The New Prenatal Screening Tests St. Paul’s Hospital CME Conference for Primary Physicians November 22, 2007 Ken Seethram, MD, FRCSC, FACOG Obstetrics and Gynecology Thank you very much for your attendance and attention for this section. This talk, and all relevant literature, is posted on our website. pacificfertility.ca

Disclosure statement I have no financial relationship with pharmaceutical or medical ultrasound corporations associated with prenatal screening and/or diagnosis. I have no conflict of interest with any representation from ultrasound or diagnostic corporations which are involved with prenatal screening.

..wow, things have changed This slide is here to remind me of just how many things have changed in screening. I am a OBGYN here in Vancouver, at Burnaby hospital. I also direct the fetal screening program at the pacific centre for reproductive medicine. I have been involved in sonography for the past 11 years, and spent the first 7 years of my practice in a small regional centre, providing all OB diagnostic imaging and testing for the region. Over the last 18 months, our program has conducted approximately 1000 studies. Our program is modeled after something called OSCAR (one stop clinic for assessment of risk) and employs lab staff, nursing, a genetic counselor, and myself for the sonograms. I’m here to update you on screening, and help you understand the new forms of prenatal genetic screening, since so much has changed so quickly.

Objectives To make you current with 2007/08 guidelines from ACOG and SOCG with regards to Prenatal screening options Help fully understand all options in order to better undertake counseling Help understand how and when to get your patients screened once their options are known I’ve outlined three core objectives: To update you regarding the new guidelines To help you understand the terminology and rationales of screening I hope I’ll be able to help you sift through all the information and allow for you to better counsel patients regarding their options.

This is where we’ve come from in the last 42 years This is where we’ve come from in the last 42 years. This caption says: Audacious experiments promise decades of added life, superbabies with improved minds and bodies, and even a kind of immortality. That’s 1965…..so where are we now?

Outline Definitions Background and Evolution Second Trimester Serum Screening First Trimester Screening Combined Screening Guidelines Final words and resources Real quick, we’re going to run through background, second and first trimester screening, as well as combined methods, and the new guidelines. We’ll spend the bulk of this time reviewing first trimester screening, combined screening and current guidelines.

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

Background What are we screening for? Secondary screening benefits? Aneuploidy: majority of which is Trisomy 21, with T18, T13, and monosomy X (45X) Secondary screening benefits? Dating the pregnancy Anatomy evaluation, placental evaluation, twins, early anomalies We’re screening for aneuploidy, and it’s important to remember that there are a myriad of other developmental and gene defect abnormalities which can affect a pregnancy, but the largest contributor is aneuploidy.

Evolution of screening 1887 – John Langdon Down presented 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 – aneuploidy results late 1970’s – age was first put to use to triage women for amniocentesis -1887 when Down first presented to the royal society his findings on what was later termed in 1961 as Down’s syndrome -1930 was when maternal age was recognized to be linked with major malformations -the problems occur with the integrity of the spindle mechanism which declines with age, resulting in aneuploidy

Evolution of screening 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. Bad news: it’s the worst screening tool, with only 30-40% detection rate Today: don’t use age 35 as a cut-off From then on, age 35 became the age of ‘high risk’. Ie the age when the risk of any aneuploidy was the same as the miscarriage rates from invasive testing. And therefore, age became the first ‘screening tool’. But the bad news is, it is a terrible screening tool, and both current recommendations strongly tell us to stop using age alone as a screening tool for aneuploidy.

1980’s – 2nd Trimester serum Inhibin A AFP Total hCG Unconjugated estriol uE3 Triple marker screen (TMS) Inhibin A Just to review what the options are for second trimester screening…..there’s the Triple marker screen, and the quad screen. They differ only by the addition of Inhibin A Quad Screen (TMS/Quad = multiple marker scrg test, maternal serum screen)

TMS and Quad Screening DR FPR TMS <72% 7-25% Quad 77% 5.2% Nothing really has changed with multiple marker screening tools Uses 2-4 biochemical markers to adjust the age related risks Problem - specificity drops as disease prevalence increases i.e. Many false positive’s DR FPR TMS <72% 7-25% Quad 77% 5.2% In terms of triple and quad screening, nothing has really changed. The important things to note is that TMS is not as efficient as quad screening. In fact, provinces which are using Triple screening, such as BC, are not conforming with the recent SOGC guidelines (which I will later review with you) for meeting the bare minimum standards for screening. Quad provides 5-7% higher detection rates for lower false positive rates.

What has evolved in the first trimester? (11-14 weeks) Nuchal Translucency (NT) Serum biochemistry Nasal Bone (NB) Tricuspid regurgitation (TR) Frontomaxillary facial angle (FMF Angle) So for this next little bit, I’m going to shift focus to the first trimester. There has been three revolutionary discoveries regarding first trimester ultrasound. NT, biochemistry, and nasal bone. There are a few others on the horizon such as ductus venosus flow, Tricuspid regurge, and FMF angle, which I will mention for sake of completeness.

The First Trimester - NT US measurement, 11-14w: spine to skin Fetal Medicine Foundation Aneuploidy - a change in extracellular matrix and potential for cardiac/lymphatic changes causing increased NT Congenital hearts, others This was the most revolutionary discovery published first by Nicolaides of the fEtal Medicine Foundation , in 1992, and was the sonographic equivalent of ‘excess skin behind the neck’ first described by John Langdon Down in 1888

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

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 99% of euploid fetuses have Nasal bone tremendous increase in detection rates of FTS. High learning curve Nasal bone was added into the screening software in the early 2000s by FMF. Note: there is a very high learning curve, and even experienced first trimester sonographers need at least 80 cases before their personal detection rates are suitable.

The First Trimester – TR, FMF, Ductus Venosus Tricuspid Regurge, DV, and FMF angle are somewhat experimental and not wide clinically used outside of research settings I mention TR, DV and FMF angle as you are bound to hear about them in the next 12-18 months

First Trimester Screening (FTS performance) Criteria DR FPR 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% When you look at first trimester screening in isolation, here are some performance statistics. The most simple test which makes basic standards is the NT alone, but combining with biochemistry and Nasal bone give very accelerated rates of detection. I’m going to shift now to screening strategies which combine first and second trimester.

Screening Strategies First Trimester Screening Second Trimester Screening Serum integrated Integrated Sequential Contingency What are some screening strategies? You can do just First trimester screening, or second trimester screening alone. Most strategies involve combining first and second trimester screening, with newer options just focusing on first trimester detection. And I will quickly go over all of these strategies, as they are frequent in the literature, and a basic understanding is key. Combined Screening

Screening Strategies Serum Integrated Pregnancy Screening (SIPS) 1st TM PAPP-A + Quad (SURUSS trial, 2003) Results disclosed at 17/18w Integrated Pregnancy Screening (IPS) 1st TM PAPP-A + NT + TMS/Quad Same as SIPS but with NT SURUSS and FASTER trials 2003/2005 We already talked about FTS alone with NT/NB. SERUM SIPS is integrating serum only, and is based on a trial from Nick Wald, called the SURUSS trial. This 72 page publication details the use of serum only based screening. It is based on the supposition that you can get to fairly high detection rates, without sonographic studies. Ie. Combine First trimester papp-a, and second trimester quad screen IPS is the same, but adds in the NT only portion of first trimester screening, and elevates detection rates. IT IS IMPERATIVE TO NOTE THAT IN BOTH OF THESE STRATEGIES, ALL RESULTS ARE BLINDED TO THE PHYSICIAN AND PATIENT UNTIL THE QUAD SCREEN RETURNS, EVEN IF THE NT OR PAPP-A IS EXTREMELY ABNORMAL.

Screening Strategies Sequential screening model IPS but disclosed after 1st, and then 2nd TM People may opt for testing after 1st TM Contingency Screening models FTS done - <1:1000, no further testing If risks >1:50, CVS offered If risks 1:50-1:999 - quad offered or Nasal bone contingency: offer NB to intermediate group Probably best for high DR’s in population based screening WITH SEQUENTIAL, THE BLINDING IS REMOVED, AND PATIENT’S ARE INFORMED AFTER THE FIRST TRIMESTER AS TO THEIR LEVEL OF RISK, AND MAY OPT FOR TESTING, OR FOR WAITING FOR THE QUAD SCREEN Contingency screening is the new kid on the block, using risk adjustments to stratify the next steps. A recent trial by Cicero using Nasal bone as the contingency back up holds promise.

Which test is best? How does each model perform… From a population perspective, probably a contingency model will serve us best, with the lowest false positive risks, and only 10% of women waiting for a 18 week result.

Nasal Bone Contingency 90% 2.5% 90% finished in 1st TM RCT DR FPR Weeks Trial NT+NB+Serum 92-95% 3-5% 11-14 FMF Serum integrated 88% 5% 17-18w SURUSS Fully Integrated 93% 96% 92% FASTER Meta Sequential 95% 13-18w Contingency 91-92% 85% finished in 1st TM Cuckle Nasal Bone Contingency 90% 2.5% 90% finished in 1st TM RCT Here’s how they all stack up. The screens with the highest detection rates, and lowest false positive rates are highlighted in yellow. Essentially, an FTS with Nasal bone and IPS are about equal. Nasal bone contingency is close, but has a lower false positive rate. All of these methods are certainly good population based screening tools.

Best performance For a first trimester result: For a combined result: FTS with NT + NB + serum Contingency screening programs For a combined result: IPS/Contingency screening programs For Late entry Quad screen In summary, if you really want to know by 13w6d, do a comprehensive FTS. If you can wait until the second trimester, do a contingency screen. It’s important to have mutliple points of entry for patients who don’t present until after the first trimester There is a lot of European consumer evidence to suggest that people wish to know results of any screening early, and quickly, rather than waiting for a second trimester result hence the growing popularity of first trimester screening

What do the guidelines say? ACOG released similar guidelines in January 2007, and SOGC in February Basics: Triple screening is no longer good enough Don’t use age as a screening tool Aim for highest DR’s and lowest FPR’s in any method Consent and review all options Quality assurance important in FTS programs ACOG and SOCG criteria released this year are quite similar: -TMS is no longer good enough -don’t use age as a screening tool: use age plus some other criteria (QUAD, FTS, combined) -Quality assurance programs are very important

Quality Assurance? Image and data audit Initial certification, and on-going audit FMF UK/USA NTQR? Importance on program based screening: Pre/post test counseling Lab and clinical QA Why I mention this is due to an increasing phenomenon of providers reporting NT measurements outside of an external quality assurance program. It is important in any screening program – and it should be a program, not just a report regarding the measurement on an NT, that some form of on-going QA should be in place to ensure accreditation of the individuals performing the studies, and audit of the curves. When I say program, it also means having pre and post test counseling, and appropriate follow up arrangements. There are only two accreditation programs in place, FMF, and NTQR. FMF is currently recognized as the global standard in this.

ACOG Regardless of which screening tests you decide to offer your patients, information about the detection and false-positive rates, advantages, disadvantages, limitations, and risks and benefits of diagnostic procedures, should be available to patients so 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 2008 Minimum standard: 75% DR, 5% FPR Amnio/CVS can be offered to women over age 40, without screening, but screening should still be offered.

SOGC 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 Using age 35 as a cut-off should be abandoned.

What’s the best test? 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 risks 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 Edmonton/Calgary – FTS programs, provincially insured British Columbia TMS program (does not yet comply with SOGC) SIPS for women over age 38 IPS for women over age 40 Private centre's for FTS with or without NB (complies) MOH investigating new options Of note, the SIPS and IPS programs are age cut-off related, which do not comply with ACOG and SOGC recommendations. This was done to ensure the flow of funding for these programs.

FMF Accredited FTS Centre's, BC BCWH (block funding for special groups) IPS (over age 40), SIPS (over age 38) Prior aneuploidy, Twins Pacific Ctr for Reproductive Medicine ($495) FTS - NT + NB + serum + genetic counseling o-s-c-a-r modeling after FMF Genesis Fertility Centre ($495) FTS - NT + serum + genetic counseling

Resources www.fetalmedicine.com www.earlyriskassessment.com www.mfmedicine.com www.genesis-fertility.com www.pacificfertility.ca On our website, I have a St. Paul’s CME link, with this talk, and all relevant papers, and guidelines, if you wish to have these available to your patients.