1. Early Prenatal Screening in Primary Care BC College of Family Physicians 21 st Annual Scientific Assembly Ken Seethram, MD, FRCSC, FACOG Pacific Centre for Reproductive Medicine Clinical Lecturer, University of British Columbia kseethram@pacificfertility.ca

2.  Update Family physicians on early prenatal screening  What’s new and exciting? 1 st and 2 nd trimester screening strategies ACOG and SOGC guidelines  What will your patients want, and where to get it?  Presentation: pacificfertility.ca Outline and Objectives

3. One thing to keep in mind Screening is Simple Know what’s there Find out what your patients wish Put the two together

4. History: A Canadian Invention  Medical ultrasound is derived from Sound Navigation and Ranging discoveries (SONAR)  First SONAR was built in the USA by Canadian Reginald Fessenden, 1914

5. Life Magazine® in 1954 The Somascope is a water immersion motorised B-mode scanner Posakony was the subject and his scanned kidney can be seen on the oscilloscope screen

7. Early Prenatal Screening What are we screening for? Most associate prenatal screening with aneuploidy, commonly Trisomy 21, 18, 13, monosomy X But there is a lot more than aneuploidy: Congenital defects Post dates screening Twin screening (chorionicity, anomalies) TTTS Complex congenital cardiac defects Pre-eclampsia screening

8. Screening is simple: there are only four ways to check a pregnancy 1. Check the blood of the mother 2. Check the baby by sonography 3. Do both 4. Make wild assumptions without doing any of the above (aka voodoo) Remember: Screening is Simple

9. What are all of the screening options prior to 20 weeks? NT/Nuchal Translucency NB/Nasal Bone determination FTS serum (PAPP-A, free-beta hCG) DV (Ductus Venosus) FMF angle (Frontomaxillary facial angle) TR (Tricuspid Regurgitation) Uterine artery dopplers Quadruple screen (uE3, dimeric Inhibin-A, total hCG, AFP) IPS (1 st and 2 nd combined) SIPS (1 st and 2 nd serum combined) Sequential screening Contingency Screening Detailed sonogram

10. I know what you’re thinking  When did all this happen?  What ever happened to the amnio?  Why is he telling us that screening is simple? Because it is:  Maternal Serum  Ultrasound  or both

11. When did all this change?  era of age-based screening  recommendations began in the 1970’s When the statistical increase of aneuploidy started exceeding the risks of amniocentesis, that age 35 be established as a cut-off (Resta)  1980’s introduction of AFP screening leading to Triple Marker Serum screening which in combination with age, increased detection rates of DS to 50-70%. False positive rates ranged from 10-25%, increasing with maternal age Also 60% Detection rate for Trisomy 18 1970’s 1980’s

12. When did all this change?  1996 – introduction of Quad screen (TMS + dimeric inhibin A). Detection rate for Down syndrome increased to 75-77% with a 5% false positive rate  Around the same time, a pivotal paper was published in 1992 in the BMJ by Nicolaides (Kings College, London) describing nuchal translucency (NT) which gave a 75% DR at 11-13w6d via ultrasound 1990’s

13. Nuchal Translucency (NT)

14. -midsagittal -zoom -Settings -Calipers -Flexion -Amnion -Size (CRL) -FMF born

15. When did all this change?  1996 – Nicolaides introduced first trimester serum (using free beta hCG and PAPP-A) to give DR with NT of 85-88% with a 4-5% false positive rate called FTS or First Trimester screening PAPP-A (pregnancy associated placental protein A, made by embryo and placenta, immune function, increases placental growth)  1996-2000 – numerous papers looking at combining 1 st and 2 nd trimester screening: With serum (serum integrated pregnancy screening/SIPS) With NT (integrated pregnancy screening/IPS) Mid- 1990’s Early 2000’s

16. When did all this change?  2003 – Wald SURUSS Trial, compared FTS, SIPS, IPS, and Quad screening Setting an 85% DR  IPS with lowest FPR (1%).  SIPS with 2-3% FPR  FTS with 4% FPR  Quad with 6% FPR  NT alone with 15% FPR  Flaws – obtaining NT was an issue

17. When did all this change?  2003-2008 – Nicolaides introduces a new series of markers to increase DR to 95-96% with 4-5% FPR in the first trimester Nasal Bone FMF angle Ductus Venosus Tricuspid Regurgitation 2003- 2008

18. What are these exciting new markers?  Nasal Bone 70-80% of T21 do not have nasal calcification (vs. 0.5% in euploidy) Gives DR up to 97% with 5% FPR

19. What are the exciting new markers?  Ductus Venosus

20. What are the exciting new markers?  FMF Angle  Increased beyond 85 with T21

21. What are the exciting new markers?  Tricuspid Regurgitation

22. The new techniques Blood only Second Trimester Quad (16-20w) First (PAPP-A – 12w) + Second Trimester Quad (16-20w) Ultrasound and Blood First Trimester NT (12w) + SIPS First Trimester NT/NB/other markers + hCG/PAPP-a QUAD SIPS IPSFTS

23. All stacked up MarkersDetects?WhenSensitivityFPRName AgeTrisomy 21, 18, 13 @Conception/ @Delivery 30%Archaic Age + TMSTrisomy 21, 18, 45X, NTD’s 16-20w50-70% (for DS) 10-25%TMS Age + QuadTrisomy 21, 18, ONTDs 16-20w75-77% (for DS) 5.2%Quad Age + NT+PAPP-A + fβhCG Trisomies 21,18,13 11-13w6d85-88%5%FTS Age + NT+ PAPP-A+ fβ- hCG+Nasal bone Trisomies 21, 18, 13 11-13w6d92-97%4-5%FTS with Nasal Bone Age + PAPP-A + fβ hCG +Quad Trisomies 21 +18, ONTDs 12w and again at 16- 20w 84-86%5%SIPS Age+NT+ PAPP-A+ Quad Trisomies 21 +18,ONTDs 12w and again at 16- 20w 92-96%3-5%IPS

24. Sequential versus integrated?  You hear the terms a lot – Integrated is blinded/Sequential is not  What is the difference? Sequential screening means that people go through some form of 1 st +2 nd combined screening, but if their 1 st marker (eg, NT) is abnormal, they are informed and offered invasive testing Gives the benefit of identifying patients at risk earlier, and offering earlier testing, but at the cost of declining detection rates when the Quad is added IPS currently in BC is a sequential model, and therefore does not perform at 92-96% DR

25. Why did 1 st and 2 nd trimester screening evolve  Largely due to a patent interest on free beta hCG in the US, which made FTS limited until recently  To maintain high DR without fb-hCG, had to combine NT/PAPP-A with total hCG in the Quad screen  Currently Nick Wald (SURUSS trial) holds a patent on any screening performed which uses 1 st and 2 nd Trimester markers

26. Moving On  While aneuploidy detection is important, it is only one of the possible array of screening results  Let’s move on to other conditions that can be screened for

27. congenital defect screening  Conventional 18-20w sonograms will give information on anatomic defects and ‘soft markers’ (intracardiac focus, choroid plexus cysts)  However, increasing use of sonography before 13w to determine: Limb deformities, hydrocephalus, holoprosencephaly, renal and GI abnormalities, exomphalos Still 18-20w scan is best for heart, brain, spine  Ample evidence now that 18-20w sonogram is almost diagnostic for neural tube defects DR=90-95% MS-AFP DR=80%

30. post dates screening  Ample evidence that an early ultrasound (first trimester) is useful to reduce incidence of post-dates induction of labour and to rule out ectopic and multiple gestations  In some countries with FTS programs, the FTS is the only early ultrasound required, giving aneuploidy and other information in the single visit

31. twins  Establish Chorionicity  In monochorionic twins, the largest risk is that of twin-twin transfusion syndrome (TTTS)  Available evidence suggests that monochorionic twins should share the same NT and, if not, this is an early sign of impending severe TTTS  Quad screening hard to interpret with twins  FTS now includes serum analysis (September 2008) for twins

32. cardiac defect screening  An elevated NT has a 6X increased association with complex congenital heart disease (as opposed to 2-3% in the patient with a prior history) and therefore is a very important marker for disease  An abnormal NT in the presence of normal karyotype requires fetal echocardiography

33. pre-eclampsia and adverse prenatal outcomes screening  PAPP-A and (uterine artery dopplers) at 11-14w to predict adverse outcomes (Faster Trial)  Odds ratios of PAPP-A < 5 th percentile: Intrauterine growth restriction 3.22 Birth weight at or below fifth percentile 2.81 Fetal loss before 24 weeks 2.50 Fetal or neonatal loss 2.15 Preterm birth at or before 32 weeks 2.10 Preterm birth at or before 37 weeks 1.87 Placental abruption 1.80 Premature preterm rupture of membranes 1.54 Preeclampsia 1.54 Gestational hypertension 1.47  If abnormal, increased surveillance to detect early oligohydramnios, IUGR, or hypertension is essential

34. The first problem with quality  Nuchal translucency training and quality assurance Appropriate training of sonographers and adherence to standard technique for NT are essentials for good clinical practice. success of a screening program necessitates system for regular audit continuous assessment of the quality of images. Training is based on theoretical course + practical instruction on how to obtain the appropriate image, make the correct measurement of NT, and presentation of a logbook of images. Ongoing quality assurance is based on assessment of the distribution of fetal NT measurements and examination of a sample of images  Current standard: Fetal Medicine Foundation (UK, Canada, USA) for initial accreditation, and yearly QA

35. The second problem with quality  Accredited NT is not meaningful by itself, and must be part of a screening program, using software to ‘adjust’ risks, in concert with age, laboratory, and counselling

36. ACOG and SOGC  ACOG released similar guidelines in January 2007, and SOGC in February 2007  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 2008 Minimum standard: 75% DR, 5% FPR Quality assurance important in FTS programs

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

38. ACOG and SOGC  The practice of solely using maternal age of 35 or older at the estimated date of delivery (EDD) to identify at-risk pregnancies should be abandoned

39. ACOG and SOGC  One size does not fit all As long as the definitive diagnosis involves an invasive procedure which can cause miscarriage, there is simply no substitute to explaining all the options, their benefits, and risks best screen is the one which will address the patient’s needs in terms of time of results and action depending on the results

40. Conclusions to take home  Adjust Risks Don’t use age alone anymore Use age plus a high detection screening tool Highest are:  FTS with Nasal Bone (11-14w)  IPS (1 st TM NT, PAPP-A + Quad) (12w+16-20w)  Any NT/NB must be performed by accredited facilities – look for ‘program based screening’  Offer all options  Beware that screening isn’t just aneuploidy, it’s much more

41. Screening is simple Ultrasound Blood Ultrasound Blood 11-13w6d16-20w hCG, AFP, uE3, Inhibin Quad75-77% Quad + PAPP-a SIPS82-84% SIPS + NT IPS92-95% NT+NB+ PAPP- a+hCG FTS with Nasal Bone 92-95% 17w to 20w 13w

42. Where?  Quad - all women (MSP)  SIPS - over age 38  IPS - over age 40 Twins/Prior aneuploidy/HIV Over age 35 with 3 prior miscarriages Accredited NT + SIPS, report sent to MD at 17- 18w or later

43. Options (Non-MSP, accredited)  Pacific Centre for Reproductive Medicine PacificFertility.ca NT+NB+serum  Calgary Health Region EarlyRiskAssessment.com NT+NB+serum  Genesis Fertility Centre Genesis-fertility.com NT + serum

44. Other Web Resources  www.mfmedicine.com www.mfmedicine.com Fetal Medicine Canada  www.fetalmedicine.com www.fetalmedicine.com Fetal Medicine UK Video from Prof Nicolaides  SOGC statement: http://www.sogc.org/guidelines/documents/18 7E-CPG-February2007.pdf http://www.sogc.org/guidelines/documents/18 7E-CPG-February2007.pdf

45. FMF reports 2008 Age Weight Ethnic Parity FHR markers