Handbook of Genetic Counseling/Maternal Serum Triple Screen-2

Maternal Serum Triple Marker Screening (Triple Screen)

Contracting

• What do you know about why you have been referred for genetic counseling?
• What have you been told about the triple screen? What is your understanding of your test results?
• What questions or concerns would you like to address?

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.