Milestones in Antenatal Screening

Intensive Course on Screening for Down’s SyndromeWolfson Institute of Preventive Medicine

London

May 2013

Jack Canick

BROWNWomen & Infants’

Prevalence of NTDs at Birth in England and Wales1965-1973

Adapted from: Wald NJ, Leck I. Antenatal and Neonatal Screening,Oxford, 2000

Spina bifida

Anencephaly

BROWNWomen & Infants’

Milestones in Antenatal Screening:Maternal Serum Screening for Open Neural Tube Defects

Year Milestone Investigator(s)

1956 First description of alpha-fetoprotein Bergstrand and Czar

1960s Extremely high rates of NTD’s in regions Elwoodof the UK

1972 Raised amniotic fluid AFP and NTDs Brock and Sutcliffe

1972/3 Raised serum AFP and anencephaly Hino; Brock

1974 Raised serum AFP and open spina bifida Wald ; Brock

1976 The concept of the MoM Wald

1977 The specification and performance of AFP Wald and screening for NTDs (the first example of a Cuckle

routine serum screening programme forbirth defects)

David BrockUniv. of Edinburgh

BROWNWomen & Infants’

Milestones in Antenatal Screening:Maternal Serum Screening for Open Neural Tube Defects

Year Milestone Investigator(s)

1956 First description of alpha-fetoprotein Bergstrand and Czar

1960s Extremely high rates of NTD’s in regions Elwoodof the UK

1972 Raised amniotic fluid AFP and NTDs Brock and Sutcliffe

1972/3 Raised serum AFP and anencephaly Hino; Brock

1974 Raised serum AFP and open spina bifida Wald; Brock

1976 The concept of the MoM Wald

1977 The specification and performance of AFP Waldscreening for NTDs (the first example of a and routine serum screening programme for Cucklebirth defects)

Prevalence of NTDs at Birth in England and Wales1965-1997

Folic acid: primary prevention of neural tube defects (Wald)

Adapted from: Wald NJ, Leck I. Antenatal and Neonatal Screening,Oxford, 2000

John Langdon Down1828-1896

OC Ward, John Langdon Down, A Caring Pioneer, Royal Soc Med Press, 1998

At one time, Langdon Down was on staff at the Royal London Hospital, which is now joined with Barts.

Patient photographed byLangdon Down in 1865

BROWNWomen & Infants’

Milestones in Antenatal Screening:Screening for Down’s Syndrome Using Maternal Age

Year Milestone Investigator(s)

1933 Maternal age and risk of Down’s syndrome Penrose

1959 Discovery of trisomy 21 in Down’s syndrome Lejeune; Jacobs

1968 First antenatal diagnosis of Down’s syndrome Valenti

1970s Antenatal screening for Down’s syndrome

1966 First chromosomal analysis from amniotic Steele and Bregfluid

1970s using maternal age: Amniocentesis offeredto older women

Lionel PenroseGalton Professor of

Human Genetics, UCL

Jerome LejeuneUniversité Rene Descartes, Paris

Patricia JacobsMedical Research Council, Edinburgh

BROWNWomen & Infants’

Year Milestone Investigator(s)

1970s Prenatal screening for open neural tubedefects using maternal serum AFP

1970s Prenatal screening for Down’s syndromeusing maternal age:Amniocentesis offeredto older women

1983 Association of low serum AFP and fetal Merkatzchromosomal abnormalities

1984 Low serum AFP and Down’s syndrome Cuckle and Wald

1987 Estimating the risk of Down’s syndrome Cuckle and Waldpregnancy using maternal age and serumAFP to older women

Milestones in Antenatal Screening:Second Trimester Serum Screening for Down’s Syndrome I

Howard CuckleUniv. of Leeds

Irwin MerkatzAlbert Einstein

College of Medicine, NY

BROWNWomen & Infants’

Year Milestone Investigator(s)

1987 Elevated serum hCG & Down’s syndrome Bogart

1988 Low serum uE3 & Down’s syndrome Canick, Haddow,Wald

1988 Serum screening for Down’s syndrome Wald, Haddow, using the ‘triple test’ Canick

1992 Immunoreactive inhibin as a second van Lithtrimester marker for Down’s syndrome

1996 Four marker serum screening with addition Waldof inhibin A

Milestones in Antenatal Screening:Second Trimester Serum Screening for Down’s Syndrome II

BROWNWomen & Infants’

Milestones in Antenatal Screening:First Trimester Screening for Down’s Syndrome

Year Milestone Investigator(s)

1985 Abnormal skin thickening of neck in fetuses Benacerrafwith Down’s syndrome in the second trimester

1990 Increased nuchal translucency and Down’s Szabosyndrome in the first trimester (Brohnstein 1989)

1991 PAPP-A and Down’s syndrome in the first Brambatitrimester

1992 Free beta-hCG and Down’s syndrome in the Spencerfirst trimester

1992 Nuchal translucency as a screening test for NicolaidesDown’s syndrome

1996 Combining ultrasound and biochemical Waldmarkers in first trimester screening

Milestones in Antenatal Screening:Integrated Screening for Down’s Syndrome

Year Milestone Investigator(s)

1999 Combining first and second trimester Waldmarkers into a single ‘integrated’screening test for Down’s syndrome

2000s Sequential strategies for the integrated test

BROWNWomen & Infants’

June 14, 2008,a major event in

screening history:

The Queen’s birthday honor list.

Milestones in Antenatal Screening:Fetal Nucleic Acids in the Maternal Circulation

Year Milestone Investigator(s)

1997 free fetal DNA in maternal blood Lo

2008 proof of concept papers using Quakemassively parallel genomic sequencing Lo

2010-13 rapidly advancing field

Nov 2011 clinical implementation by Sequenom

In the year 2013, we have many choices:

The Screening Café Menu

Starters1st trimester ultrasound ₤ 201st trimester doppler ₤ 30

Main Dish1st trimester combined ₤ 202nd trimester quad ₤ 30Serum integrated ₤ 40Full integrated ₤ 50Sequential integrated ₤ 50

Desserts2nd trimester anomaly scan ₤ 30Secondary DNA screening ₤400