The New Prenatal Screening Tests St. Paul’s Hospital CME Conference for Primary Physicians November 22, 2007 Ken Seethram, MD, FRCSC, FACOG Obstetrics

The New Prenatal Screening The New Prenatal Screening TestsTests

St. Paul’s Hospital CME Conference St. Paul’s Hospital CME Conference for Primary Physiciansfor Primary Physicians

November 22, 2007November 22, 2007

Ken Seethram, Ken Seethram, MD, FRCSC, FACOGMD, FRCSC, FACOGObstetrics and GynecologyObstetrics and Gynecology

pacificfertility.capacificfertility.ca

Disclosure statementDisclosure statement

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

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

ObjectivesObjectives

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

II.II. Help fully understand all options in order to Help fully understand all options in order to better undertake counselingbetter undertake counseling

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

OutlineOutline

DefinitionsDefinitions Background and EvolutionBackground and Evolution Second Trimester Serum ScreeningSecond Trimester Serum Screening First Trimester ScreeningFirst Trimester Screening Combined ScreeningCombined Screening GuidelinesGuidelines Final words and resourcesFinal words and resources

Quick DefinitionsQuick Definitions

DR = Detection rateDR = Detection rate:: the rate at which a test will pick up the problem. This the rate at which a test will pick up the problem. This

is accuracy, not reliabilityis accuracy, not reliability FPR = False positive rateFPR = False positive rate::

the chance that the screening tool will be positive the chance that the screening tool will be positive when the condition is absentwhen the condition is absent

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

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

BackgroundBackground

What are we screening for?What are we screening for? Aneuploidy: majority of which is Trisomy 21, Aneuploidy: majority of which is Trisomy 21,

with T18, T13, and monosomy X (45X) with T18, T13, and monosomy X (45X) Secondary screening benefits?Secondary screening benefits?

Dating the pregnancyDating the pregnancy Anatomy evaluation, placental evaluation, Anatomy evaluation, placental evaluation,

twins, early anomaliestwins, early anomalies

Evolution of screeningEvolution of screening

1887 – John Langdon Down presented1887 – John Langdon Down presented

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

due to egg age, declining quality of spindle due to egg age, declining quality of spindle mechanism: nondisjunction at meiosis I prior to mechanism: nondisjunction at meiosis I prior to fertilization – aneuploidy results fertilization – aneuploidy results

late 1970’s – age was first put to use to triage late 1970’s – age was 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 to at which the rate of aneuploidy was equal to

the rate of amniocentesis/CVS related the rate of amniocentesis/CVS related miscarriage. miscarriage.

Therefore, maternal age was the first screening Therefore, maternal age was the first screening tool.tool.

Bad news:Bad news: it’s the worst screening tool, it’s the worst screening tool, with only 30-40% detection ratewith only 30-40% detection rate

Today:Today: don’t use age 35 as a cut-off don’t use age 35 as a cut-off

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

AFPAFP Total hCGTotal hCG Unconjugated estriol Unconjugated estriol

uE3uE3

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

Triple marker screen (TMS)

Inhibin AInhibin A

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

changed with multiple changed with multiple marker screening toolsmarker screening tools

Uses 2-4 biochemical Uses 2-4 biochemical markers to adjust the age markers to adjust the age related risksrelated 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?

(11-14 weeks)(11-14 weeks)

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, 11-US measurement, 11-

14w: spine to skin 14w: spine to skin Fetal Medicine Fetal Medicine

Foundation Foundation Aneuploidy - a change in Aneuploidy - a change in

extracellular matrix and extracellular matrix and potential for potential for cardiac/lymphatic cardiac/lymphatic changes causing changes causing increased NTincreased NT

Congenital hearts, othersCongenital hearts, others




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

Serum biochemistrySerum biochemistry Free beta hCG Free beta hCG (different than TMS/Quad)(different than TMS/Quad) PAPP-A PAPP-A (Preg Assoc. plasma protein-A)(Preg Assoc. plasma protein-A) relative levels are used to predict T21, T13, relative levels are used to predict T21, T13,

T18T18 Low PAPP-A –Low PAPP-A –

may be associated with a poorly developing may be associated with a poorly developing placentaplacenta

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




Nasal Bone (NB)Nasal Bone (NB)

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

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

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

The First Trimester – TR, The First Trimester – TR, FMF, Ductus VenosusFMF, Ductus Venosus

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

First Trimester First Trimester Screening Screening (FTS (FTS

performance)performance)CriteriaCriteria DRDR FPRFPR

Age + NT AloneAge + NT Alone 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

Serum integratedSerum integrated IntegratedIntegrated SequentialSequential ContingencyContingency

First Trimester First Trimester ScreeningScreening

Second Second Trimester Trimester ScreeningScreening

Combined Combined ScreeningScreening

Screening StrategiesScreening Strategies Serum Integrated Pregnancy Screening Serum Integrated Pregnancy Screening

(SIPS)(SIPS) 11stst TM PAPP-A + Quad (SURUSS trial, 2003) TM PAPP-A + Quad (SURUSS trial, 2003) Results disclosed at 17/18wResults disclosed at 17/18w

Integrated Pregnancy Screening (IPS)Integrated Pregnancy Screening (IPS) 11stst TM PAPP-A + TM PAPP-A + NTNT + TMS/Quad + TMS/Quad Same as SIPS but with NT Same as SIPS but with NT Results disclosed at 17/18wResults disclosed at 17/18w SURUSS and FASTER trials 2003/2005SURUSS and FASTER trials 2003/2005

Screening StrategiesScreening Strategies

Sequential screening modelSequential screening model IPS but disclosed after 1IPS but disclosed after 1stst, and then 2, and then 2ndnd TM TM People may opt for testing after 1People may opt for testing after 1stst TM TM

Contingency Screening modelsContingency Screening models 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 -If risks 1:50-1:999 -

quad offered orquad offered or Nasal bone contingency: offer NB to intermediate groupNasal bone contingency: offer NB to intermediate group Probably best for high DR’s in population based screeningProbably best for high DR’s in population based screening

Which test is best?Which test is best?

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

DRDR FPRFPR WeeksWeeks TrialTrial

NT+NB+SerumNT+NB+Serum 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 in finished in 11stst TM TM

CuckleCuckle

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

90% 90% finished in finished in 11stst 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: IPS/Contingency screening programsIPS/Contingency screening programs

For Late entryFor Late entry Quad screenQuad screen

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: Triple screening is no longer good enoughTriple screening 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

Quality Assurance?Quality Assurance?

Image and data auditImage and data audit Initial certification, and on-going auditInitial certification, and on-going audit FMF UK/USAFMF UK/USA NTQR?NTQR? Importance on program based screening:Importance on program based screening:

Pre/post test counselingPre/post test counseling Lab and clinical QALab and clinical QA

ACOGACOG

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

decide to offer your patients, information about decide to offer your patients, information about

the detection and false-positive rates, the detection and false-positive rates,

advantages, disadvantages, limitations, and advantages, disadvantages, limitations, and

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

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

make informed decisions.make informed decisions.

SOGCSOGC

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

2008 Minimum standard: 75% 2008 Minimum standard: 75% DRDR, 5% , 5% FPRFPR

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

SOGCSOGC

The practice of using solely the previous cut-off of maternal age of 35 or over at the estimated date of delivery (EDD) to identify at-risk pregnancies should be abandoned

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 involves an As long as the definitive diagnosis involves an

invasive procedure which can cause invasive procedure which can cause miscarriage of a normal pregnancy, there is miscarriage of a normal pregnancy, there is simply no substitute to explaining all the simply no substitute to explaining all the options, their benefits, and risksoptions, their benefits, and risks

best screen is the one which will service best screen is the one which will service patient’s needs for time of results, and action patient’s needs for time of results, and action depending on the resultsdepending 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 SIPS for women over age 38 IPS for women over age 40 IPS for women over age 40 Private centre's for FTS with or without NB (complies)Private centre's for FTS with or without NB (complies) MOH investigating new optionsMOH investigating new options

FMF Accredited FTS FMF Accredited FTS Centre's, BCCentre's, BC

BCWH BCWH (block funding for special groups)(block funding for special groups)

IPS (over age 40), SIPS (over age 38)IPS (over age 40), SIPS (over age 38) Prior aneuploidy, TwinsPrior aneuploidy, Twins

Pacific Ctr for Reproductive MedicinePacific Ctr for Reproductive Medicine ($495)($495)

FTS - NT + FTS - NT + NBNB + serum + genetic counseling + serum + genetic counseling o-s-c-a-r modeling after FMFo-s-c-a-r modeling after FMF

Genesis Fertility Centre Genesis Fertility Centre ($495)($495)

FTS - NT + serum + genetic counselingFTS - NT + serum + genetic counseling

ResourcesResources

www.fetalmedicine.comwww.fetalmedicine.com www.earlyriskassessment.comwww.earlyriskassessment.com www.mfmedicine.comwww.mfmedicine.com www.genesis-fertility.comwww.genesis-fertility.com

www.pacificfertility.cawww.pacificfertility.ca

Documents

The New Prenatal Screening Tests St. Paul’s Hospital CME Conference for Primary Physicians November 22, 2007 Ken Seethram, MD, FRCSC, FACOG Obstetrics