2.4%) case mothers Among singleton births, ART was associated with septalheart defects(adjusted odds ratio [aOR] 2.1, 95% confidence intervals [CI] 1.1–4.0), cleft lipwith or without cleft palate (aOR2.4, 95% CI 1.2–5.1), oesophageal atresia(aOR4.5, 95% CI 1.9–10.5) and anorectalatresia(aOR3.7, 95% CI 1.5–9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied. Findings suggest that surgically important birth defects occur more often among infants conceived with ART
42. National Health and Medical Research Council
Ethical Guidelines on the use of assisted reproductive technology in clinical practice and research
S11: Do not select sex for non-medical purposes
•Sex selection is an ethically controversial issue.
•The Australian Health Ethics Committee (AHEC) believes that admission to life should not be conditional upon a child being a particular sex. Therefore, pending further community discussion, sex selection (by whatever means) must not be undertaken except to reduce the risk of transmission of a serious genetic condition….
•Regulatory powers –clinic accreditation
46. Victorian Assisted Reproductive Treatment Act 2008
•Sex selection is prohibited in the following terms:
s28 (1) A person carrying out a treatment procedure must not use gametes or an embryo, or perform the procedure in a particular way, with the purpose or a purpose of producing or attempting to produce a child of a particular sex.
Penalty: 240 penalty units or 2 years imprisonment or both.
(2) Subsection (1) does not apply if—
(a) it is necessary for the child to be of a particular sex so as to avoid the risk of transmission of a genetic abnormality or a genetic disease to the child; or
(b) the Patient Review Panel has otherwise approved the use of the
gametes or embryo for the purpose or a purpose of producing or attempting to produce a child of a particular sex.
47. JS and LS v Patient Review Panel [2011] VCAT 856
•“In our view, arguments based on completion of family, replacement of a child, or family balance do not advance the welfare or interests of a child born to fulfilthat end.”
