The New Prenatal The New Prenatal Screening TestsScreening Tests

Langley Memorial Hospital Langley Memorial Hospital Grand RoundsGrand Rounds

November 8, 2007November 8, 2007

Ken Seethram, Ken Seethram, MD, FRCSC, FACOGMD, FRCSC, FACOGObstetrics and Gynecology, Burnaby HospitalObstetrics and Gynecology, Burnaby Hospital

Pacific Centre for Reproductive MedicinePacific Centre for Reproductive Medicine

Disclosure statementDisclosure statement

I have no financial relationship I have no financial relationship with pharmaceutical or medical with pharmaceutical or medical ultrasound corporations ultrasound corporations associated with prenatal screening associated with prenatal screening and/or diagnosis.and/or diagnosis.

I will provide a website link from I will provide a website link from pacificfertility.capacificfertility.ca for relevant for relevant literature and a copy of this talk.literature and a copy of this talk.

..wow, things have changed..wow, things have changed

ObjectivesObjectives

I.I. To make you current with 2007/08 To make you current with 2007/08 information and guidelines from ACOG information and guidelines from ACOG and SOCG with regards to Prenatal and SOCG with regards to Prenatal screening optionsscreening options

II.II. Help fully understand all options in Help fully understand all options in order to better counselorder to better counsel

III.III. Help understand how and when to get Help understand how and when to get your patients screened once their your patients screened once their options are knownoptions are known

Quick DefinitionsQuick Definitions DR = Detection rateDR = Detection rate::

the rate at which a test will pick up the the rate at which a test will pick up the problem. This is accuracy, not reliabilityproblem. This is accuracy, not reliability

FPR = False positive rateFPR = False positive rate:: the chance that the screening tool will be the chance that the screening tool will be

positive when the condition is absentpositive when the condition is absent Note the use of ‘screen positive’Note the use of ‘screen positive’

Screen positive:Screen positive: the literature term to describe the number of the literature term to describe the number of

times the test will be positive (either truly or times the test will be positive (either truly or falsely)falsely)

BackgroundBackground

What are we screening for?What are we screening for? Aneuploidy:Aneuploidy: majority of which is majority of which is

Trisomy 21, with T18, T13, and Trisomy 21, with T18, T13, and monosomy X (45X) being less likelymonosomy X (45X) being less likely

Secondary screening benefits?Secondary screening benefits? Dating the pregnancyDating the pregnancy Anatomy evaluation, placental Anatomy evaluation, placental

evaluation, twins, early anomaliesevaluation, twins, early anomalies

Evolution of screeningEvolution of screening

1930’s – first association made with 1930’s – first association made with maternal age and risk of major maternal age and risk of major malformations malformations

due to egg age, declining quality of due to egg age, declining quality of spindle mechanism: nondisjunction at spindle mechanism: nondisjunction at meiosis I prior to fertilization - triples meiosis I prior to fertilization - triples chromosomes chromosomes

late 1970’s - first put to use to triage late 1970’s - first put to use to triage women for amniocentesiswomen for amniocentesis

Evolution of screeningEvolution of screening

Age 35 became the ‘high risk age’ Age 35 became the ‘high risk age’ at which the rate of aneuploidy was equal at which the rate of aneuploidy was equal

to the rate of amniocentesis/CVS related to the rate of amniocentesis/CVS related miscarriage. miscarriage. Therefore, maternal age Therefore, maternal age was the first screening tool.was the first screening tool.

Bad news:Bad news: it’s the worst screening it’s the worst screening tool, with only 30% detection ratetool, with only 30% detection rate

Today:Today: erosion of the ‘age 35 as erosion of the ‘age 35 as a cut-off’a cut-off’

1980’s – 21980’s – 2ndnd Trimester serum Trimester serum

AFPAFP Total hCGTotal hCG Unconjugated Unconjugated

estriol uE3estriol uE3 Inhibin AInhibin A

Quad Screen (TMS/Quad = multiple marker scrg test, maternal serum screen)

Triple marker screen (TMS)

TMS and Quad ScreeningTMS and Quad Screening Nothing really has Nothing really has

changed with multiple changed with multiple marker screening marker screening toolstools

Uses 2-4 biochemical Uses 2-4 biochemical markers to adjust the markers to adjust the age related risksage related risks

Problem - specificity Problem - specificity drops as disease drops as disease prevalence increasesprevalence increases i.e. Many false positive’si.e. Many false positive’s

DRDR FPRFPR

TMSTMS <72%<72% 7-25%7-25%

QuadQuad 77%77% 5.2%5.2%

What has evolved in the first What has evolved in the first trimester?trimester?

Nuchal Translucency (NT)Nuchal Translucency (NT) Serum biochemistrySerum biochemistry Nasal Bone (NB)Nasal Bone (NB)

Tricuspid regurgitation (TR)Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)Frontomaxillary facial angle (FMF Angle)

The First Trimester - NTThe First Trimester - NT

US measurement, US measurement, 11-14w: spine to 11-14w: spine to skin skin

Fetal Medicine Fetal Medicine Foundation Foundation

Aneuploidy - a Aneuploidy - a change in change in extracellular matrix extracellular matrix and potential for and potential for cardiac/lymphatic cardiac/lymphatic changes causing changes causing increased NTincreased NT

What has evolved in the first What has evolved in the first trimester?trimester?

Nuchal Translucency (NT)Nuchal Translucency (NT) Serum biochemistrySerum biochemistry Nasal Bone (NB)Nasal Bone (NB)

Tricuspid regurgitation (TR)Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)Frontomaxillary facial angle (FMF Angle)

PAPP-A & free beta hCGPAPP-A & free beta hCG

Serum biochemistrySerum biochemistry Free beta hCG (different than Free beta hCG (different than

TMS/Quad)TMS/Quad) PAPP-A (Preg Assoc. plasma protein-A)PAPP-A (Preg Assoc. plasma protein-A) relative levels are used to predict T21, relative levels are used to predict T21,

T13, T18T13, T18 Low PAPP-ALow PAPP-A – –

may be associated with a poorly may be associated with a poorly developing placentadeveloping placenta

Evolving method of screening for Evolving method of screening for placental disease (IUGR, PIH)placental disease (IUGR, PIH)

What has evolved in the first What has evolved in the first trimester?trimester?

Nuchal Translucency (NT)Nuchal Translucency (NT) Serum biochemistrySerum biochemistry Nasal Bone (NB)Nasal Bone (NB)

Tricuspid regurgitation (TR)Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)Frontomaxillary facial angle (FMF Angle)

Nasal Bone (NB)Nasal Bone (NB)

60-70% of T21 60-70% of T21 absent Nasal boneabsent Nasal bone

99% of euploid 99% of euploid fetuses have Nasal fetuses have Nasal bonebone

tremendous tremendous increase in increase in detection rates of detection rates of FTS. High learning FTS. High learning curvecurve

The First Trimester – TR The First Trimester – TR and FMF and FMF

Tricuspid Regurge and FMF angle are Tricuspid Regurge and FMF angle are somewhat experimental and not somewhat experimental and not wide clinically used outside of wide clinically used outside of research settingsresearch settings

On the horizonOn the horizon

Frontomaxillary Facial Frontomaxillary Facial AngleAngle

First Trimester First Trimester Screening (FTS)Screening (FTS)

CriteriaCriteria DRDR FPRFPR

Age + NT Age + NT AloneAlone 75%75% 5-10%5-10%

Age + NT + Age + NT +

hCG / PAPP-AhCG / PAPP-A83-85%83-85% 5%5%

Age + NT + Age + NT + hCG/PAPP-A + hCG/PAPP-A + Nasal BoneNasal Bone

92-95%92-95% 3-5%3-5%

Screening StrategiesScreening Strategies

First Trimester First Trimester ScreenScreen

Second Trimester Second Trimester ScreenScreen

Combined Combined screeningscreening

Serum integratedSerum integrated IntegratedIntegrated SequentialSequential ContingencyContingency FTS onlyFTS only

Models of Screening with high Models of Screening with high detection ratesdetection rates

FTS with NT + NB + serum aloneFTS with NT + NB + serum alone

Serum Integrated Pregnancy Screening Serum Integrated Pregnancy Screening (SIPS)(SIPS) 11stst TM PAPP-A + Quad (SURUSS trial) TM PAPP-A + Quad (SURUSS trial) Results disclosed at 17/18wResults disclosed at 17/18w

Integrated Pregnancy Screening (IPS)Integrated Pregnancy Screening (IPS) 11stst TM PAPP-A + NT alone + TMS/Quad TM PAPP-A + NT alone + TMS/Quad Results disclosed at 17/18wResults disclosed at 17/18w

Models of ScreeningModels of Screening

Sequential screening modelSequential screening model IPS but disclosed after 1IPS but disclosed after 1stst, and then 2, and then 2ndnd

TMTM Contingency Screening modelContingency Screening model

FTS done - <1:1000, no further testingFTS done - <1:1000, no further testing If risks >1:50, CVS offeredIf risks >1:50, CVS offered If risks 1:50-1:999, quad offeredIf risks 1:50-1:999, quad offered Nasal bone contingency: offer NB to Nasal bone contingency: offer NB to

intermediate groupintermediate group

Which test is best?Which test is best?

The recent data would suggest that The recent data would suggest that Contingency screening with the nasal Contingency screening with the nasal bone model will turn out to be the bone model will turn out to be the highest detection rates, with least highest detection rates, with least amount of resources, and lowest FPRamount of resources, and lowest FPR -gives 90% DR for 2.5% FPR-gives 90% DR for 2.5% FPR

How does each model perform…How does each model perform…

DRDR FPRFPR WeeksWeeks TrialTrial

NT+NB+SerNT+NB+Serumum 92-95%92-95% 3-5%3-5% 11-1411-14 FMFFMF

Serum Serum integratedintegrated 88%88% 5%5% 17-18w17-18w SURUSSSURUSS

Fully Fully IntegratedIntegrated

93%93%

96%96%

92%92%

5%5%

5%5%

5%5%

17-18w17-18w

17-18w17-18w

17-18w17-18w

SURUSSSURUSS

FASTERFASTER

MetaMeta

SequentialSequential 95%95% 5%5% 13-18w13-18w FASTERFASTER

ContingencyContingency 91-92%91-92% 5%5%85% 85% finished finished in 1in 1stst TM TM

CuckleCuckle

Nasal Bone Nasal Bone ContingencyContingency 90%90% 2.5%2.5%

90% 90% finished finished in 1in 1stst TM TM

RCTRCT

Best performanceBest performance

For a first trimester result:For a first trimester result: FTS with NT + NB + serumFTS with NT + NB + serum Contingency screening programsContingency screening programs

For a combined result:For a combined result: Contingency screening programsContingency screening programs

What do the guidelines What do the guidelines say?say?

ACOG released similar guidelines in ACOG released similar guidelines in January 2007, and SOGC in FebruaryJanuary 2007, and SOGC in February

Basics:Basics: TMS is no longer good enoughTMS is no longer good enough Don’t use age as a screening toolDon’t use age as a screening tool Aim for highest DR’s and lowest FPR’s in any Aim for highest DR’s and lowest FPR’s in any

methodmethod Consent and review all options Consent and review all options Quality assurance important in FTS programsQuality assurance important in FTS programs

ACOGACOG

Regardless of which screening tests you decide Regardless of which screening tests you decide

to offer your patients, information about the to offer your patients, information about the

detection and false-positive rates, advantages, detection and false-positive rates, advantages,

disadvantages, and limitations, as well as the disadvantages, and limitations, as well as the

risks and benefits of diagnostic procedures, risks and benefits of diagnostic procedures,

should be available to patients so that they can should be available to patients so that they can

make informed decisionsmake informed decisions

SOGCSOGC

All women regardless of age, should be All women regardless of age, should be offered consented screening for the most offered consented screening for the most significant aneuploidies, and a second significant aneuploidies, and a second trimester sonogram for dating, growth and trimester sonogram for dating, growth and anomaliesanomalies

age screening is a poor minimum standard age screening is a poor minimum standard and should be removedand should be removed

Amnio/CVS can be offered to women over Amnio/CVS can be offered to women over age 40, without screening, but screening age 40, without screening, but screening should still be offered. should still be offered.

What’s the best test?What’s the best test?

One size does not fit allOne size does not fit all As long as the definitive diagnosis As long as the definitive diagnosis

involves an invasive procedure which involves an invasive procedure which can cause miscarriage of a normal can cause miscarriage of a normal pregnancy, there is simply no substitute pregnancy, there is simply no substitute to explaining all the options, their to explaining all the options, their benefits, and downsides to all our benefits, and downsides to all our patientspatients

best screen is the one which will service best screen is the one which will service patient’s needs for time of results, and patient’s needs for time of results, and action depending on the resultsaction depending on the results

Current Western Canada Current Western Canada optionsoptions

AlbertaAlberta Edmonton/Calgary – FTS programs, provincially Edmonton/Calgary – FTS programs, provincially

insuredinsured

British ColumbiaBritish Columbia TMS program (does not yet comply with SOGC)TMS program (does not yet comply with SOGC) SIPS for women over age 38 (does not comply)SIPS for women over age 38 (does not comply) IPS for women over age 40 (complies)IPS for women over age 40 (complies) Private centre's for FTS with or without NB Private centre's for FTS with or without NB

(complies)(complies) MOH investigating new optionsMOH investigating new options

Accredited FTS Centres, Accredited FTS Centres, BCBC

Pacific Centre for Reproductive MedicinePacific Centre for Reproductive Medicine NT + NB + serumNT + NB + serum

Genesis Fertility CentreGenesis Fertility Centre NT + serumNT + serum Follow with TMS in second trimesterFollow with TMS in second trimester

ResourcesResources

www.fetalmedicine.comwww.fetalmedicine.com www.earlyriskassessment.comwww.earlyriskassessment.com www.pacificfertility.cawww.pacificfertility.ca