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

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 % 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

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

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 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 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 Consider Early morphology Tertiary referral Detailed echo Infection screen Monitoring for resolution Nicolaides, Fetal Medicine Foundation, The 11-13 week scan

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

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

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

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

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

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

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 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

Questions?