1. GP Shared Care Maternal screening for adverse pregnancy outcome 14th March 2015
Dr Rosalie Grivell
Consultant Obstetrician and Maternal Fetal Medicine Specialist, WCH
Senior Lecturer, The University of Adelaide

2. How can we help women have a healthy pregnancy?
How can we best support women and their families through a healthy pregnancy?
One answer might be through antenatal care
Use appropriate technology - sophisticated or complex technology should not be applied when simpler procedures may suffice or be superior.
Evidence-based - supported by the best available research

3. The big picture
Approx 300,000 births in Australia each year (20,000 in SA)

4. Pregnancy complications
Mother and baby
Antenatal
Neonatal
Postnatal
Psycho-social

5. Fetal congenital anomalies
Birth prevalence is 2-3% = 2.8% in SA 2010
(doesn’t include <400g, < 20 weeks)
Approx half diagnosed before birth
Prenatal detection rates depend on nature, type and frequency of abnormalities, as well as maternal factors
160 TOPs for fetal reasons in 2010 (1% of all births)
Gibson et al, Prenatal screening for congenital anomalies in SA , SA Birth defects register, WCHN, 2013.

6. Fetal congenital anomalies
All States and Territories notify fetuses and infants with major congenital malformations to a national monitoring system
Most common - Muculoskeletal, cardiac
Chromosomal
T % - T18 and T13 less common but different implications
Non-chromosomal
NTDs – 0.07%
Cleft lip and palate – 0.15%
diaphragm/abdo wall – 0.07%
Gibson et al, Prenatal screening for congenital anomalies in SA , SA Birth defects register, WCHN, 2013.

8. How might we encounter fetal abnormalities in pregnancy?
Serum screening – first trimester/second trimester
Ultrasound markers
Nuchal translucency
Nuchal fold
Echogenic bowel
Short femurs
Echogenic focus
Choroid plexus cyst
Syndromes
Multiple anomalies
Chromosomal abnormalities

9. Current practice?
81% of all pregnancies have some form of screening for T21
70% first trimester
11% second trimester
Scheil et al, Pregnancy Outcome in South Australia 2010, SA Pregnancy Outcome Unit, 2013.

10. First trimester combined screening – SAMSAS and FMF
% of pregnancies identified as “increased risk”
4.6%
5.1%
Total procedures performed on pregnancies identified as increased risk
77.6%
79.1%
Sensitivity
85.3%
87.9%
Risk of an affected pregnancy in those at increased risk (PPV)
1:19
1:15
Sensitivity of second trimester screening
80%
PPV 1:34

11. What does this describe?

13. What would you do with this?
35 yr old G4P1
IVF pregnancy
Previous MC x 3
Currently at 12+4 weeks
Adjusted risk T21 = 1:100

14. Make sure the form is completed properly

15. And ,…..
Get her in ASAP for discussion
Offer early diagnostic test

16. Trisomy 21 Increases with maternal age
But most prevalent in young women
Screening for T21 is offered as part of routine AN screening
Counselling pre-test and timely follow up of abnormal results is a crucial part of the process

17. False Positive Rate (%) # Invasive tests to detect
Screening Strategies for Trisomy 21
Strategy
Detection Rate (%)
False Positive Rate (%)
# Invasive tests to detect
1 case T21
Maternal age 55 22
200
Trimester 2 Biochemical screen 65 7 54
Trimester 1 NT alone 80 5 31
Trimester 1 NT + biochemistry 90 4
Trimester 1 NT + biochemistry + new marker 95 3 16
NIPT 99
0.3
1.5
Ongoing role for CVS / amnio
Confirm abnormal NIPT
Single gene defects / translocation carriers
Past history chrom abnormlaity
Fetal structural abnormalities
Early IUGR
Theoretical population; 100,000 women and 200 trisomy 21 fetuses

18. Invasive testing in pregnancy
CVS
weeks
Risk MC 1:100
Can’t do FISH
Results in 2 weeks
Need a full bladder

19. Invasive testing in pregnancy
Amniocentesis
15+0 onwards
Risk MC 1:200
FISH in 2 days but need to meet criteria or pay
Would act on + FISH??
Full results in 2 weeks

20. What would you do with this?
30 yr old G1P0
16 weeks
You ordered second trimester screen
Based on dates and clinical assessment
T21 is 1:20

21. What would you do with this?
30 yr old G1P0
16 weeks
You ordered second trimester screen
Based on dates and clinical assessment
T21 is 1:20

22. Importance of correct gestational age
Get a dating scan
Measure or utilise a CRL before 14 weeks or all biometry after 14 weeks
Work out the “AUA”
Ring SAMSAS
Adjust the risk based on the corrected dates

23. What would you do with this?
30 yr old G1P0
14 weeks
Has had first trimester screen
T21 risk is 1:120

24. What would you do with this?
30 yr old G1P0
14 weeks
Has had first trimester screen
T21 risk is 1:120
No maternal factors entered
Her weight is 140kg

25. Importance of maternal characteristics
Ring SAMSAS
Ask them to adjust the risk based on her weight

26. What is this?

27. What would you do with this?
NT 4.0mm
But low risk for T21 and T18

29. Significance of individual NT measurement
Very large NT - % of pregnancies with NT thickness and risk of pregnancy outcome
NT may be thickened but the T21 risk in N range
Also – abnormal ductus flow
Both result in an increased risk of cardiac and skeletal anomalies NT
Chromosomal defects (%)
N chrom but fetal death (%)
Normal chrom but major anomaly (%)
Alive and well (%)
<95th %
0.2
1.3
1.6 97
95-99%
3.7
2.5 93 mm
21.1
2.7
10.0 70 mm
33.3
3.4
18.5 50 mm
50.5
10.1
24.2 30
>6.5mm
64.5
19.0
46.2 15
Consider
Early morphology
Tertiary referral
Detailed echo
Infection screen
Monitoring for resolution
Nicolaides, Fetal Medicine Foundation, The week scan

30. Individual components of the test
Maternal age
CRL NT
Nasal bone
Ductus venosus flow
PAPP-A
BHCG

31. Additional markers
Addition of NB, TR, DV to the algorithm adds an extra 5% detection rate for a set FPR (5%)

32. What else is the test screening for??
ISUOG suggested anatomical asssessment at time of week scan
Organ/anatomical area
Present and/or normal
Head
Present, cranial bones, falx
Neck
Normal appearance, NT
Face
Eyes with lens, NB, profile, lips
Spine
Verebrae, intact overlying skin
Chest
Symmetrical lung fields, no effusions/masses
Heart
4 symmetrical chambers, regular cardiac activity
Abdomen
Stomach present in LUQ, bladder and kidneys
Abdominal wall
Normal cord insertion, no umbilical defects
Extremities
4 limbs with 3 segments, hands and feet
Placenta
Size and texture
Cord
3 vessel cord
What can we rule out?
Anencephaly
Abdo wall defects
Cardiac anomalies
Skeletal defects
Megacystis

33. Cranial anatomy

34. Facial anatomy

35. Hands and feet etc

36. Intra-abdo structures

37. Cardiac screen

38. Kidneys and spine

39. How does the “anatomy screen” test perform?
In experienced hands, can identify close to 100% of targeted structures by 13 weeks
“Detection’ increases from 11 weeks
But takes longer at 13 weeks
Approx 10% will need TV approach
In fetuses with normal karyotype
3% will have a structural anomaly, 1-1.5% major
40-50% will be detected at week scan
Luchi et al, The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(6): 675–678
Pilalis et al, The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(9): 1814–1817

40. Copyright © motifolio.com
NIPT – Non invasive prenatal testing
Since 1997, rapid expansion of our knowledge in relation to “trafficking” of nucleic acid material between the mother and the fetus.
Acknowledgements to Dr Jane Woolcock for slide content
Copyright © motifolio.com

41. What do we know?
Majority of fetal DNA present in the maternal circulation comes from the placenta (syncytiotrophoblast).
Fragments are small and released through apoptosis
Only constitute a small proportion of total cell-free nucleic acids (majority derived from maternal cells) in maternal circulation – about 3-6%
Half life is short – 15 minutes (4-30 m)
Present in useful amounts from 8-9 weeks of pregnancy

42. Key clinical applications
Gender determination – X linked disorders and congenital adrenal hyperplasia
Single gene disorders – CF, thal major, myotonic dystrophy, achondroplasia
Aneuploidy
Rh D

43. What is NIPT?
Maternal blood test – identify a fetus with Down Syndrome
Now > 5 large clinical trials evaluating NIPT in high and low risk women
Detection rates 99.5 % T21 and 99% T18
False positive rates 0.2%

44. Current program – first trimester screen
Also
Correct dating
Information about multiples
Anatomy assessment
Increased NT marker for other structural anomalies
Esp cardiac
Low Papp-A
Marker for IUGR etc
Potential to screen for pre-eclampsia
NIPT is not a replacement for week scan + blood

45. Incorporation into clinical practice
Will be influenced by
Patient and doctor awareness
Cost and availability
No Australian guidelines yet
First step
An option instead of invasive testing in case of high risk first trimester screen
Another option
Routine NIPT then routine 12 week scan
Expensive
Contingent screening??
First trimester screen first then NIPT for intermediate risk group

46. Incorporation into clinical practice
Will be influenced by
Patient and doctor awareness
Cost and availability
No Australian guidelines yet
First step
An option instead of invasive testing in case of high risk first trimester screen
Another option
Routine NIPT then routine 12 week scan
Expensive
Contingent screening??
First trimester screen first then NIPT for intermediate risk group

47. First Trimester Screening ? Preeclampsia screening
Proposed algorithm
Morphology USS
Low risk < 1/250
10+6 to 13+6 weeks
First Trimester Screening
Ultrasound NT
PAPP-A
BhCG
? Preeclampsia screening
High Risk 1/50 to 1/250
Offer NIPT
High risk
≥ 1/50 OR
≥ 1/250 and NT ≥ 3.5mm
Invasive Procedure
NT ≥ 3.5mm
– Tertiary Morphology USS
PAPP-A < 0.3MoM
– Growth USS
28, 32, 36 weeks

48. Elective NIPT from 10 weeks?
Informed patient choice
Still need nuchal translucency ultrasound
If high risk result must have amnio or CVS
Missed first trimester screening
Advanced maternal age
Infertility
Recurrent miscarriages
Anxiety
Previous affected baby with trisomy 21, 18, 13

49. What should our approach be? (in an ideal world…)
Focus our attention on the bigger picture
Much more likely to have a significant non-chromosomal anomaly or a very preterm infant than a fetus with T21
Improve the screening test – offer the best technology
Screen for PE and preterm birth
Improve screening for T18, T13
Get women in for antenatal care and counselling early
All women should have a good anatomy screen at weeks (even if they don’t want to know T21 risk)
For those with an increased T21 risk some better suited to an invasive test
Facilitate NIPT in those with an “uncomplicated” increased risk

50. Practicalities
Offer all women accurate dating of pregnancy and a 12 week scan
REGARDLESS of their desire to know T21 risk
Book the NT scan for weeks but bloods can be done and perform better earlier – 9 weeks onwards
Facilitate counselling ASAP after a high risk result
Very happy to see women JUST for counselling, don’t have to go ahead with a test on the day
Waiting for an appointment is distressing
All women with an abnormal first trimester test should be offered CVS and/or NIPT

51. Take home messages
The purpose of first trimester screening is to offer first trimester diagnosis and decision making
Women don’t like waiting for 2-3 weeks to have their invasive test or discussion about options…..
Most women prefer a surgical TOP rather than a medical procedure.
Most women who are offered or NIPT where appropriate will go ahead with testing.

52. Take home message Non-Invasive Prenatal Testing
Good test (Sensitivity; T %, T18 98%, T13 80%)
Low false positive (0.2%)
High risk results still need invasive test
Cost coming down
Test failure - 2% (higher if weight > 140kg)
Care: twins, multiples
Still need week ultrasound
with nuchal translucency + bloods
Twins:
Each twin contributes about the same amount of fetal DNA therefore performance should be similar to singletons
Insufficient fdata for clinical use
Technology rapidly changing
Eventually the whole fetal genome and some monogenic deiseases will be able to be tested
Need an international quality control mechanism
Flase negative rate hard to Police

53. Questions?