Prenatal Screening

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Prenatal Screening

• Some postnatal screening as well
• Dr Kate Neas
• Central and Southern Regional Genetic Service

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History

• 1966 Steele and Breg published analysis of fetal
  chromosomes from cultured amniocytes.
• 1972 association between raised alpha-fetoprotein
  in amniotic fluid and NTDs recognised.
• 1974 association between raised maternal serum
  AFP and fetal NTD recognised
• 1984 association between MSAFP and Down
  Syndrome identified

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More History.

• 1987 incorporation of other serum biochemical
  markers (oestriol and HCG) with MSAFP to
  identify risk of fetal aneuploidy.
• 1990s saw the recognition of the role of soft
  USS markers in assessing aneuploidy risk.
• Late 1990s evaluation of combined MSS and USS
  (1st trimester NT) for fetal aneuploidy screening

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Prenatal screening in NZ

• Currently
• Maternal age alone (usually gt35)
• /- nuchal translucency (NT) scan (hopefully with
  formal assessment of risk, by a person accredited
  to do so usually by the FMF (UK) (Government
  funded practice charges)
• /- second trimester MSS (private pay)
• Minimal use of test integration

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Problems with current system

• It is inefficient
• Low efficacy screening
• High numbers of unnecessarily worried women
• High numbers of unnecessary invasive procedures

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Antenatal Down Syndrome Screening Advisory Group

• Eclectic bunch of individuals
• Broadly categorized into
• Health care professionals with some involvement
  in maternity services (including midwifery,
  clinical genetics, cytogenetics, obstetrics,
  radiology ...)
• Consumer groups (for pregnant women, for disabled
  people, parents of disabled children/adults...)

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Our remit

• To provide advise to the Minister of Health
  concerning
• The need for
• The utility of
• The ethical and social issues related to
• ANTENATAL SCREENING FOR DOWN SYNDROME

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The process

• Many meetings
• Three subgroups
• Serum screening
• NT
• Ethical and Social Issues
• Lots of dissention
• ONE important area of agreement
• The Advisory Group agreed that the current
  practice of screening by NT and/or maternal age
  alone is unacceptable and should not continue

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Majority view

• to continue to offer screening and to improve
  the quality and safety of screening tests using
  the structures of a nationally organised
  screening programme to facilitate improvements in
  quality and safety

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Good start

• Where to from here...
• Current situation

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NT

• Accuracy is operator dependent
• Sensitivity can be as high as 77, for a 5 false
  positive rate
• other trials (SURUSS (47,000) and FASTER(33500))
  give a lower sensitivity of 60, for a 5 FPR
  (presumably due to difficulty in getting
  uniformity of screening practice in a large
  population of sonographers)

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2nd trimester serum screening

• 1420 wks for chromosome abnormalities, 15-20 wks
  for NTD
• In NZ using maternal age, free a-hCG, free ß-hCG,
  unconjugated oestriol and a-fetoprotein with
  Alpha risk evaluation software
• Successful pilot 1994-1996
• User pays since then

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User pays

• Serum screening is essentially a statistical
  exercise sorting likely affected from not likely
  affected
• Since user pays only about 600 tests are done
  annually
• Insufficient for a really good program
• Although external QA program results are good

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Partial Integrated test

• Can offer from Alpha software
• Incorporates NT measurement plus T2 biochemistry
  to give a combined risk result
• Presently offered to some patients who request it
• Best results if NT screen result not released
  until serum results available.

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First trimester serum screening

• Free-ßhCG, pregnancy associated protein A
  (PAPP-A)
• Not formally available in NZ
• Can be arranged through the national testing
  centre, for individual patients (user pays)

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SURUSS

• Serum, Urine and Ultrasound Screening Study 2002
• Objective To identify the most effective, safe
  and cost-effective method of antenatal screening
  for Down Syndrome using nuchal translucency,
  maternal serum and urine markers in the first and
  second trimesters of pregnancy, and maternal age
  in various combinations.

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SURUSS methods.

• 47,053 singleton pregnancies (101 with Down
  Syndrome)
• 25 maternity units
• UK 24 Austria 1
• NT measurement 9-13 weeks
• serum and urine collected and stored in 1st and
  2nd trimester
• matched each case for 5 controls for gestation,
  storage duration and centre

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SURUSS biochemistry

• In serum
• PAPP-A
• free B-hCG
• dimeric inhibin-A
• AFP
• total hCG
• uE3

• In urine
• invasive trophoblast antigen (ITA)
• beta-core fragment
• total hCG
• free B-hCG

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SURUSS Outcome Measures

• Efficacy
• false positive rate(FPR) for 85 detection rate
  (DR)
• Safety
• fetal loss due to amniocentesis or CVS in 10,000
  women screened
• Cost-effectiveness
• cost of screening 10,000 women and cost per Down
  Syndrome pregnancy diagnosed

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Integrated Screening
NT Scan
Exclude if anencephaly
Exclude if cystic hygroma
First Trimester serum screen
Second Trimester serum screen
Result to patient
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Sequential Screening
NT Scan
Exclude if anencephaly
Exclude if cystic hygroma
First Trimester serum screen
POSITIVE (cut-off 130)
PENDING
Second Trimester serum screen
Diagnostic test
Result to patient
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Contingent Screening
NT Scan
Exclude if anencephaly
Exclude if cystic hygroma
First Trimester serum screen
HIGH RISK POSITIVE (cut-off 130)
NEGATIVE (cut-off lt12000)
LOW RISK POSITIVE
Second Trimester serum screen
NO further testing
Diagnostic test
Result to patient
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Combined Screening
NT Scan
Exclude if anencephaly
Exclude if cystic hygroma
First Trimester serum screen
Result to patient
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SURUSS Outcomes Efficacy

• Integrated test
• NT and PAPP-A at 10 weeks
• AFP,uE3,free B-hCG, inhibin-A at 14 weeks
• FPR 1.2 (1.0-1.4)
• Combined test
• NT, free B-hCG , PAPP-A at 10 weeks
• FPR 6.1 (5.6-6.5)
• Quadruple test
• AFP,uE3,B-hCG,inhibin-A at 14 weeks
• FPR 6.2 (5.8-6.6)

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SURUSS Outcomes Efficacy

• NT alone (at 12 weeks)
• FPR 20.0 (18.6-21.4)
• Overall, the Integrated Test had the best FPR for
  85 DR

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SURUSS Outcomes

• Safety
• for Integrated test, 9 procedure-related fetal
  losses per 10,000 women screened
• for Combined test 44 losses
• for Quadruple test 45 losses
• Cost-effectiveness
• to achieve 85 detection rate in UK NHS (cost per
  Down Syndrome pregnancy detected)
• Integrated test 15,300
• Quadruple test 16,800
• Combined test 19,000

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SURUSS Conclusions

• No support for continued NT alone or triple test.
• Tests in 1st trimester had similar efficacy to
  tests in 2nd trimester
• An Integrated 1st and 2nd trimester test was
  better than all the rest in all criteria

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Recommendations

• Integrated test
• If no NT available, serum integrated test (PAPP-A
  at 10 weeks, full biochemistry at 14)
• If presenting in 2nd trimester, Quadruple test
• For 1st trimester only, Combined test

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Evidence

• SURUSS
• FASTER
• Both agree that Integrated Testing has the best
  sensitivity for the lowest FPR

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Best evidence

• Supports INTEGRATED screening
• Combines
• First trimester MSS ( PAPP-A)
• NT
• Second trimester MSS (free B-HCG, Inhibin, AFP,
  oestriol)
• FPR 1.2 for an 85 Sensitivity (SURUSS)
• FPR 0.8 for an 85 Sensitivity (FASTER)

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Issues are

• Involves a two (or even three) stage testing
  process
• Results available in early to mid second
  trimester
• How will women feel about this?
• How will practitioners feel about this?
• What about women who only present for 1 or 2 of
  the 3 tests, what happens to those results? (up
  to 7 according to Wald et al 2006)

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Some advocate

• First trimester combined screening
• Sequential or contingent screening (with top
  slicing)
• Allowing maternal choice re which method
• Allowing maternal choice re diagnostic testing

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Screening Programme

• Current situation
• Not a formal programme
• Just ad hoc
• No control over information given, whether
  consent taken, test provided, result reporting
  etc
• Pretty poor results

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A formal programme

• Mandates information and consent
• Mandates minimum standards for each part of the
  pathway
• Keeps track of utilisation
• BUT it is expensive!
• Also, would remove individual autonomy to some
  extent

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So what has the Minister Decided

• NO DECISION YET
• We await a decision with interest
• Whatever is implemented will need to come with a
  large amount of funding for education for
  providers, and written information for women
• Will be a somewhat lengthy lead-time!

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Post script

• Postnatal
• Newborn Metabolic Screening
• Has been expanded
• Uses a tandem mass spectrometer (expensive black
  box)
• To detect a large range of rare metabolic
  conditions, including MCAD (a fatty acid
  oxidation disorder)

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Tandem Mass Spectrometer

• Ability to measure a wide range of chemicals
  based on mass and charge in a spot of blood
  quickly, accurately and cheaply
• Tap into existing Newborn Screening programme
• Expanded newborn screening
• Screen all NZ babies in first week of life for
  20 metabolic disorders

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Expanded Newborn Screening

• Based on NSW and SA figures
• 8-10 babies diagnosed (excluding PKU)/year
• 3-5 lives saved/year
• 3-5 children/year with significantly reduced
  morbidity

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Expanded Newborn Screening Summary

• Start up costs 660 000
• Annual costs 170 000
• Lives Saved 3-5 per year
• Morbidity decreased 3-5 per year