First and Second Trimester Trisomy Screening

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First and Second Trimester Trisomy Screening

• J. Christopher Glantz

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Trisomies 21, 18, and 13

• Incidence (live births)
• 21 1/6-800 18 1/7,000 13 lt1/10,000
• Trimester Frequency FirstgtSecondgtThird
• Spontaneous and induced losses
• 20-30 for 21, 40 for 13, 66 for 18
• Mental Retardation
• Congenital anomalies

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Risk Factors

• Congenital anomalies
• Maternal age
• Multiple gestation
• Previous aneuploidy (patient or family)
• 70 have no identifiable risk factors

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Screening

• Identifying in apparently healthy individuals
  those who are sufficiently at risk of a specific
  disorder as to justify a subsequent diagnostic
  test or procedure

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Diagnostic versus Screening
No overlap Positive test is abnormal
Overlap Positive test could be normal or abnormal
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Sensitivity Specificity
Unaffected
Affected
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Essential Elements of Screening

• It is NOT diagnostic!
• Screen positive rates and PPV depend on a priori
  population risk and the desired detection rate
  (sensitivity)
• An acceptable diagnostic test or procedure must
  be available for screen-positives
• Should be cost effective and low risk
• A treatment must be available for true positives

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Second Trimester Screening (Triple/Quadruple
Marker)

• 65-70 detection with 5 false positives
• Incorporating the Genetic Sonogram (soft signs)
  may lower the false positive rate
• Information on open defects
• NTD, ventral wall, etc.
• Only 50 of Finger Lakes women have triple marker
  screening

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Problems with Second Trimester Screening

• False positives
• Patient anxiety
• Lessened by better pre-test counseling
• Unnecessary amniocentesis
• Procedural loss 0.5
• Late diagnosis
• Psychologically and technically more difficult to
  terminate
• Suboptimal sensitivity

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Advantages to 1st Trimester Screening

• Earlier diagnosis
• Pregnancy less obvious, more private
• May be less bonding
• Pregnancy termination easier and safer
• Surveys Many patients prefer it
• CAVEAT Need test to have high sensitivity and
  low false positives
• Account for spontaneous (and procedural) losses
• Preferentially identify high risk for loss?

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First Trimester Nuchal Translucency

• Lymphatic obstruction or distensible tissue
• Cystic hygroma or precursor
• May resolve or persist
• Associated with increased risk of trisomy
• Also with cardiac anomalies (5-10x RR)
• Normal values depend on gestational age
• No one cut point for all pregnancies (3? mm)
• The wider the translucency, the higher the risk

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Nuchal Translucency (NT)
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Nuchal Translucency Results

• 30 studies including 316,000 patients
• Trisomy 21 frequency 0.1-1.6
• Detection rate (population dependent)
• Range 29-100 (mean 77)
• False positive 0.3-12 (mean 6)
• PPV 2-50 training disparity?
• Issues with T-21 freq, ascertainment, losses

Malone DAlton, 2003
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Biochemical Markers

• Pregnancy associated plasma protein A (PAPP-A)
• Protease for IGF binding protein
• Decreased with trisomies
• Human chorionic gonadotropin (ßhCH)
• Increased with 21 and 18, decreased with 13
• Free versus Total?
• PAPP-A and ßhCG for Trisomy 21
• 60 sensitive, 5 false positive rate

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Distribution of PAPP-A Measurements
Down
Unaffected
Syndrome
42
5
0.2
0.5
1
2
7
PAPP-A (MoM)
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Distribution of First Trimester Free bhCG
Measurements
Down
Unaffected
Syndrome
28
5
0.2
0.5
1
2
5
10
Free-beta (hCG) MoM
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Are Cute Acronyms Required For NIH Funding? (CAR
Fund)

• VIP
• Vaginal Infections in Pregnancy
• RADIUS
• Routine Antenatal Diagnostic Imaging with
  UltraSound
• MR FIT
• Multiple Risk Factor Intervention Trial
• PROVE IT
• PRavastatin or atrOVastatin Evaluation and
  Infection Therapy
• COOL AID
• COOLing for Acute Ischemic brain Damage

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Acronyms in Trisomy Screening

• Acceptable SURUSS
• Serum, URine, Ultrasound Screening Study
• Tortured BUN???
• First trimester maternal serum Biochemistry and
  fetal Nuchal translucency screening study
• FTMSBFNTSS

• MISnamed and Already TAKEn (MISTAKE) FASTER
• First And Second Trimester Evaluation of Risk
• Publication still pending despite years of hype
• Fibrinolytic Aggrastat ST Elevation
  Resolution
• First Albarelix Study for Treating
  Endometriosis Rapidly

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First Trimester Screening with NT and Biochemistry

• Eight studies with 85,000 patients
• Trisomy 21 frequency 0.2-0.9
• Detection rate (population dependent)
• Range 62-92 (mean 82)
• False positive 3-8 (mean 5)
• PPV 5

Malone DAlton, 2003
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ACOG July 2004

• First and second trimester screening have
  comparable detection and false positive rates.
• Criteria for Offering 1st Trimester Screening
• Appropriate ultrasound training and QA
• Comprehensive counseling to women (options,
  risks, benefits)
• Access to appropriate diagnostic testing for
  positive screens
• - CVS in first trimester

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Disadvantages of First Trimester Screening

• Patients must present early
• Does not assess neural tube defects
• CVS is less available, slightly higher risk, and
  not as accurate as amnio
• Prolonged anxiety if no diagnostic test
• Difficulties with multiple gestations
• First trimester screening may identify fetuses
  destined to abort spontaneously

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Approaches to Screening

• Nuchal translucency alone
• First trimester biochemistry alone
• Combined NT and first trimester biochemistry
• Integrated first and second trimester
• No result until both tests done
• Sequential first and second trimester
• Results known after first test
• Second trimester screening alone

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Integrated 1st and 2nd Trimester Screening

• NT/PAPP-A in the 1st trimester and ßhCG, AFP,
  estriol, and inhibin in the 2nd trimester
• Detection rates 85-90-93
• False positive rates 1-2-5, respectively
• 1 higher if NT not used
• Most cost effective
• Results not available until the 2nd trimester
• Ethics of not sharing abnormal 1st trim results

SURUSS, 2003
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Sequential 1st and 2nd Trimester Screening

• 4300 patients who were informed of 1st trimester
  results and chose also to have 2nd trimester
  screening
• High (98) sensitivity but poor specificity
• 17 had positive 1st or 2nd trimester screens
• How to interpret second test (or genetic
  sonogram) in light of normal first test?
• Changes a priori risks

BUN, 2004
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Approximate Detection Rates
Various studies
5 False Positives
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SURUSS Screen-Positive Rates for 85 Trisomy 21
Detection
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Finger Lakes Women

• Combined test and CVS available through SMH
• Insurance issues persist
• Offer patients various options?
• May depend on when patient presents for care
• Integrated most efficient but later diagnosis
• Unresolved issues with sequential testing
• Combined test for aneuploidy, then MSAFP for open
  defects

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NT Technique

• 11-14 weeks (CRL 45-84 mm)
• High magnification, 3 measurements
• Sagittal midline, mid-position neck
• Proper caliper placement
• Practice makes perfect
• May take up to 20 minutes
• Best labs get 80-99

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First Trimester NT Measurements
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