Transcript Prenatal Diagnosis of Congenital Malformations

Max Brinsmead MB BS PhD
November 2014
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Some 1- 2% of babies will have a major disability
that dates from the prenatal period
Either
 Chromosomal disorder e.g. Down syndrome
 Structural abnormality e.g. “Hole in the Heart”
 Other e.g. Cerebral palsy
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While a good deal of antenatal care in the 21st
century is directed to the prenatal detection of
these problems....
It is worth remembering that, for most,
termination of the pregnancy is the only option
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All chromosomal abnormalities
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About half of the major structural abnormalities
 May be difficult in the 1st half of pregnancy
 And varies with the resources available
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Very few of the patients with cerebral palsy
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Diagnostic tests
 Have a high degree of accuracy
 e.g. Amniocentesis for chromosomes
 May be invasive, carry risk and expensive
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Screening tests
 Cheap and safe tests suitable for whole population
 Selects a subgroup for diagnostic testing
 So sensitivity and positive predictive value is important
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Ultrasound can be used for both screening
and diagnosis
 Limited only by the resources available
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Sensitivity
 The number of patients selected by the test as positive
as a proportion of the total number of patients with
the condition sought
 e.g. A DRA test that identifies 3 out of 4 mothers with
a Down syndrome baby has a sensitivity of 75% and
will therefore miss 25% of the babies with this problem
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Positive Predictive Value (PPV)
 The likelihood that a patient identified by the test has
the condition sought
 e.g. A DRA with PPV of 10% means that 90% of women
selected to undergo amniocentesis will NOT have this
condition
Risk of Baby with Chromosomal Abnormality by Maternal Age
Mother's Age at Expected Date Chance of Baby with Down’s
of Delivery
Syndrome
(Years)
*At 10-20 wks
Chance of live-born baby with
a chromosomal abnormality
20 - 24
1:1420
1:500
25 - 30
1:1250
1:480
31 - 34
1:1140
1:420
35
1:355*
1:179
36
1:300*
1:149
37
1:220*
1:124
38
1:165*
1:105
39
1:125*
1:81
40
1:90*
1:64
41
1:70*
1:49
42
1:50*
1:39
43
1:40*
1:31
44
1:35*
1:24
45
1:25*
1:21
46
1:20*
1:16
47
1:18*
1:13
48
1:14*
1:10
49
1:11*
1:8
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Ultrasound
 Nuchal translucency (NT)
↑with DS
 Nasal bone (absent with DS)
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Maternal Serum
 PAPP-A
↓
 Beta HCG
 AFP
↓
with DS
↑with DS
with DS and
 Oestriol
↓
↑with NTDs
with DS
 Inhibin-A (useful in 2nd trimester testing)
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Use the combined test (i.e NT measure, betaHCG & PAPP-A )for patients who present in the
first trimester
 Sensitivity when optimally timed is 85-88%
 Can help many patients avoid amnio & CVS
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Use the Triple Test (i.e. beta-HCG, E3 and AFP)
for patients who present in the 2nd trimester
 Sensitivity when optimally timed is 65 – 75%
 Also screens for NTDs
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Integrated (1st and 2nd trimester) testing offers
greater sensitivity and higher PPV but results are
late
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Gestational age with accuracy
 And this is why ultrasound with NT is so useful
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Maternal age
 Advancing age will increase the chance of a +ve result
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Maternal ethnicity and weight
Multiple pregnancy?
Assisted conception?
Maternal diabetes?
Maternal smoking?
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From 10w gestation up to 10% of DNA fragments
in maternal blood is of fetal origin
Useful for fetal sexing (Y chromosome) and Rh
karyotype (RHD gene)
Massively parallel sequencing (MPS) used to
quantify total maternal and fetal DNA linked to
specific chromosomes
Will detect 99% Down syndrome (excess Ch21)
But only 80 – 92% of Trisomy 13 & 18
Up to 2% plasma unsuitable for testing
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Tests currently cost $800 - 1400
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◦ Too little DNA esp. in mothers who are ><160 Kg
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Uses cell-free fetal DNA in maternal blood
Should be regarded as a screening test
despite high sensitivity and specificity
Useful for the high risk patient who is very
keen to avoid the risks of CVS and amnio
Uncertain role for low risk/unselected group
◦ Does not provide all the information that comes
from 1st trimester ultrasound and maternal triple
testing
◦ Cost effectiveness uncertain
◦ Ethical issues e.g. routine fetal sexing?
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Firstly it is desirable to make a diagnosis
before 14w so that TOP is simple and safe
1st blood test between 9 – 13w&6d
 Optimally 10 -12 w
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NT measure at 11 – 13w&6d
 Optimally at 11.5 – 13.5w
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Second trimester blood test 14 – 20w
 Optimally 14 – 18w
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CVS can be performed any time after 9.5w
Amniocentesis after 15w
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Most Down Syndrome babies are born to
women over the age of 35
Because my other pregnancies and babies
were normal I do not need testing
There is no Family History of Downs so I do
not need testing
Husband’s age is important
The chance of aneuploidy after a positive
screen test is equivalent to the risk calculated
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Practitioners of both state that the increased
loss associated with both is about 1:100
Large studies say 0.5% for amnio and 1-2%
for CVS
Most pregnancy losses occur within 7 – 10d
A few patients leak liquor after amnio
CVS is done PA for an anterior placenta and
PV for a posterior placenta
Both procedures require US guidance
And are best done by practitioners of >50/yr
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What the test is for
And what it will not detect
What is their risk of the condition
What is the likelihood that the test will be
positive
What are the sensitivity and PPV of the test
What will they do if the test is positive
What are the risks associated with further
testing. What will that test reveal
What will they do if their baby is affected
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Pre test counselling will help to reduce post
positive test anxiety
Resources are required for the optimal
management of screen-positive patients
And the continuing care of patients who are
screen-positive but amnio/CVS normal
Because they do have pregnancies at
increased risk
 Consultation with a MFM specialist may be desirable
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