Dr Rosalie GrivellConsultant Obstetrician and Maternal Fetal Medicine Specialist, WCHSenior Lecturer, The University of Adelaide

GP Shared CareMaternal screening for adverse pregnancy outcome14th March 2015

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

The big picture• Approx 300,000 births in

Australia each year (20,000 in SA)

Pregnancy complications

Mother and baby

Antenatal

Neonatal

Postnatal

Psycho-social

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.

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

• T21 - 0.07% - 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.

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

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.

First trimester combined screening – SAMSAS and FMF

SAMSAS 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

What does this describe?

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

Make sure the form is completed properly

And ,…..

Get her in ASAP for discussion

Offer early diagnostic test

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

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 22

Trimester 1 NT + biochemistry + new marker

95 3 16

NIPT 99 0.3 1.5

Theoretical population; 100,000 women and 200 trisomy 21 fetuses

Screening Strategies for Trisomy 21

Invasive testing in pregnancy

CVS

• 10-13+ weeks• Risk MC 1:100• Can’t do FISH• Results in 2 weeks• Need a full bladder

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

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

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

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

What would you do with this?

• 30 yr old G1P0• 14 weeks• Has had first trimester screen• T21 risk is 1:120

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

Importance of maternal characteristics

• Ring SAMSAS• Ask them to adjust

the risk based on her weight

What is this?

What would you do with this?

• NT 4.0mm• But low risk for T21 and T18

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 flowBoth 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 1.3 2.5 93

3.5-4.4mm 21.1 2.7 10.0 70

4.5-5.4mm 33.3 3.4 18.5 50

5.5-6.4mm 50.5 10.1 24.2 30

>6.5mm 64.5 19.0 46.2 15

Nicolaides, Fetal Medicine Foundation, The 11-13 week scan

ConsiderEarly morphologyTertiary referralDetailed echoInfection screenMonitoring for resolution

Individual components of the testMaternal age

CRLNTNasal boneDuctus venosus flow

PAPP-ABHCG

Additional markers

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

What else is the test screening for??

• What can we rule out? – Anencephaly– Abdo wall defects– Cardiac anomalies– Skeletal defects– Megacystis

ISUOG suggested anatomical asssessment at time of 11-13+6 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

Cranial anatomy

Facial anatomy

Hands and feet etc

Intra-abdo structures

Cardiac screen

Kidneys and spine

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 11-13 week scan

Luchi et al, The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(6): 675–678Pilalis et al, The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(9): 1814–1817

Since 1997, rapid expansion of our knowledge in relation to “trafficking” of nucleic acid material between the mother and the fetus.

Copyright © motifolio.com

NIPT – Non invasive prenatal testing

• Acknowledgements to Dr Jane Woolcock for slide content

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

Key clinical applications

• Gender determination – X linked disorders and congenital adrenal hyperplasia

• Single gene disorders – CF, thal major, myotonic dystrophy, achondroplasia

• Aneuploidy • Rh D

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%

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 11-13 week scan + blood

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

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

Proposed algorithm

Low risk < 1/250

High Risk 1/50 to 1/250

High risk ≥ 1/50 OR≥ 1/250 and NT ≥ 3.5mm

Morphology USS

Offer NIPT

Invasive Procedure

10+6 to 13+6 weeksFirst Trimester Screening

UltrasoundNT

PAPP-ABhCG

? Preeclampsia screening

NT ≥ 3.5mm – Tertiary Morphology USS

PAPP-A < 0.3MoM – Growth USS

28, 32, 36 weeks

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

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 11-13 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

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 11-13 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

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.

Take home message

Non-Invasive Prenatal Testing• Good test (Sensitivity; T21 99.9%, 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 11-13 week ultrasound with nuchal translucency + bloods

Questions?