Preconception Early Pregnancy Genetic Screening Dr Joo Teoh

Preconception & Early Pregnancy Genetic Screening Dr Joo Teoh FRANZCOG MRCP(Ire) MRCOG MBBCh MSc(Lon) MD Res(Glasgow) Subspecialty Repromed(UK) SJOG Mt Lawley SJOG Subiaco, Genea Hollywood Fertility

Reproductive Genetic Screening in CLINICAL PRACTICE Parental carrier screening Early pregnancy screening Pre-conception genetic screening

Reproductive Genetic Screening in CLINICAL PRACTICE Parental carrier screening Early pregnancy screening Pre-conception genetic screening I will let you know what do I do

Reproductive Genetic Screening in CLINICAL PRACTICE Parental carrier screening Early pregnancy screening Pre-conception genetic screening

Parental Carrier Screening Targeted Medical, obstetrics & family Hx; consanguinity Recurrent miscarriage Karyotyping- male & female Significant male factor infertility y-chromosome deletion Universal FBC (thalassaemia & other haemoglobinopathies)

Parental Carrier Screening. Universal Australian Genomics Advisory Working Group & Women’s Health Committee (March 2019)

Parental Carrier Screening. Universal Australian data from 12, 000 screened individual • Majority of cases from low risk parents

Carrier Screening: What Do I Do? Offer to all patients as recommended Personal experience low uptake from patients

Reproductive Genetic Screening in CLINICAL PRACTICE Parental carrier screening Early pregnancy screening Pre-conception genetic screening

Early Pregnancy Screening USS (1950 s) In obstetrics after WWII Professor Ian Donald- Queen Mom’s Hospital Glasgow Not quite 3 D/4 D at the early stage

Early Pregnancy Screening Serum markers (1980 s) Originally for screening of neural tube defects & anencephaly Double test, triple, quadruple (AFP & h. CG + E 3 + inhibin) Sensitivity ~80%; false positive 5% 2 nd trimester (14 – 20 weeks) Combining with other factors Age Weight

Early Pregnancy Screening Serum markers (1980 s) Originally for screening of neural tube defects & anencephaly Double test, triple, quadruple (AFP & h. CG + E 3 + inhibin) Sensitivity ~80%; false positive 5% 2 nd trimester (14 – 20 weeks) Combining with other factors Age Weight

Early Pregnancy Screening Serum markers (1980 s) Originally for screening of neural tube defects & anencephaly Double test, triple, quadruple (AFP & h. CG + E 3 + inhibin) Sensitivity ~80%; false positive 5% 2 nd trimester (14 – 20 weeks) Combining with other factors Age Weight Progress: Earlier detection ésensitivity éspecificity

2 nd Trimester Quadruple Test ? Beginning of AI in medical practice

Early Pregnancy Screening Nuchal translucency (early 2000 s) Kypros Nicolaides (King’s College, UK) Combining NT + PAPP-A & HCG Sensitivity up to 90%; false positive 5% as early as 11 weeks

Early Pregnancy Screening

Early Pregnancy Screening

Non-Invasive Prenatal Testing(NIPT) Discovery in 1997

Non-Invasive Prenatal Testing(NIPT) • Discovery in 1997 • Commercially from 2014 • Rapid adaptation & expansion

Non-Invasive Prenatal Testing(NIPT) • Discovery in 1997 • Commercially from 2014 • Rapid adaptation & expansion Hurrah, do we still need invasive tests? ?

Non-Invasive Prenatal Testing(NIPT) From 10 weeks gestation

Disadvantages of NIPT Cost Still a screening test Inconclusive results More likely to have a chromosomal aberration Up to 20% failed repeat NIPT Different QC standards Vanishing twins Confined placental mosaicism An issue for CVS as well (1 -2%) May miss triploidy SNP technology can identify triploidy PAPP-A can assess risk of IUGR, stillbirth, pre-eclampsia USS can detect other fetal anomalies

NIPT guidelines Some suggest 2 nd line screening test for NIPT Most public service internationally still recommend conventional combined screen as 1 st line Counseling and result: A GOOD SCREENING TEST, not diagnostic

NIPT or Not: What Do I Do? I offer NIPT to all private obstetric patients I also recommend early 1 st/2 nd trimester anomaly USS The highest chance of detecting chromosomal conditions & anatomy anomalies Patients with low risk conventional screening, I don’t recommend NIPT

Reproductive Genetic Screening in CLINICAL PRACTICE Parental carrier screening Early pregnancy screening Pre-conception genetic screening

Pre-conception Genetic Screening Service not practiced nor offered at SJOG

Pre-conception Genetic Screening Polar bodies biopsy • Technical/logistic difficulties • High costs Cleavage biopsy • Fresh transfer possible • Missed many abnormalities • Implantation 31% vs. 53% • Mosaicism Blastocyst biopsy • Preferred modern method • Vitrification with high implantation rates • Better mosaicism detection

Pre-conception Genetic Screening Pre-implantation genetic screening (PGS) Improve IVF success rates Prevent miscarriages Hx Age Pre-implantation genetic diagnosis (PGD) Parental chromosomal translocation Known heritable gene or chromosomal disorder

Pre-conception Genetic Screening Pre-implantation genetic screening (PGS) Improve IVF success rates Prevent miscarriages Hx Age Pre-implantation genetic diagnosis (PGD) Parental chromosomal translocation Known heritable gene or chromosomal disorder ✔

Pre-conception Genetic Screening Pre-implantation genetic screening (PGS) Improve IVF success rates Prevent miscarriages Hx Age The debate goes on • Cost • Time • Mosaicism • Sex selection • ? Any good Pre-implantation genetic diagnosis (PGD) Parental chromosomal translocation Known heritable gene or chromosomal disorder ✔

Embryo mosaicism (PGS) Mosaicism rate up to 50% of embryos

Embryo mosaicism (PGS) • Throwing away good embryo • “Self-correct” • Tendency to push abnormal cells to the trophectoderm

Embryo mosaicism (PGS) 50 shades of embryo mosaicism • Embryos can have different levels (%) of mosaicism • a. CGH can only detect high level mosaicism (>40 -50%)

Embryo mosaicism (PGS) New technology & findings • NGS can detect low level mosaicism (20%) • Concordance rates in the ICM for whole chromosome aneuploides 97% • Whole chromosome aneuploidy in TE +ve predictive value >95%

Embryo mosaicism (PGS) New technology & findings • NGS can detect low level mosaicism (20%) • Concordance rates in the ICM for whole chromosome aneuploides 97% • Whole chromosome aneuploidy in TE +ve predictive value >95% i. e. the chance of throwing away a good embryo is <5%. • Some mosaic embryos can be transferred

Pre-conception Genetic Screening: What Do I Do? Service not practiced nor offered at SJOG PGD recommended based on history PGS Recurrent miscarriage with abnormal fetal karyotype It does not change the embryos!! i. e. it does not treat I only offer to certain patients undergoing IVF Avoid chromosomal abnormalities Traumatised by miscarriages Higher age women with good ovarian reserve (not common) Counseling

Summary Parental carrier screening Offer to patients as recommended Early pregnancy screening NIPT better detection rates but still a screening tool Pre-conception genetic screening PGD commonly practiced PGS only for certain patients <35 years old approval needed from RTC This area is rapidly evolving Fetal gene therapy Non-invasive PGS

I was born in Glasgow, Scotland

Moved to Perth to be with Eliza

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