Womens health update ante natal screening final

Ante Natal Screening An update about the latest screening available in NZ including the new non-invasive prenatal diagnosis Professor Peter Stone Women’s Health Update 14 March 2015

SCOPE • • • • • • • •

Antenatal(pre) natal screening-for what The role of the GP What is currently available Problems at present-how is the process performing?

What is new -NIPT what does it mean for screening what is it used for what are the challenges

NIPT is screening

?

Are you interested in finding out about the health of the baby?

We can be specific about what “health” means

The offer of prenatal screening • An offer of prenatal screening provides prospective mothers the option of choosing or declining to receive (genetic) information pertinent to their personal situation prior to conception. • After conception, prenatal screening-diagnosis provides various benefits: it determines the outcome of pregnancy and identifies possible complications that can arise during birth.

It can be helpful in improving the outcome of pregnancy using fetal treatment.

Screening can help couples determine whether to continue the pregnancy and prepares couples for the birth of a child with an abnormality

It is all about the offer- what is being offered and why

The role of the GP-primary carer • At first chance- get involved!

• Lock in pregnancy care • Be part of “life course” approach

~70% women have pregnancy confirmed by GP or FPC Many opportunities to influence care are missed

There is evidence that most women-couples want screening There is also evidence that carers often prejudge woman’s approach to screening

% Women with LMCs by gestation and ethnicity

The question is • Chromosomal • Genetic-identified-known De novo Risk recurrence What goes wrong • Structural • Environmental-Infection with babiesEpigenetic?

And worries • Unknown-multiple abns parents Cerebral palsy Neurodevelop.delay

• What do you want to know?

•

What goes “wrong” with babies Microdeletion syndromes • DiGeorge 22q11 del • Miller Dieker 17p13.3 del • Prader Willi 15q11-13 del • Smith Magenis 17p11.2 del • Wolf Hirshhorn 4p16.3 del • WilliamsBeuren 7q11.23 del

Nonsyndromic Microdel/dup • 16p11.2 Autism • 1q21.1 ID, microceph,cardiac cataracts • 16p13.11 Austism, ID, schizophrenia ID: Intellectual disability Postnatally 15-20% by CMA vs 3% by G-band karyotype

T21 may be in the lexicon of many when they really are thinking of other problems Some NIPT can do some of these

Perceptions T21 could be the lexicon for all this • • • • •

•

Spectrum of disability Extra help at school Sequelae of prematurity-NICU ADHD Cerebral palsy Profound developmental delay-mental retardation Outcomes of structural fetal abnormality

What are the problems?

What are we trying to detect and avoid?

• • • • • • •

Preeclampsia Fetal growth restriction Gestational diabetes Fetal abnormalities* Risk of Preterm birth Obstetric problems current pregnancy Historical problems

3-5% 5-10% 5+% 3% 2-7% 5% 5%

Factors are additive and change risk eg obesity, hypertension, history

What we do now • Current pathways • Antenatal and newborn screening history*-what are key questions?

Bloods, incl HIV,Chlamydia,smear as needed Screening for Down Syndrome and other conditions • Newborn metabolic and audiology

The current pathways and outcomes offer

1stT combined

Nt + 2nd T serum

Increased risk

Low risk 62%

No action

+2ndT serum

Invasive diagnostic Low risk

outcome

1st and 2nd T serum

National Practitioner Guidelines Laminated summary sheet

Most common chromosomal abnormalities • • • • • • •

Trisomy 21 (Downs Syndrome) Trisomy 18 (Edwards Syndrome) Trisomy 13 (Patau’s Syndrome) 45XO (Turners Syndrome) 47XXY (Klinefelters Syndrome) Triploidy 69xxx or 69xxy Mosaics/translocations/inversions

NIPT

Young women are less likely to be screened and less likely to have a T1 screen 35 30

100.0

% births

89.9

% Screens

90.0 80.0

25

91.0

91.9

91.9

83.4 77.1 71.4

70.0

20

60.0 50.0

15

40.0

10

30.0 20.0

5 10.0 0.0

0 Under 16

16–19

20–24

25–29

30–34

35–39

40 and over

15-20

21-25

26-30

31-35

36-40

41-45

>45

Maori and Pacific peoples less likely to be screened, less likely to have T1 screen 70.0 60.0

% births %screens

50.0 40.0

100.0

93.4 87.7

90.0

30.0

80.0

87.3

87.1

Other

Not stated

78.9 67.5

70.0 60.0

20.0

50.0 40.0 30.0

10.0

20.0 10.0

0.0

0.0

MÄ ori

MÄ ori

Pacific peoples

Asian

European

Other

Total screens

Not stated

Pacific peoples

Asian

European

1st T screens (of all screens done)

NZDep v relative amount of screening 140 120 100 80 60 R2 = 0.6647 40

Rich

20

Poor

0 4

4.5

5

5.5

6

6.5

7

7.5

8

Performance Issues in NZ Detection rate

78%

False pos rate

~3%

Ultrasound NT performance standards

Meet standard

22%

Too few scans to analyse Underperforming to 0.4mm Unclassifiable

40% 31% 7%

(nasal bone reporting very low-2 practices only)

>100 sonographers < 25 NT scans /year

We are in a revolution Non Invasive Prenatal Testing

THE LANCET Vol 350 â&#x20AC;˘ August 16, 1997

Presence of fetal DNA in maternal plasma and serum Y M Dennis Lo, Noemi Corbetta, Paul F Chamberlain, Vik Rai, Ian L Sargent, Christopher W G Redman, James S Wainscoat

485

Single base change

Microarrays ď&#x192;

3-4Mb Slide courtesy of Trent Burgess GHSV

Why is NIPT not diagnostic?

• Not only fetal DNA-placental as well • It is a counting exercise with bioinformatics and cut offs • It needs diagnostic tests for confirmation

“Data obtained from a variety of clinical scenarios suggest that the placenta is the predominant source of the circulating fetal nucleic acids, although apoptotic haematopoietic cells may contribute to the pool as well”. Bianchi DW Placenta 2004

73µm

Syncytial knots 53µm

Or

Syncytial nuclear aggregates

Schmorl 1893

NIPT techniques • Massively Parallel Sequencing Fetal chromosome copy number determined by comparing number of sequence reads from chromos of interest to those from reference chromos • SNPs targetted amplification and sequencing of SNPs • Microarray based cf DNA analysis

DANSR- digital analysis of selected regions

Juneau K et al Fetal Diag Ther 2014

Normalised chromosome values

Massively Parallel Sequencing Counting statistics Follow a normal distribution

Cut off determines false positive rate 3SD above mean 4SD above mean

~0.13% ~0.003%

Factors affecting test performance Bianchi D Obstet Gynecol 2012

Maternal Obesity Gestation Chromosome Biology Depth of sequencing Bioinformatics

Effect of Gestation and Maternal weight on fetal fraction

Dars et al 2014

maternal

fetal

Fetal Fraction- important

Reference chromo

Chrom 21

Low fetal fraction may occur in: Overweight Low PAPP-A and low bHCG T18 and T13

Companies need to test and report this It affects the results

Performance 1stT Combined screening

NIPT

• • • • •

• • • • •

Detect rate False neg False pos False pos rate PPV (NZ)

78-88% >20% 95% 3-5% 8%

>99% <2% <2% <1% >80%

NIPT is very attractive as those positive-increased chance are highly likely to be a true positive on diagnostic-invasive testing And also fewer false negatives

DOWN SYNDROME SCREENING APPROACH OBSERVED DETECTION RATES FOR 5% FALSE POSITVE RATES 100%

FPR 0.1%

FPR ~3%

90% 80% Current NZ performance

70% 60% 50% 40% 30% 20%

1:100

1:60

1:40

1:25

1:5

1:4

10% 0%

Age Triple Quad Comb Int cfDNA 1960 1970 1990 2005 2005 2012

OAPR

Meta analysis • • • • •

T21 DR99.2%(98.5-99.6) FPR0.09% (0.05-0.14) T18 DR 96.3%(94.3-97.9) FPR0.13%(0.07-0.20) T13 DR 91.0%(85.0-95.6) FPR 0.13%(0.05-0.26) X O DR 90.3%(85.7-94.2) FPR 0.23%(0.14-0.34) SCA DR93.0%(85.8-97.8) FPR 0.14% (0.06-0.24)

Ultrasound Obstet Gynecol 2015 DOI: 10.1002/uog.14791 Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis M. M. GIL, M. S. QUEZADA, R. REVELLO, R. AKOLEKAR, K. H. NICOLAIDES

Summary of NIPTclinically realistic setting • • • •

T21 DR 100% no false -ve Repeat testing 1.16% (Lau et al 2014) Non reportable-failure rate 0-4.9% (Benn P 2013) T18 DR~100%, T13 DR~91.% (Dan S 2012;Palomaki GE 2012)

Ultrasound Obstet Gynecol 2014; 43: 254–264Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage wholegenome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single centerT. K. LAU, S. W. CHEUNG, P. S. S. LO, A. N. PURSLEY,M. K. CHAN, F. JIANG,H. ZHANG, W. WANG, L. F. J. JONG, O. K. C. YUEN, H. Y. C. CHAN, W. S. K. CHAN K. W. CHOY n=1982cases

Other examples of use of NIPT • Fetal blood group genotyping* Targeted antenatal AntiD Determining surveillance in sensitised women • Fetal congenital adrenal hyperplasia • Cystic fibrosis • Spinal muscular atrophy etc * Available now

Some Companies • ARIOSA (US)

«Harmony» (?array approach)

• VERINATA (US)

«verifi» (Illumina)

• NATERA (US)

«Panorama» (SNP approach)

• SEQUENOM (US)

«MaterniT21»

• BGI (China)

«NIFTY»

• LIFE-CODEXX (Germany) «PrenaTest» Ask about fetal fraction, risk approach, failed test rate, what result is produced, coping with problems such as obesity, claims for twins- “expanded” screens and perhaps lastly cost

Verifir – by Illumina From 10 weeks 7 day turn around 21 18 13, ask doctor other SCAs Can do twins Cost-negotiate

basic verifi® Test screens for: T21 (Down syndrome) T18 (Edwards syndrome) T13 (Patau syndrome) Now a wider option is available for sex chromosomes at no extra charge: Monosomy X (MX; Turner syndrome) XXX (Triple X) XXY (Klinefelter syndrome) XYY (Jacobs syndrome) Fetal sex (XX or XY)—aids in stratifying the risk for X-linked disorders such as hemophilia, Duchenne muscular dystrophy, or cases of ambiguous genitalia, such as congenital adrenal hyperplasia

Panoramaâ&#x201E;˘ provides sensitivity >99% and positive predicted value (PPV) > 91% for Down syndrome. A microdeletion panel (including 22q11.2 deletion syndrome) is also available to provide unparalleled scope and reliability among non-invasive prenatal screens.

MATERNIT21速 PLUS 22q deletion syndrome (DiGeorge) 5p (Cri-du-chat syndrome) 15q (Prader-Willi/Angelman syndromes) 1p36 deletion syndrome 4p (Wolf-Hirschhorn syndrome) 8q (Langer-Giedion syndrome) 11q (Jacobsen syndrome) Trisomy 16 Trisomy 22

From 10 weeks From 5 day turnaround Can expand Can do twins

Request form You do need to have counselled patient and you do need to know what you are requesting

MATERNIT21® PLUS

The clinician has to explain the results and discuss the limitations In practice, probably no difference from currently and for common trisomies Probably much more straightforward as the difference in likelihood of a true pos or neg result Is very wide compared with current tests ( eg 1:2chance of pos versus 1:1000 if negative)

Main difference is that clinicians are dealing with off shore companies and we have little idea of their QA and science We also take all responsibility for outcomes and it is no easy to “call up the lab”

The pathway and outcomes Future

Current Pathway offer

offer

1stT combined Low risk

Increased risk

No action

1stT combined Low risk

No action Invasive diagnostic

outcome

Risk cut off

NIPT

outcome

Increased risk

Invasive diagnostic

A radical option?

Offer* NIPT + scan**

Low risk

High risk Invasive-amnio CVS

outcome • *Be clear and simple what is the question?

• **scan check list- no NT no part charge • Decide best timing of scan and ?do NIPT after

What might be missed-at this time cfDNA may not detect: • rare trisomies • unbalanced structural rearrangements • deletions and duplications • triploidy • marker chromosomes • mosaicism.

Challenges • Making a decision to do it- we have to -it speaks for itself • What are “the other conditions”?

- what trade offs - understanding we get what we ask for - Where would NIPT fit in- for all women or some?

• Costing the format • Getting started in the Lab and validation • Impact on invasives- skills of invasive operators

Cost- its not too bad actually • Funded in Canada • Insurance pays in USA • UK study suggests can be cost neutral (Morris S PLoS 2014)

• Costs vary with Company Techniques eg MPS vs SNPs Volumes Cutoffs in risk (if contingent) What is screened for No one costs false negs

Currently , on bulk contract could get for ~$250 NZ per test

Assumptions Number screened now 45,000 Serum Costs

Identifiable costs Screening and invasives

Serum 120 Scan

112

Total

232

$10,440,000

FPR 3%

1350

Invasives (75%)

1013@$1,000

$1013000

Missed cases

16

?$$$

11,453,000

Total NIPT Costs NIPT

200

Scan

87

Total

287

12,915,000

False pos ~0.1 Invasives (80%) Missed cases Total

~50

50,000

1-2

12,965,000

Not included: Capital costs to set up Falling costs with volumes Doing in a contingent way Changed costs to patients eg cheaper scans less travel, less anxiety, fewer false pos and false negs for trisomies

Summary • • • • • • •

NIPT a great new advance- a new paradigm!!

New era in performance Very low false pos and neg Much more reassuring for women Will further reduce invasive tests Provides a platform for the future- can change It is here now – lets do it well and ?offer to all

Medscape Medical News > Conference News Test for Fetal Abnormalities Finds Maternal Cancer Neil Osterweil March 06, 2015

"I feel like the luckiest person alive," Dr Lee, a San Francisco-based anesthesiologist, When she was 15 weeks pregnant, she underwent a wholebody MRI scan and a 7 cm tumor in the sigmoid colon was detected.

With laparoscopic resection, the surgeons were able to completely remove the tumor. Postsurgical staging showed that it was T3N0M0 colon cancer â&#x20AC;&#x153;The abnormalities seen are not diagnostic of cancer, Dr van den Boom explained. They could come from systemic lupus erythematosus, organ transplant rejection, or other causes, but test results in several cases have come back suggestive of various malignanciesâ&#x20AC;?.

As this expands do we need national and bioethical standards and controls?