Early Prenatal Screening in Primary Care

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Early Prenatal Screening in Primary Care

• BC College of Family Physicians
• 21st Annual Scientific Assembly
• Ken Seethram, MD, FRCSC, FACOG
• Pacific Centre for Reproductive Medicine
• Clinical Lecturer, University of British Columbia
• kseethram_at_pacificfertility.ca

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Outline and Objectives

• Update Family physicians on early prenatal
  screening
• Whats 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

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One thing to keep in mind

• Screening is Simple
• Know whats there
• Find out what your patients wish
• Put the two together

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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

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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
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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

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

• Check the blood of the mother
• Check the baby by sonography
• Do both
• Make wild assumptions without doing any of the
  above (aka voodoo)
• Remember Screening is Simple

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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 (1st and 2nd combined) SIPS (1st and 2nd
serum combined) Sequential screening Contingency
Screening Detailed sonogram
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I know what youre 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

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When did all this change?

• era of age-based screening
• recommendations began in the 1970s
• When the statistical increase of aneuploidy
  started exceeding the risks of amniocentesis,
  that age 35 be established as a cut-off (Resta)
• 1980s 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

1970s
1980s
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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

1990s
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Nuchal Translucency (NT)
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Nuchal Translucency (NT)
-midsagittal -zoom -Settings -Calipers -Flexion -A
mnion -Size (CRL) -FMF born
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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-1990s
Early 2000s
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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

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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
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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

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What are the exciting new markers?

• Ductus Venosus

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What are the exciting new markers?

• FMF Angle
• Increased beyond 85? with T21

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What are the exciting new markers?

• Tricuspid Regurgitation

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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
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All stacked up
Markers Detects? When Sensitivity FPR Name
Age Trisomy 21, 18, 13 _at_Conception/_at_Delivery 30 Archaic
Age TMS Trisomy 21, 18, 45X, NTDs 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 NTPAPP-A fßhCG Trisomies 21,18,13 11-13w6d 85-88 5 FTS
Age NT PAPP-A fß-hCGNasal bone Trisomies 21, 18, 13 11-13w6d 92-97 4-5 FTS with Nasal Bone
Age PAPP-A fß hCG Quad Trisomies 21 18, ONTDs 12w and again at 16-20w 84-86 5 SIPS
AgeNT PAPP-A Quad Trisomies 21 18,ONTDs 12w and again at 16-20w 92-96 3-5 IPS
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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

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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

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Moving On

• While aneuploidy detection is important, it is
  only one of the possible array of screening
  results
• Lets move on to other conditions that can be
  screened for

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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
• DR90-95
• MS-AFP DR80

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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

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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

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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

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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 lt 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

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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

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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

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ACOG and SOGC

• ACOG released similar guidelines in January 2007,
  and SOGC in February 2007
• Basics
• Triple screening is no longer good enough
• Dont use age as a screening tool
• Aim for highest DRs and lowest FPRs in any
  method
• Consent and review all options
• 2008 Minimum standard 75 DR, 5 FPR
• Quality assurance important in FTS programs

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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.

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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

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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
  patients needs in terms of time of results and
  action depending on the results

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Conclusions to take home

• Adjust Risks
• Dont 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) (12w16-20w)
• Any NT/NB must be performed by accredited
  facilities look for program based screening
• Offer all options
• Beware that screening isnt just aneuploidy, its
  much more

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Screening is simple
11-13w6d
16-20w
hCG, AFP, uE3, Inhibin Quad 75-77
Quad PAPP-a SIPS 82-84
SIPS NT IPS 92-95
NTNBPAPP-ahCG FTS with Nasal Bone 92-95
17w to 20w
13w
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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

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Options (Non-MSP, accredited)

• Pacific Centre for Reproductive Medicine
• PacificFertility.ca
• NTNBserum
• Calgary Health Region
• EarlyRiskAssessment.com
• NTNBserum
• Genesis Fertility Centre
• Genesis-fertility.com
• NT serum

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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/187E-CPG-
  February2007.pdf

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• FMF reports 2008
• Age
• Weight
• Ethnic
• Parity
• FHR
• markers