1. Prenatal Diagnosis of Congenital Malformations for Undergraduates
Max Brinsmead MB BS PhD
November 2014

2. 3 categories of congenital disorder
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
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

3. What can be detected in utero?
All chromosomal abnormalities
About half of the major structural abnormalities
May be difficult in the 1st half of pregnancy
And varies with the resources available
Very few of the patients with cerebral palsy

4. Types of Tests Diagnostic tests Screening tests
Have a high degree of accuracy
e.g. Amniocentesis for chromosomes
May be invasive, carry risk and expensive
Screening tests
Cheap and safe tests suitable for whole population
Selects a subgroup for diagnostic testing
So sensitivity and positive predictive value is important
Ultrasound can be used for both screening and diagnosis
Limited only by the resources available

5. Two Practical Characteristics of a Screening Test
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
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

6. Most screening tests are a compromise
between Sensitivity and Positive Predictive Value

7. Risk of Baby with Chromosomal Abnormality by Maternal Age
Mother's Age at Expected Date of Delivery
(Years)
Chance of Baby with Down’s Syndrome
*At wks
Chance of live-born baby with a chromosomal abnormality
1:1420
1:500
1:1250
1:480
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

8. Markers for Down Syndrome
Ultrasound
Nuchal translucency (NT) ↑with DS
Nasal bone (absent with DS)
Maternal Serum
PAPP-A ↓ with DS
Beta HCG ↑with DS
AFP ↓ with DS and ↑with NTDs
Oestriol ↓ with DS
Inhibin-A (useful in 2nd trimester testing)

9. Down Syndrome screening tests
Use the combined test (i.e NT measure, beta- HCG & PAPP-A )for patients who present in the first trimester
Sensitivity when optimally timed is 85-88%
Can help many patients avoid amnio & CVS
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
Integrated (1st and 2nd trimester) testing offers greater sensitivity and higher PPV but results are late

10. Information required for the interpretation of tests
Gestational age with accuracy
And this is why ultrasound with NT is so useful
Maternal age
Advancing age will increase the chance of a +ve result
Maternal ethnicity and weight
Multiple pregnancy?
Assisted conception?
Maternal diabetes?
Maternal smoking?

11. Cell-free DNA in Maternal Plasma
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
Too little DNA esp. in mothers who are ><160 Kg
Tests currently cost $

12. Role of Non-invasive Prenatal Testing (NIPT)
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?

13. Timing is all important
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 w
NT measure at 11 – 13w&6d
Optimally at 11.5 – 13.5w
Second trimester blood test 14 – 20w
Optimally 14 – 18w
CVS can be performed any time after 9.5w
Amniocentesis after 15w

14. Some myths surrounding PND
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

15. Amniocentesis and CVS
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

16. Issues a patient needs to understand before undergoing a test
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

17. So Patient Counselling is Important
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

18. Any Questions or Comments?
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