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

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

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

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

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

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

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 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

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)

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

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?

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 $800 - 1400

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?

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 10 -12 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

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

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

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

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

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