# 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.