The future of prenatal diagnosis

Yves JacquemynUZA

AntwerpBelgium

Preliminary thoughts

• Technology

– HIGH END/ ASYMPTOTIC IMPROVEMENTS FOR THE HAPPY FEW versus

– LOW END/ BETTER SCREENING FOR ALL

– From general screening to personalized care

• Society and ethics

Limitations

– Only on congenital malformations

• Structural

• Genetic

• Functional!!??

– Not on prediction, prevention of IUGR, PE, PTL

– Not on multiple pregnancy ( the T of EurocaT)

– Just a glimpse on therapy

What is the ideal ?

• 100 % antenatal detection

– Not just “screening” but also “diagnosis”

• As early in pregnancy as possible

– If possible preconceptionally

• Treat antenatally and offer optimal perinatal support

– Avoid TOP

But is it really all on the perfect baby?

Where do we stand and what’s coming up?

• Trends– From late to early

• 2 trimester AC enUS, first trimester to PGD to preconceptioncare

– From invasive to non invasive ?• Eg hemoglobinopathy: from FBS to PCR on DNA in CVS or AF

to…..?

– From screening /risk determination to immediatediagnosis

– From selective in high risk cases to the generalpopulation

• Imaging

• Lab testing

• Integration

Imaging

3D 4D ever increasing image quality:

• What with the operators

• Better image ~better diagnosis?

• Ultrafast MRI: will it really add anything?

• Fetoscopy/embryoscopy: not for the general populationin a purely diagnostic setting

11-13 weeks ultrasound and non-chromosomal anomalies

• 100 % DR of some major anomalies: acrania, alobar holoprosencephaly, exomphalos…

• 50 % DR for diaphragmatic hernia, lethal skeletaldysplasia

• 34% major cardiac anomaly

• 14% spina

• 5% facial clefts

• 0% for: agenesis corpus callosum ( cfrembryology); most renal defects, talipes…

(Nicolaides Prenat Diagn 2010)

• This is in higly skilled hands

• Can be achieved with good and continous training in all Europe?

• But not yet, actually after second trimester scan (Eurocat 2003-2007):

– 96% anencephaly

– 83% gastroschisis

– 68% spina

Garne, J Med Screen ,2010

Problem of early detection of spinabifida

• Only the most severe cases in 1st trim• Often the ones associated with other major

abnormalities• Due to

– Poor ossification of the fetal spine– Small size– Maternal habitus

• Possible improvement by detailed examination of the posterior fossa at 11-13 week (intracranialtranslucency)

(Sepulveda,Prenat Diagn 2011)

Ever increasing list of new markers of aneuploidy

• Nasal bone• Increased impedance in Ductus venosus• Tricuspid regurgiation• Facial angle• Liver volume• Increased Hepatic artery blood flow• Maternal thyroid function

• Want to publish: just increase the list

There will always be anomalies

• That are always detectable– anencephaly

• Sometimes detectable– SPINA BIFIDA at 11-13 weeks– FACIAL CLEFT at 11-13 weeks– Multicystic kidney at 11-13 weeks

• Can never be detected– Microcephaly at 11-13 weeks, only > 30 weeks– Agenesis of corpus callosum before 18 weeks– Postinfectious problems appear only after a few

weeks

Syngelaki et al Prenat Diagn 2011

What can be improved in fetalultrasound?

• DR of heart and skeleton lag behind

– Routine assessment cardiac outflow in all

– Training+++

– Telecardiology with STIC volumes analysed by expert elsewhere?

• More early systematic screening at 11-13 weeks

Robson, Prenat Diagn 2010

The near future

• Optimalisation of prenatal ultrasound– First trimester structural detection– Second trimester scan

• Soft martkers for aneuploidy are part of this

• Appropriate training of sonographers• Take more time for the scan• Include detailed examinatiuon of the fetal heart• Refer hig NT for expert echocardiography• Development of new easily recognizable markers for

high risk groups that can be referred to expert ( cardiac, brain?, kidney?)

What will come in ultrasound

• Still better 4D

• HIFU: high intensity focused ultrasound

– Local necrosis of tumors: TTS?

– Local delivery of drugs in mircospheres

– Local delivery of DNA

• Miniaturisation of devices

Lab tests

Lab tests

• Maternal serum screening versus

• Fetal material in maternal circulation

Actual limitation of maternal serum screening

• Is basically screening for Down syndrome– DR up to 96 %, false positive rate 3-5%

• For Trisomy 18 and 13: – DR 75 % with DS algorithms– DR up to 95 % with specific algorithms and increase in

FPR 0.1%– 85 % DR for triploidy

• Incidental finding of other abnormalities– Triple X, Smith-Lemli-Opitz, X linked ichtyosis

• NT increase associated with seemingly ever increasing list of other anomalies

Panigrahi, Prenat Diagn 2010; Nicolaides, Orenat Diagn 2010

Fetal material in maternal circulation

• Fetal cells

– Will it ever keep it promesses???? Since 1980…

• Cell free fetal DNA (RNA)

Fast evolution in genetics will influenceprenatal diagnosis

• Spreading use of array-based comparative genomic hybridisation

• Single nucleotide polymorphism detection

• DNA sequencing including shot gun or massive sequencing

• Single cell analysis

• Human epigenome project

CFFDNA

• ~5% DNA is maternal circulation is fetal

• Established for– Y = male/ fetal sexing ( from 6 weeks)

– Rhesus D

• Emerging for– Aneuploidy egTrisomy 18 (Tong, 2006)

– Detection paternal genome for dominant disorders eg Huntington

– Antenatal genome analysis?? ( Pergament, 2010)

Lo, Prenat Diagn 2010

CFFDNA

• DNA sequencing?

• “massive parallel DNA sequencing” (Chiu 2008, Lo 2010)

• Determine aneuploidy

• Search for monogenic diseases

• Resulting in systematic trisomy 21 diagnosis in stead of screening

• It is the COST that limit the use of this technology

Is there a future for invasive diagnosis?

YES

• Microarrays on CVS give >>>>>> fetal genetic information than classic karyotype>>> than CFFDNA

• ~1% will demonstrate significant disease

– How to counsel?

• =changes risk/benefit ratio for the procedure

• Offer invasive testing to all??

(Wapner, Prenat Diagn 2011)

Some problems

• More screening more “collateral damage”

• Create anxiety ( prenatal care becomes prenatal scare)

• Will the obesity epidemic neutralise the development of high definition ultrasound?(Cfr J Rankin,

abstract, this congress)

• Obesity will increase NTD/CV (P Tennant, abstract, this congres)

Some problems

• Accurate interpretation

– Of structural malformations

• How to counsel in case of hydrocephaly?

– Of lab tests

• How to counsel a CMV infection?

• Of DNA sequencing: what to do with an incidental finding?/ what to do when your “epigenomic analysis” tells you wil develop cancer …

What the adversaries say and why it is wrong

• It can be used for eugenic reasons and social purposes

– Eg sex selection cfr India, US vs Europe

– Is it not the aim that every generation improves

– Our western ethics are not superior

• Strive to eradicate

– Indeed why not for CF, thalassemia,hemaphilia…?

– We strive to eradicate TBC, malaria, polio also!

conclusion

• Improve DR for cardiac / skeleton

• More early US diagnosis

• CFFDNA could replace serum screening for chromosome abnormalities

conclusion

• How can we make this high tech care affordable for all?

• How can we still respect free choice for all?