Advances in Prenatal Diagnosis Dr Bryan Beattie Consultant in Fetal Medicine Cardiff and Vale UHB

Advances in Prenatal Diagnosis NIPT CGH Genome Sequencing Congenital Heart Disease  Smartphone Apps

Brave New World The title is from Miranda's speech in William Shakespeare's The Tempest O wonder! How many goodly creatures are there here! How beauteous mankind is! O brave new world, That has such people in't. — William Shakespeare, The Tempest, Act V, Scene I, ll. 203–206 Brave New World is a novel written in 1931 by Aldous Huxley and published in Set in London of AD 2540 (632 A.F. – "After Ford" – in the book), the novel anticipates developments in reproductive technology, sleep-learning, psychological manipulation, and classical conditioning that combine to profoundly change society.

QUAD TRIPLE Combined NIPT 65% 75% 85% 99% 1:40 1:1000 Test SensitivityFalse Positive 15-18w 11-14w 10+w Gest. 1:30 1:20

Brave New World YEAR TRIPLE QUAD TRIPLE QUAD TRIPLE QUAD TRIPLE QUAD Combined NIPT National Screening Programmes - UK

Maternal Blood White Blood Cell Red Cell Syncytiotrophoblast Cell Free DNA Plasma Protein Cell Free RNA

Cells - Extraction and Separation Syncytiotrophoblast Fetal Cell

Dennis Lo Chemical Pathologist Dennis Lo, Chinese University of Hong Kong Discovered in 1997: roughly 10% of the cell-free DNA floating in a pregnant woman's blood stream stems from her fetus. Published in 2010 “Science Translational Medicine” enough fragments of fetal DNA to reconstruct the fetus's whole genome should be possible to use this DNA to test the unborn child for genetic diseases without exposing it to the risk of an invasive procedure. biggest advantage saving all those babies that would be lost Warned Use it to target specific conditions Not whole genome or late onset cardiovascular disease, Alzheimers etc

Free Fetal DNA and RNA Cell Free DNA Cell Free RNA

Fetal DNA in Maternal Blood

How It Works What: –Blood Sample 10+ weeks after counselling Who: –Advanced maternal age –Positive screening test (Quad, NT) –Ultrasound abnormalities –Previous aneuploidy –?ANY PREGNANT WOMAN Accuracy over 99% False Positive 1:1000 Trisomy 21,18,13,XO, Gender

Anytime from 10 weeks Free Fetal DNA 10wks

USA 2011 San Diego Redwood City San Jose

Big Business Demand for prenatal testing is likely to increase USA non-invasive market could exceed US$1 billion a year. Sales volumes by Sequenom “substantially exceeded expectations” Unaffordable for low-income or uninsured women (or the NHS?) Costs ranged from £500 for Ariosa to £1700 for Sequenom (same test!)

Legal Battles 14 Oct 2005 Sequenom licenses patent for non-invasive prenatal diagnosis 10 Aug 2010 Sequenom’s lawyers send Verinata warning that Verinata is developing tests that will infringe on Sequenom’s patent and patent application. 30 Aug 2011 Stephen Quake — founder of Verinata — and Hei-Mun Fan issued a patent for ‘Determination of fetal aneuploidies by massively parallel DNA sequencing’. 17 Oct 2011 Sequenom launches the MaterniT21 test. 6 Dec 2011 Sequenom sends Aria Diagnostics a letter warning about patent infringement. 19 Dec 2011 Aria files a complaint against Sequenom. 6 Jan 2012 Natera files a complaint against Sequenom. 24 Jan 2012 Sequenom sues Aria. 22 Feb 2012 Verinata and Stanford University sue Sequenom. 1 Mar 2012 Verinata launches the Verifi prenatal test. 7 May 2012 Ariosa (formerly Aria) launches the Harmony prenatal test.

EUROPE 2012 Praena Germany Lichenstein Austria Switzerland

UK 2012 Harmony blood test and scan10 weeks £750 Free CVS if Pos Results 12 weeks Option STOP Detection 99% False Pos 0.1% December 2012 Cardiff

UK 2013 Blood test and scan 10 weeks £320 Results 14 working days Detection 99% False Pos 0.1% September 2103 Cardiff

RCOG 2014 Non-invasive Prenatal Testing is likely to become a primary screening method in pregnancy Combined Screening £100 85% for 1:40 FP NIPT in NHS £100 99% for 1:1000 FP GP MAILSHOT

2014 – Time for Change?

But How Long Will it Take!!

Combined Test - Wales 2014 Welsh Executive National Standards Advisory Group Most Obstetricians

RAPID Study Lynn Chitty UCLH Publish 2015

QUAD TRIPLE Combined NIPT Test Detected Amnios / Miscarriage 15-18w 11-14w 10+w Gest Wales - 3 years 100,000 births – 100 cases of Down Syndrome. (100% uptake)

Case For Universal NIPT Proven screening test in low risk population S imple simple blood test, Pos or Neg A ccurate 99% detection, 1:1000 FP F lexibleanytime from 10 weeks, twins E conomical £100 each test and very few amnios R eliablequality control is a laboratory issue

Conventional Karyotyping G Banding

Array CGH RESOLUTION Standard 5-10kbp High resolution 200 bp EACH STUDY Miscarriage Dev. Delay Abnormal Scan 10% Extra

Congenital Heart Disease Commoner than Down Syndrome1:200 Detection rate at Anomaly Scan UK poor 30% Detection rate at Anomaly Scan WALES better50% Detection at Fetal Echo95% Detection at Pulse Oximetry90% Cardiologist Dr Orhan Uzun and Llanelli sonographers Hand and Foot – 10 minutes

Too Much Too Soon? Ethics / Counselling

Eugenics and Sex Selection

Brave New World? P.A.G.E. Whole genome sequencing

Whats Next?

Smartphone Doppler Unbornheart See, Hear, Record, Monitor, Share

Smartphone Tracker Bellabeat Doppler, Kicks, Diary, weight, Mood

Smartphone Custom Growth Charts

Smartphone Vitals Pulse/BP Body Composition AnalysisGlucose