The New Prenatal Screening Tests Langley Memorial Hospital Grand Rounds November 8, 2007 Ken Seethram, MD, FRCSC, FACOG Obstetrics and Gynecology, Burnaby Hospital Pacific Centre for Reproductive Medicine

Disclosure statement I have no financial relationship with pharmaceutical or medical ultrasound corporations associated with prenatal screening and/or diagnosis. I will provide a website link from pacificfertility.ca for relevant literature and a copy of this talk.

..wow, things have changed

Objectives  To make you current with 2007/08 information and guidelines from ACOG and SOCG with regards to Prenatal screening options  Help fully understand all options in order to better counsel  Help understand how and when to get your patients screened once their options are known

Quick Definitions DR = Detection rate: DR = Detection rate: the rate at which a test will pick up the problem. This is accuracy, not reliability the rate at which a test will pick up the problem. This is accuracy, not reliability FPR = False positive rate: FPR = False positive rate: the chance that the screening tool will be positive when the condition is absent the chance that the screening tool will be positive 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 times the test will be positive (either truly or falsely) the literature term to describe the number of times the test will be positive (either truly or falsely)

Background What are we screening for? What are we screening for? Aneuploidy: majority of which is Trisomy 21, with T18, T13, and monosomy X (45X) being less likely Aneuploidy: majority of which is Trisomy 21, with T18, T13, and monosomy X (45X) being less likely Secondary screening benefits? Secondary screening benefits? Dating the pregnancy Dating the pregnancy Anatomy evaluation, placental evaluation, twins, early anomalies Anatomy evaluation, placental evaluation, twins, early anomalies

Evolution of screening 1930’s – first association made with maternal age and risk of major malformations 1930’s – first association made with maternal age and risk of major malformations due to egg age, declining quality of spindle mechanism: nondisjunction at meiosis I prior to fertilization - triples chromosomes due to egg age, declining quality of spindle mechanism: nondisjunction at meiosis I prior to fertilization - triples chromosomes late 1970’s - first put to use to triage women for amniocentesis late 1970’s - first put to use to triage women for amniocentesis

Evolution 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 the rate of amniocentesis/CVS related miscarriage. Therefore, maternal age was the first screening tool. at which the rate of aneuploidy was equal to the rate of amniocentesis/CVS related miscarriage. Therefore, maternal age was the first screening tool. Bad news: it’s the worst screening tool, with only 30% detection rate Bad news: it’s the worst screening tool, with only 30% detection rate Today: erosion of the ‘age 35 as a cut- off’ Today: erosion of the ‘age 35 as a cut- off’

1980’s – 2 nd Trimester serum AFP AFP Total hCG Total hCG Unconjugated estriol uE3 Unconjugated estriol uE3 Inhibin A Inhibin A Quad Screen (TMS/Quad = multiple marker scrg test, maternal serum screen ) Triple marker screen (TMS)

TMS and Quad Screening Nothing really has changed with multiple marker screening tools Nothing really has changed with multiple marker screening tools Uses 2-4 biochemical markers to adjust the age related risks Uses 2-4 biochemical markers to adjust the age related risks Problem - specificity drops as disease prevalence increases Problem - specificity drops as disease prevalence increases i.e. Many false positive’s i.e. Many false positive’s DRFPR TMS<72%7-25% Quad77%5.2%

What has evolved in the first trimester? Nuchal Translucency (NT) Serum biochemistry Nasal Bone (NB) Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)

The First Trimester - NT US measurement, w: spine to skin US measurement, w: spine to skin Fetal Medicine Foundation Fetal Medicine Foundation Aneuploidy - a change in extracellular matrix and potential for cardiac/lymphatic changes causing increased NT Aneuploidy - a change in extracellular matrix and potential for cardiac/lymphatic changes causing increased NT

What has evolved in the first trimester? Nuchal Translucency (NT) Serum biochemistry Nasal Bone (NB) Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)

PAPP-A & free beta hCG Serum biochemistry Serum biochemistry Free beta hCG (different than TMS/Quad) Free beta hCG (different than TMS/Quad) PAPP-A (Preg Assoc. plasma protein-A) PAPP-A (Preg Assoc. plasma protein-A) relative levels are used to predict T21, T13, T18 relative levels are used to predict T21, T13, T18 Low PAPP-A – Low PAPP-A – may be associated with a poorly developing placenta may be associated with a poorly developing placenta Evolving method of screening for placental disease (IUGR, PIH) Evolving method of screening for placental disease (IUGR, PIH)

What has evolved in the first trimester? Nuchal Translucency (NT) Serum biochemistry Nasal Bone (NB) Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle)

Nasal Bone (NB) 60-70% of T21 absent Nasal bone 60-70% of T21 absent Nasal bone 99% of euploid fetuses have Nasal bone 99% of euploid fetuses have Nasal bone tremendous increase in detection rates of FTS. High learning curve tremendous increase in detection rates of FTS. High learning curve

The First Trimester – TR and FMF Tricuspid Regurge and FMF angle are somewhat experimental and not wide clinically used outside of research settings Tricuspid Regurge and FMF angle are somewhat experimental and not wide clinically used outside of research settings On the horizon On the horizon

Frontomaxillary Facial Angle

First Trimester Screening (FTS) CriteriaDRFPR Age + NT Alone 75%5-10% Age + NT + hCG / PAPP-A 83-85%5% Age + NT + hCG/PAPP-A + Nasal Bone 92-95%3-5%

Screening Strategies First Trimester Screen First Trimester Screen Second Trimester Screen Second Trimester Screen Combined screening Combined screening Serum integrated Integrated Sequential Contingency FTS only

Models of Screening with high detection rates FTS with NT + NB + serum alone FTS with NT + NB + serum alone Serum Integrated Pregnancy Screening (SIPS) Serum Integrated Pregnancy Screening (SIPS) 1 st TM PAPP-A + Quad (SURUSS trial) 1 st TM PAPP-A + Quad (SURUSS trial) Results disclosed at 17/18w Results disclosed at 17/18w Integrated Pregnancy Screening (IPS) Integrated Pregnancy Screening (IPS) 1 st TM PAPP-A + NT alone + TMS/Quad 1 st TM PAPP-A + NT alone + TMS/Quad Results disclosed at 17/18w Results disclosed at 17/18w

Models of Screening Sequential screening model Sequential screening model IPS but disclosed after 1 st, and then 2 nd TM IPS but disclosed after 1 st, and then 2 nd TM Contingency Screening model Contingency Screening model FTS done - <1:1000, no further testing FTS done - <1:1000, no further testing If risks >1:50, CVS offered If risks >1:50, CVS offered If risks 1:50-1:999, quad offered If risks 1:50-1:999, quad offered Nasal bone contingency: offer NB to intermediate group Nasal bone contingency: offer NB to intermediate group

Which test is best? The recent data would suggest that Contingency screening with the nasal bone model will turn out to be the highest detection rates, with least amount of resources, and lowest FPR The recent data would suggest that Contingency screening with the nasal bone model will turn out to be the highest detection rates, with least amount 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…

DRFPRWeeksTrial NT+NB+Seru m 92-95%3-5%11-14FMF Serum integrated 88%5%17-18wSURUSS Fully Integrated 93%96%92%5%5%5%17-18w17-18w17-18wSURUSSFASTERMeta Sequential95%5%13-18wFASTER Contingency91-92%5% 85% finished in 1 st TM Cuckle Nasal Bone Contingency 90%2.5% 90% finished in 1 st TM RCT

Best performance For a first trimester result: For a first trimester result: FTS with NT + NB + serum FTS with NT + NB + serum Contingency screening programs Contingency screening programs For a combined result: For a combined result: Contingency screening programs Contingency screening programs

What do the guidelines say? ACOG released similar guidelines in January 2007, and SOGC in February ACOG released similar guidelines in January 2007, and SOGC in February Basics: Basics: TMS is no longer good enough TMS is no longer good enough Don’t use age as a screening tool Don’t use age as a screening tool Aim for highest DR’s and lowest FPR’s in any method Aim for highest DR’s and lowest FPR’s in any method Consent and review all options Consent and review all options Quality assurance important in FTS programs Quality assurance important in FTS programs

ACOG Regardless of which screening tests you decide to offer your patients, information about the detection and false- positive rates, advantages, disadvantages, and limitations, as well as the risks and benefits of diagnostic procedures, should be available to patients so that they can make informed decisions Regardless of which screening tests you decide to offer your patients, information about the detection and false- positive rates, advantages, disadvantages, and limitations, as well as the risks and benefits of diagnostic procedures, should be available to patients so that they can make informed decisions

SOGC All women regardless of age, should be offered consented screening for the most significant aneuploidies, and a second trimester sonogram for dating, growth and anomalies All women regardless of age, should be offered consented screening for the most significant aneuploidies, and a second trimester sonogram for dating, growth and anomalies age screening is a poor minimum standard and should be removed age screening is a poor minimum standard and should be removed Amnio/CVS can be offered to women over age 40, without screening, but screening should still be offered. Amnio/CVS can be offered to women over age 40, without screening, but screening should still be offered.

What’s the best test? One size does not fit all One size does not fit all As long as the definitive diagnosis involves an invasive procedure which can cause miscarriage of a normal pregnancy, there is simply no substitute to explaining all the options, their benefits, and downsides to all our patients As long as the definitive diagnosis involves an invasive procedure which can cause miscarriage of a normal pregnancy, there is simply no substitute to explaining all the options, their benefits, and downsides to all our patients best screen is the one which will service patient’s needs for time of results, and action depending on the results best screen is the one which will service patient’s needs for time of results, and action depending on the results

Current Western Canada options Alberta Alberta Edmonton/Calgary – FTS programs, provincially insured Edmonton/Calgary – FTS programs, provincially insured British Columbia British 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 (complies) Private centre's for FTS with or without NB (complies) MOH investigating new options MOH investigating new options

Accredited FTS Centres, BC Pacific Centre for Reproductive Medicine Pacific Centre for Reproductive Medicine NT + NB + serum NT + NB + serum Genesis Fertility Centre Genesis Fertility Centre NT + serum NT + serum Follow with TMS in second trimester Follow with TMS in second trimester

Resources