Handbook of Genetic Counseling/Maternal Serum Triple Screen-2

Maternal Serum Triple Marker Screening (Triple Screen)

Contracting

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What have you been told about the triple screen? What is your understanding of your test results?
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Overview of maternal serum screening

Background
- Screening test
  - Not a diagnostic test
  - Used to identify women who are at increased risk for certain birth defects
    - These women then offered diagnostic testing
    - Negative or "normal" result does not mean that a child will not have a birth defect
    - Positive result is not a diagnosis of an abnormality
  - Can identify women at increased risk for Trisomy 21, Trisomy 18, or open neural tube defects
- Blood test
  - Fetal and placental products can be detected in mother's blood serum during pregnancy
  - Can be offered from 14-22 weeks but most accurate at 16-18 weeks
- Indirect measure of levels of three substances in mother's blood
  - Alpha-fetoprotein (AFP)
    - Produced by liver of fetus and excreted into amniotic fluid
    - Passes into mother's bloodstream and concentration rises gradually throughout pregnancy
  - Human chorionic gonadotropin (HCG)
    - Pregnancy hormone made by the placenta
    - Level peaks at 10 weeks and declines throughout pregnancy
  - Unconjugated estriol (uE3)
    - Pregnancy hormone made by fetus and placenta
    - Level increases throughout pregnancy
  - Some laboratories also measure levels of inhibin-A
    - Product of placenta
    - Quadruple-marker screening may increase detection rate for Down Syndrome
- Risk assessment
  - Markers are expressed as multiples of the median (MoM) in report
    - MoM determined by examining results from a large number of women and establishing an "average"
    - The median for all markers is 1.0 MoM
    - An individual's values expressed as marker level in patient/median marker level
  - Laboratory calculates a woman's risks based on levels of three substance plus other factors
    - Multiple gestations would cause levels to be elevated
    - Gestational age
      - Marker levels change throughout pregnancy
      - Inaccurate dates are common reason for false positive
      - Gestational age can be confirmed by ultrasound
    - Maternal weight
      - Increased weight means increased blood volume
      - Markers will be diluted in serum and their concentration lower
    - Maternal race
    - Maternal age
      - Increased risk for having child with chromosomal abnormality as maternal age increases
      - Women over age 35 have higher detection rate and false positive rate
    - Diabetic status
      - Insulin-dependent diabetics have increased risk for neural tube defects
      - Tend to have lower AFP levels, so use lower AFP cutoff
  - Evaluation of screening performance
    - Up to 100 of every 1,000 women who take test will have abnormal result
      - Only 3 of those 100 women will have a baby with a birth defect
      - Most abnormal test results indicate dates are wrong or another factor above has not been accurately accounted for
      - Abnormal result could also be normal variation
    - Pattern of variation in levels may indicate that a woman is at increased risk for a particular birth defect
Evaluation of abnormal results
- Elevated MSAFP
  - Greater than 2.5 MoM
  - Conditions possibly causing elevated MSAFP
    - Normal variant
    - Underestimation of gestational age
    - Multiple pregnancies
    - Open neural tube defects
    - Abdominal wall defects
    - Feto-maternal bleeding
    - Fetal demise
    - Finnish nephrosis
    - Some other birth defects
  - Increased risk for 3rd trimester complications
  - Follow-up strategies:
    - Repeat MSAFP
      - If patient's gestational age is within testable range
      - If only mild elevation (2.5-3.0 MoM)
    - Confirm gestational age by ultrasound
    - Offer ultrasound and amniocentesis
    - Serial ultrasounds and antenatal testing
      - If AFP greater than 3.0 MoM
      - When cause of elevation is not identified
  - Neural tube defects
    - Includes spina bifida, anencephaly most commonly
    - Also includes such conditions as encephalocele and hydrocephalus
    - Neural tube is part of developing embryo that brain and spine develop from
      - Neural tube defects due to failure of this tube to close properly
      - About 2,500 babies born each year in US with neural tube defect
    - Spina bifida
      - Backbone does not form properly
      - Often spinal cord is malformed and protrudes from back
      - Can cause leg paralysis and bladder and bowel problems
    - Anencephaly
      - Upper end of neural tube fails to close
      - Brain and skull severely malformed
      - Babies usually don't survive
    - Multifactorial inheritance
      - Both genetic and environmental factors interact to cause this condition
      - About 90-95% of babies with NTDs born into families with no prior history
- Screen positive for Down Syndrome
  - Positive if calculated risk is greater than 1 in 270
  - Occurs when AFP is decreased, hCG elevated, and uE3 decreased
  - Conditions possibly associated with screen positive for Down Syndrome
    - Normal variant
    - Overestimation of gestational age
    - Multiple pregnancies (uncommon)
    - Down syndrome
    - Another chromosome abnormality
    - Triploidy
  - Increased risk for 3rd trimester complications
  - Follow-up recommendations
    - Confirm gestational age with ultrasound
    - Repeat test only if patient was at too early a gestational age for the screen to be performed
    - Offer diagnostic ultrasound and amniocentesis
    - Ultrasound for growth and monitoring for preeclampsia in 3rd trimester if hCG greater than 2.5 MoM for unknown reason
  - Down Syndrome
    - Explain chromosomes and nondisjunction
    - Discuss age-related risk and adjusted risk for Down syndrome
    - Clinical features and prognosis
      - Due to extra copy of chromosome 21
      - May cause characteristic facial features, mental retardation, heart defects, and other health problems
      - Cannot predict severity
- Screen positive for Trisomy 18
  - When calculated risk is greater than 1 in 100
  - Occurs when AFP, hCG, and uE3 are all decreased
  - Conditions associated with positive screen
    - Normal variant
    - Gestational age inaccurate
    - Trisomy 18
    - Another chromosome abnormality
    - Fetal demise
    - Steroid sulfatase deficiency (X-linked ichthyosis)
  - Follow-up recommendations
    - Confirm gestational age by ultrasound
    - Repeat only is gestational age at time of screen found to be too early
    - Offer diagnostic ultrasound and amniocentesis
    - Monitor for preeclampsia and offer ultrasound in 3rd trimester if hCG above 2.5 MoM and no cause identified
  - Trisomy 18
    - Explain chromosomes and nondisjunction
    - Discuss age related and adjusted rates for trisomy 18
    - Clinical features and prognosis
      - Caused by extra copy of chromosome 18
      - Causes severe mental retardation and health problems
      - Usually fatal within first year of life
Capabilities and limitations of screening
- Benefits
  - May provide reassurance that fetus does not appear to have certain birth defects
  - Can help woman manage pregnancy better
    - When problems detected, woman can prepare for delivery or treatment needed right after birth
    - Prepare mentally, emotionally, and socially for birth of child with birth defect
  - May help women over age 35 determine whether to have more invasive procedure
    - Negative screen may actually lower risk for chromosome abnormality
    - Women with negative screen may choose to avoid more risky procedure
  - Monitoring of women with abnormal test result may prevent 3rd trimester complications
- Limitations
  - Not diagnostic test
    - False positive may produce unnecessary anxiety
    - Negative test does not mean fetus does not have birth defect, only that not at increased risk for conditions mentioned
  - May be no explanation for abnormal result
    - Abnormal results may be associated with pregnancy problems like placental abruption, preterm labor, and low birth weight
    - May cause maternal anxiety
  - Can't identify all birth defects
    - Down syndrome and Trisomy 18 are only chromosomal abnormalities that can be detected with this test
    - Amniocentesis is only way to diagnose or rule out chromosome problems

Other testing options

Ultrasound
- May be offered to confirm gestational age or identify multiple fetuses to help interpret triple screen results
- Can detect many major birth defects
- Can rule out 95% of NTDs if visualization is not limited
- Can't diagnose chromosomal abnormalities
Amniocentesis
- Performed after 15 weeks
- Risks/Benefits
  - 99.7% accuracy for fetal chromosome analysis
  - Detects 96% of open neural tube defects by testing AFAFP
  - Cannot detect all birth defects or mental retardation
  - Risk of miscarriage due to procedure is 0.5%

References

Creasy RK, and Resnik R, eds. (1994) Maternal-Fetal Medicine 62-84.
"Maternal Blood Screening." (2001) March of Dimes Fact Sheet. http://www.modimes.org.
Gardner RJM, and Sutherland GR. (1996) Chromosome Abnormalities and Genetic Counseling 325-371.
Milunsky A, ed. (1998) Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment 179-238.

Notes

The information in this outline was last updated in 2001.