The Death Knell for
Amniocentesis and CVS
Adam Gornall
Consultant in Fetomaternal Medicine
Shrewsbury and Telford Hospital
NHS Trust
History
 Transabdominal amniocentesis in the third
trimester - Prochownick, Von Schatz and
Lambl (1877)
 Release of amniotic fluid from a patient
with polyhydramnios Hinkel (1919)
 Radio-opaque contrast injected to outline
the fetus and placenta
History
 Management of
rhesus isoimmunized
patients Bevis (1953)
 Deviation of the
spectral absorption
curve of liquor amnii
resulting from bilirubin
Liley (1961)
History
 Fetal sex from cells found in amniotic fluid,
presence or absence of the Barr body Fuchs
and Riis (1956)
 Haemophilia A in 1960, and Duchenne
muscular dystrophy in 1964
History
 Cultured amniotic fluid cells
suitable for karyotyping Steele
and Breg (1966)
 First diagnosis of trisomy 21
Nadler (1968)
History
 Antenatal genetic diagnosis
from chorionic villi
Mohr (1968)
 "Role of amniocentesis in the
intra-uterine diagnosis of
genetic defects" Nadler and
Gerbie (NEJM 1970)
 Fetal lung maturity
Gluck (1971)
History
 Excessive amounts of
AFP present in
pregnancies with NTDs
Brock and Sutcliffe
(1972)
 Inborn errors of
metabolism
Milunsky and Littlefield
(1972)
History
 Ultrasound guidance
Jens Bang and Allen
Northeved (1972)
 Direct chromosome and
biochemical analysis on first
trimester chorionic villi
Simoni and Brambati (1983)
History
 „Freehand' amniocentesis
Holzgreve (1984)
 Transabdominal fine-needle
villus aspiration SmidtJensen and Hahnemann
(1984)
 Single operator two-hands
technique Romero (1985)
Innovations
 Serum AFP and NTD diagnosis by
ultrasound
Innovations
 Fetal anaemia measured using MCA
Doppler
Innovations
 Steroids to
promote fetal lung
maturity
Prenatal diagnosis - amniocentesis or CVS
 Aneuploidy
 Single gene disorders
 Haemoglobinopathies
Prenatal diagnosis - amniocentesis or CVS
 Aneuploidy
 Single gene disorders
 Haemoglobinopathies
1% risk of miscarriage
Not possible before 11 weeks‟
Screening for Down’s syndrome
 Based upon maternal age
 Addition of serum AFP
 Two serum markers AFP/hCG
 Nuchal translucency NT
 NT plus serum markers
 Fetal nasal bones
 Fetal ductus venosus
 Integrated test
1984
1988
1991
1995
2001
2002
2003
Screening for Down’s syndrome
Double test
Triple test
Quad test
Combined test
FPR
5%
5-3%
3%
5-2%
Nasal bone / NT / serum
FPR
1%
2%
5%
DR
93.5
94.8
97.1
West Midlands amniocentesis
rates
3,500
3,000
2,500
Abnormal USS
Maternal anxiety
2,000
History/carrier
Maternal age
Screen +ve
1,500
Other
Total
1,000
500
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
West Midlands amniocentesis
rates
3,500
Total 3106/yr to 1447/yr
3,000
2,500
Abnormal USS
Maternal anxiety
2,000
History/carrier
Maternal age
Screen +ve
1,500
Other
Total
1,000
500
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
West Midlands amniocentesis
rates
3,500
Maternal age 1131/yr to 118/yr
3,000
2,500
Abnormal USS
Maternal anxiety
2,000
History/carrier
Maternal age
Screen +ve
1,500
Other
Total
1,000
500
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
CVS in the West Midlands
 Total per year 360-410 (0.5%)
 Unchanged over the past 5 years
 Indications (2007)
Abnormal scan
Bio/DNA
History
Maternal age
Screening
Other
134
69
60
56
84
2
Free fetal DNA
 Detectable from 5 weeks‟
 10-20% of total circulating cell free DNA
 Originates from trophoblast
 Cleared from circulation within 30 minutes
of delivery
Current use of ffDNA in prenatal
diagnosis
 Fetal sex determination
 Fetal RhD status in high risk pregnancies
 Some single gene disorders
Fetal sex determination
 X-linked disorders eg Duchenne
 Congenital adrenal hyperplasia
 Genital ambiguity detected on ultrasound
Fetal sex determination
 Fetal sexing using ffDNA is accurate
 Can be performed from 7 weeks
 Requires confirmation by ultrasound at a
later gestation
Rhesus disease
 Genotyping from paternally derived alleles
from ffDNA
 Available for other antibodies
RHD
D+
D-
RHCE
RHD
or
RHCE
Rhesus disease
Check fetal RHD group
-ve
+ve
AntiD
AntiD
28 weeks
34 weeks
No Anti-D
Potential for 44%
reduction in AntiD
Prevent exposure to
blood products
AntiD
40 weeks
Save £1,000,000 pa
Single gene disorders
 Paternal or de-novo mutation
Myotonic dystrophy
Achondroplasia
Cystic fibrosis
B-thalassaemia
Congenital adrenal hyperplasia
Huntingtons disease
Aneuploidy
 Direct quantification of fetal chromosome
copy number is problematic and
technically demanding
targets free from maternal background
interference
technologies that enable extremely accurate
copy number „counting‟
Massively parallel sequencing
 T21 fetuses carry additional copy of
chromosome 21 in the genome
 Contributes additional amounts of chr21
DNA fragments into the maternal plasma
 Small increments in proportional
amounts
 Termed the “genomic representation”
(GR)
 Detected with high precision by
massively parallel sequencing
 BMJ 2011
 314 pregnancies
 2-plex protocol
 Trisomy 21 fetuses detected at 100%
sensitivity and 97.9% specificity
 PPV of 96.6% and NPV of 100%.
 AJOG 2011
 480 samples prospectively
 13 removed due to insufficient quantity or quality
 18 failed prespecified assay
 39 trisomy 21 samples correctly classified
 1 sample misclassified as trisomy 21
 Overall classification showed 100% sensitivity
(95% CI, 89–100%) and 99.7% specificity (95%
CI, 98.5–99.9%)
The future for amniocentesis and CVS
 Further reductions in the short term
 Confirmatory cases of aneuploidy in the
medium term
 ?History books