Early Prenatal Screening in Primary Care BC College of Family Physicians21st Annual Scientific Assembly

Ken Seethram, MD, FRCSC, FACOG

Pacific Centre for Reproductive Medicine

Clinical Lecturer, University of British Columbia

kseethram@pacificfertility.ca

Update Family physicians on early prenatal screening

What’s new and exciting? 1st and 2nd trimester screening strategies ACOG and SOGC guidelines

What will your patients want, and where to get it?

Presentation: pacificfertility.ca

Outline and Objectives

One thing to keep in mind

Screening is Simple

Know what’s there Find out what your patients wish Put the two together

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

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

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

Screening is simple: there are only four ways to check a pregnancy

1. Check the blood of the mother2. Check the baby by sonography3. Do both

4. Make wild assumptions without doing any of the above (aka voodoo)

Remember: Screening is Simple

What are all of the screening options prior to 20 weeks?

NT/Nuchal TranslucencyNB/Nasal Bone determinationFTS serum (PAPP-A, free-beta hCG)DV (Ductus Venosus)FMF angle (Frontomaxillary facial angle)TR (Tricuspid Regurgitation)Uterine artery dopplersQuadruple screen (uE3, dimeric Inhibin-A, total hCG, AFP)IPS (1st and 2nd combined)SIPS (1st and 2nd serum combined)Sequential screeningContingency ScreeningDetailed sonogram

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

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

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

Nuchal Translucency (NT)

Nuchal Translucency (NT)

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

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 1st and 2nd trimester screening:

With serum (serum integrated pregnancy screening/SIPS)

With NT (integrated pregnancy screening/IPS)

Mid-1990’s

Early2000’s

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

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

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

What are the exciting new markers?

Ductus Venosus

What are the exciting new markers?

FMF Angle Increased

beyond 85 with T21

What are the exciting new markers?

Tricuspid Regurgitation

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

IPS

FTS

All stacked upMarkers Detects? When Sensitivity FPR Name

Age Trisomy 21, 18, 13

@Conception/@Delivery

30% Archaic

Age + TMS Trisomy 21, 18, 45X, NTD’s

16-20w 50-70% (for DS)

10-25% TMS

Age + Quad Trisomy 21, 18, ONTDs

16-20w 75-77%(for DS)

5.2% Quad

Age + NT+PAPP-A + fβhCG

Trisomies 21,18,13

11-13w6d 85-88% 5% FTS

Age + NT+ PAPP-A+ fβ-hCG+Nasal bone

Trisomies 21, 18, 13

11-13w6d 92-97% 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

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 1st +2nd combined screening, but if their 1st 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

Why did 1st and 2nd 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 1st and 2nd Trimester markers

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

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%

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

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

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

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 < 5th 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

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

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

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

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.

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

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

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 (1st 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

Screening is simple

UltrasoundBlood

UltrasoundBlood Blood

BloodBlood

Blood

11-13w6d 16-20w

hCG, AFP, uE3,

InhibinQuad 75-77%

Quad + PAPP-a

SIPS 82-84%

SIPS + NT

IPS 92-95%

NT+NB+PAPP-

a+hCG

FTS with Nasal Bone

92-95%

17w

to

20w

13w

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

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

Other Web Resources

www.mfmedicine.com Fetal Medicine Canada

www.fetalmedicine.com Fetal Medicine UK Video from Prof Nicolaides

SOGC statement: http://www.sogc.org/guidelines/documents/187

E-CPG-February2007.pdf

FMF reports 2008

•Age

•Weight

•Ethnic

•Parity

•FHR

•markers