1. Max Brinsmead MB BS PhD November 2014

2.  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 21 st 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.  All chromosomal abnormalities  About half of the major structural abnormalities  May be difficult in the 1 st half of pregnancy  And varies with the resources available  Very few of the patients with cerebral palsy

4.  Diagnostic 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.  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. 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 10-20 wks Chance of live-born baby with a chromosomal abnormality 20 - 241:14201:500 25 - 301:12501:480 31 - 341:11401:420 351:355*1:179 361:300*1:149 371:220*1:124 381:165*1:105 391:125*1:81 401:90*1:64 411:70*1:49 421:50*1:39 431:40*1:31 441:35*1:24 451:25*1:21 461:20*1:16 471:18*1:13 481:14*1:10 491:11*1:8

8.  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 2 nd trimester testing)

9.  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 2 nd trimester  Sensitivity when optimally timed is 65 – 75%  Also screens for NTDs  Integrated (1 st & 2 nd trimester) testing offers greater sensitivity and higher PPV but results are late

10. Test/Procedure First Trimester Screening (FTS) Integrated Prenatal Screening (IPS) Serum Integrated Prenatal Screening (SIPS) 1st blood sample11 - 14 weeks *Nuchal translucency ultrasound11 - 14 weeks NONE 2nd blood sampleNONE15 - 20 weeks Results available at:12 - 15 weeks16 - 21 weeks Detection rate (Accuracy)Of every 100 pregnancies with Down syndrome, about 80-85 will be detected (80-85%) Of every 100 pregnancies with Down syndrome, about 85-90 will be detected (85-90%) Of every 100 pregnancies with Down syndrome, about 80-90 will be detected (80-90%) False positive rateAbout 3 to 9 out of 100 pregnancies (3- 9%) About 2 to 4 out of 100 pregnancies (2-4%) About 2 to 7 out of 100 pregnancies (2-7%) Diagnostic test if prenatal screening test is positive CVS 11 - 13 weeks If CVS is not available, you could have amniocentesis diagnostic testing as described in the next column > Amniocentesis 15 - 22 weeks Diagnostic test results available at:13 - 15 weeks17 - 24 weeks Abortion – if you decide to have this – could be performed at: 13 - 23 weeks Abortion timing will depend on local availability 17 - 23 weeks Abortion timing will depend on local availability Or: Continuation with pregnancyBirth

11.  Gestational age with accuracy  And this is why ultrasound c 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?

12.  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

13.  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 1 st trimester ultrasound and maternal triple testing ◦ Cost effectiveness uncertain ◦ Ethical issues e.g. routine fetal sexing?

14.  Firstly it is desirable to make a diagnosis before 14w so that TOP is simple and safe  1 st 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

15.  Full chromosomal analysis from CVS or amnio takes 10 – 14d  Culture failure occurs in <0.5%  Colony mosaicism can be a problem  Some abnormalities can pose dilemmas  e.g. 47 XYY, 47XXY, 45XO  Fast FISH or DNA tests can be done overnight  But are much more expensive  And have a small risk of error

16.  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

17.  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

18.  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

19.  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

20.  When aneuploidy has been excluded...  Risk of miscarriage <20w is 1.3% for NT 95 – 99 th centile  But is 20% when NT >6.5 mm  Look for cardiac abnormalities  1.7% if NT is 2.5 – 3.4 mm  7.5% if NT >3.5 mm  Is it Cystic Hygroma? i.e. generalised oedema  5-fold increased risk of aneuploidy  12-fold increased risk of cardiac problem  6-fold increased risk of perinatal death  So monitor – consult MFM if it does not resolve

21.  When beta-HCG is high exclude Downs  (Trisomy 13 & 18 associated with low beta HCG)  When aneuploidy is excluded....  Monitor for early onset pre eclampsia & IUGR  ? Consult with MFM especially if beta HCG is high  Unexplained elevation of PAPP-A  “Not associated with any known pregnancy problem”

22.  Causes include:  Wrong dates  Pregnancy bleeding  Multiple pregnancy  Open neural tube defects*  Anterior abdominal wall defects  Some rare tumours  So refer for tertiary level scanning  and  “Watch carefully” for the rest of the pregnancy

23.  Think about: ◦ Placental sulfatase deficiency  X-linked recessive  Ichthyosis (lizard-like skin)  Mild corneal opacification  Cryptorchidism  Smith Lemli-Opitz Syndrome (rare 1:50,000)  Multiple malformtions  Mental retardation  Syndactly ◦ So consider amniocentesis or CVS