Prenatal Screening and Diagnosis for Chromosomal Abnormalities and Neural Tube Defects

  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Diagnostic testing for chromosome abnormalities and open neural tube defects (ONTD) should be offered to all pregnant women; those at high risk for either a chromosome abnormality or ONTD should have more extensive counseling
    • High risk includes
      • Previous pregnancy with chromosome disorder (eg, Down syndrome [DS]/trisomy 21 [T21], trisomy 13 [T13], trisomy 18 [T18], or Turner syndrome [TS]/monosomy X [MX])
      • Either parent is a known carrier of a Robertsonian translocation involving chromosome 13 or 21
      • Maternal age ≥35 years at estimated date of delivery (EDD)
      • Abnormal ultrasound
      • Increased risk of ONTD due to family history, use of specific medications (eg, valproic acid or carbamazepine), or diabetic status
  • Amniocentesis or chorionic villus sampling (CVS) confirms diagnosis suggested by screening tests
    • CVS – 10-13 weeks
      • Ability to examine fetal chromosomes only; uses placental tissue
      • Not appropriate for women at increased risk for ONTD
      • Small chance of identifying a chromosome abnormality that is restricted to the placental tissue and is not present in the fetus (confined placental mosaicism [CPM])
    • Amniocentesis – ≥15 weeks
      • Ability to examine fetal chromosome, amniotic fluid, alpha-fetoprotein concentration, and acetylcholinesterase, if indicated  

Many options for aneuploidy screening are available. Practices choose which screening tests to offer based on provider and patient preference, patient population, and service availability. Most professional guidelines endorse offering cfDNA screening to women at increased risk to have a child with chromosomal aneuploidy, but suggest that it is more appropriate to offer low- or average-risk women traditional serum screening first, and cfDNA as a second tier screen.

 

Prenatal Screening Test Information

Test

Recommended for

Purpose

First trimester (combined) screen

Maternal screen, first trimester

Order during the first trimester (between 11w0d and 13w6d of gestation)

Crown-rump length (CRL) must be between 44-85 mm and an NT measurement must be obtained (NT can be done when the CRL is between 39-85 mm)

Use when mother accepts higher SPR and wants results in the first trimester

Does not detect ONTD

Sequential screen combines first- and second-trimester screening results

First sample drawn between 11w0d and 13w6d of gestation

CRL must be between 44-85 mm when 1st trimester blood sample is drawn and an NT measurement must be obtained (NT can be done when the CRL is between 39-85 mm)

Second sample drawn between 15w0d and 24w6d of gestation

Sample 1 measures PAPP-A and total hCG

Sample 2 measures AFP, uE3, hCG, and DIA

Screens for T21, T18, ONTD

An interpretation is provided after the first draw so that pregnancies at very high risk for T21 can be identified in the first trimester

Women at intermediate or low risk after the first draw go on for the second draw and the complete screen

Integrated screen, combines first- and second-trimester screening results

First sample drawn between 10w0d and 13w6d of gestation

CRL must be between 34-85 mm when 1st trimester blood sample is drawn (an NT measurement is optional for this test – must be obtained when the CRL is between 39-85 mm)

Second sample drawn between 15w0d and 24w6d of gestation

Serum-only tests – do not round gestational age to nearest week; use EDD to avoid clerical errors

Sample 1 measures PAPP-A

Sample 2 measures AFP, uE3, hCG, and DIA

Screens for T21, T18, ONTD

When combined with a first-trimester certified US for NT, this test yields the best detection rate and lowest false-positive rate of all prenatal screens

Can be run without an NT (serum integrated) yielding the same detection rate with a slightly higher false-positive rate

Single Screen

(Maternal serum screen, alpha fetoprotein only)

Women who have had early amniocentesis, CVS, or first-trimester screening

Ideal time period is 16-18 wks of gestation; however, reference medians are available from 14w0d to 24w6d of gestation

Do not round gestational age to nearest week; use EDD to avoid clerical errors

Screen for fetal risk of ONTD at 14-25 wks

Quad Screen

Maternal serum screen, alpha fetoprotein, hCG, estriol, and inhibin A

ACOG recommends the quad for second-trimester aneuploidy screening for low risk women

Offer to women who

  • Present initially for second trimester
  • Do not wish to have first-trimester screening
  • Did not have access to first-trimester screening

Quad is the most economical prenatal screening test for aneuploidy

Ideal time period is 16-18 wks of gestation; however, reference medians are available from 14w0d to 24w6d of gestation

Do not round gestational age to nearest week; use EDD to avoid clerical errors

Quad screen for fetal risk of T21, T18, and ONTD

Better detection rate and a lower false-positive rate than the triple screen

Best second trimester screen available

Noninvasive prenatal testing (cfDNA) for fetal aneuploidy

Can be performed as early as 9.0 wks gestation

Offer to women who are considered to be at increased risk for carrying fetus with one of the common aneuploidy disorders: T21, T18, T13, or TS

Women are considered to be at increased risk when

  • ≥35 yrs at EDD
  • Previous child with aneuploidy
  • Current fetus has US abnormalities associated with T21, T18, T13, or TS
  • Screened positive by serum screening (±NT)
  • Either parent is a carrier of a Robertsonian translocation involving chromosome 13 or 21

Highly sensitive screening test for specific fetal aneuploidies

Intended to identify women with a current pregnancy at risk for T21, T18, T13, or TS; may also identify fetuses with other sex-chromosome aneuploidies or triploidy

Women carrying a fetus with US abnormalities who screen negative by cfDNA  should be offered diagnostic testing (ie, fetal karyotype and/or fetal microarray by CVS or amniocentesis)

All positive cfDNA results should be confirmed by fetal karyotype

 

Prenatal Diagnosis – Amniotic Fluid and Chromosome Analyses

Test

Recommended for

Purpose

Chromosome Analysis, Chorionic Villus (CVS)

Indications include

  • Increased risk for fetal aneuploidy based on maternal age, abnormal NIPT, abnormal multiple marker screening, or abnormal fetal ultrasound
  • Family history of chromosome abnormality or genetic disorder
  • Desires diagnostic testing instead of screening

Prenatal chromosome analysis on chorionic villi in pregnant woman at 10-13 wks gestation

Chorionic Villus, FISH

Rapid detection of aneuploidy involving chromosomes 13, 18, 21, X, and Y

Preliminary results usually available within 48 hr of sample receipt by lab

Order in conjunction with fetal chromosome studies

Chromosome Analysis, Amniotic Fluid

Indications include

  • Increased risk for fetal aneuploidy based on maternal age, abnormal NIPT, abnormal multiple marker screening, or abnormal fetal ultrasound
  • Family history of chromosome abnormality or genetic disorder
  • Desires diagnostic testing instead of screening

Prenatal chromosome analysis on amniotic fluid in patient >14 wks gestation

Amniocentesis is discouraged <15 wks gestation due to high rates of fetal loss, leakage of amniotic fluid, and increased risk of club foot

Chromosome Analysis, Prenatal FISH

Rapid detection of aneuploidy involving chromosomes 13, 18, 21, X, and Y

Preliminary results usually available within 48 hours of sample receipt by lab

Order in conjunction with fetal chromosome studies

Fetal Cytogenomic SNP Microarray

Indications include

  • Clarification of abnormal ultrasound findings
  • Further characterize an abnormal fetal karyotype
  • Suspicion of an imbalance in a specific genomic region that is best evaluated by microarray
  • Investigate de novo, apparently balanced translocations
  • Family history of a known or suspected chromosomal abnormality best evaluated by microarray
  • Patients undergoing invasive prenatal testing (instead of, or in addition to, chromosome analysis )

Submission of a maternal blood sample for maternal cell contamination studies is encouraged

Identify genomic abnormalities (eg, aneuploidy and microdeletions) in direct or cultured amniotic fluid and CVS samples

Amniotic Fluid AFP with Reflex to Acetylcholinesterase

Indications include

  • Abnormal MSAFP screen
  • Family history of ONTD
  • Patient taking valproic acid or carbamazepine
  • Patient with medication-dependent diabetes or uncontrolled diabetes

Do not round gestational age to nearest wk; use EDD to avoid clerical errors

Prenatal diagnosis for ONTD at 13-36 wks gestation

Amniocentesis is discouraged <15 weeks gestation due to high rates of fetal loss, leakage of amniotic fluid, and increased risk of club foot

 

Sensitivity and Initial Positive Rates for Down Syndrome

Screening Test

% T21 Detection

% Initial Positive

T21 cutoff

Quad

81

4-5

1/150

Integrated – serum only

85

3-4

1/110

Integrated – with NT

87

1.0

1/110

Sequential

63 (1st)
23 (2nd)
86 (total)

0.6 (1st)
1.0 (2nd)
1.6 (total)

1/25 (1st)
1/110 (2nd)

First trimester

85

5-6

1/230

Triple

75-80

5-6

1/190

 

Amniotic Fluid AChE Specificity and Sensitivity Rates for Open Neural Tube
Defects (Alpha Fetoprotein [Amniotic Fluid] with Reflex to Acetylcholinesterase)

 Testing for

Sensitivity

Open neural tube defects

95%

Anencephaly

97%

Open spina bifida

99%

Abdominal wall defects

40-79%

 

Targeted Ultrasound Test Results Follow-Up

Test Result

Next Action

Anomaly detected on US

Perform second-tier screening

  • cfDNA for fetal aneuploidy

OR

Confirm with follow-up tests

  • Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase and Fetal Hemoglobin
  • Chromosome Analysis, Amniotic Fluid
  • Chromosome FISH, Prenatal
  • Cytogenomic SNP Microarray - Fetal

OR

  • Chromosome Analysis, Chorionic Villus (CVS)
  • Chorionic Villus, FISH
  • Cytogenomic SNP Microarray - Fetal
  • Maternal Serum Screen, Alpha Fetoprotein (only)

No anomaly on US, but MSAFP MoM* 2.5-3.0

Repeat MSAFP (do not repeat aneuploidy screen, only the MSAFP) 2 wks after initial draw to see if AFP MoM level is increasing or decreasing; if increasing, treat patient per next row below (no anomaly on US, but MSAFP MoM >3.0)

If decreasing, probable transient maternal-fetal bleed; monitor pregnancy

  • Review or repeat level II US (including examination for signs of placental bleeding)

OR

  • Treat patient per next row below (no anomaly on US, but MSAFP MoM >3.0)

No anomaly on US, but MSAFP MoM* >3.0

Confirm with amniotic fluid tests

  • Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase and Fetal Hemoglobin
  • Chromosome Analysis, Amniotic Fluid

If AF-AFP is normal, risk increases for poor pregnancy outcome (prematurity, small-for-gestational-age infant, stillbirth)

  • Offer counseling
  • Monitor pregnancy

No anomaly on US, but hCG MoM* >3.5

Increased risk for poor pregnancy outcome (preeclampsia, imminent fetal death, small-for-gestational-age infant)

  • Offer counseling
  • Monitor pregnancy

*MoM measures are multiples of the median, calculated as the value of the substance divided by the median value based on gestational age of the fetus.  Adjustments to MoM values are made for maternal weight, race, number of fetuses and maternal medication-dependent or uncontrolled diabetes.

 

Second Trimester Maternal Serum Screening Tests – Result Patterns

AFP

hCG

uE3

DIA

Pattern

L

H

L

H

Normal, overestimated gestation, and T21

H

L

H

N

Normal, underestimated gestation

L

L

L

*

Trisomy 18, fetal death

H

H

H

H

Multiple fetuses

H

N

N

N

Spina bifida, fetal-maternal hemorrhage, ventral wall defect

VH

N

L

N

Anencephaly, fetal death

VL

H

VL

N

Mole or partial mole

L = low; H = high; N = normal; VL = very low; VH = very high; * = may be high, low, or normal; not taken into account for risk calculation

    Because most families who have a child with an open neural tube defect (ONTD) or chromosome abnormality have no prior family history of these disorders, prenatal screening should be discussed with all pregnant women.

    Down syndrome (T21)

    Epidemiology

    • Incidence – 1/600 births (regardless of race or geographical location)

    Risk Factors

    • Risk increases with maternal age in a sigmoid fashion
      • 20s – risk for a child born with T21 is ~1:1,500
      • 30s – risk rises dramatically
      • 40s – risk levels out to ~1:100
    • ~50% of babies with T21 are born to mothers <35 years

    Pathophysiology

    • Extra chromosome 21 found in all nucleated cells
    • Mosaic T21
      • Caused by an extra chromosome 21 in some, but not all, cells
      • Clinical phenotype
        • Usually milder than non-mosaic T21
        • Can vary from normal to severely affected

    Clinical Presentation

    • Moderate to severe intellectual disability
    • Characteristic facial features
      • Down-slanting palpebral fissures
      • Epicanthic folds
      • Depressed nasal bridge
      • Flat mid-face
      • Low-set ears
    • Cardiac abnormalities
      • Ventricular septal defect (VSD)
      • Endocardial cushion defect
    • Hypothyroidism
    • Leukemia

    Open neural tube defects (ONTD)

    Epidemiology

    • Incidence – 1/900 pregnancies (varies with racial background and geographical location)

    Risk Factors

    • Poorly controlled maternal diabetes mellitus
    • Family history of NTD
    • Use of certain medications in pregnancy (eg, carbamazepine, valproic acid) independent of maternal age

    Clinical Presentation

    • Most common types include spina bifida (a developmental defect of the spine and overlying skin) and anencephaly (developmental failure of the brain, skull, and overlying skin)
    • Lesions of spina bifida include the following
      • Simple meningocele
      • Lipomyelomeningocele
      • Diastematomyelia
      • Myelocystocele
      • Neuritic cyst
      • Intraspinal and intrapelvic meningoceles
      • True spina bifida occulta associated with spinal dysraphism
    • Spina bifida often results in the following sequela, but clinical severity depends on several factors, especially location and size of the lesion
      • Paralysis of the lower limbs
      • Loss of bowel and bladder control
      • Cerebral ventriculomegaly requiring shunt placement
    • Anencephaly associated with limited lifespan
      • 50% of infants are stillborn
      • Remainder of newborns die within hours or days of birth

    Trisomy 18 (T18)

    Epidemiology

    • Incidence – 1/3,000 births
    • Survival
      • 90% stillborn
      • Most infants die within the first year of life

    Pathophysiology

    • Extra chromosome 18 found in all nucleated cells

    Clinical Presentation

    • Severe intellectual disability
    • Heart defects
    • Failure to thrive
    • Clenched fists
    • Rocker bottom feet
    • Spina bifida
    • Nonambulatory
    • Inarticulate
      • Survivors can learn sign language
    • Risk – increases with maternal age

    Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

    Maternal Serum Screening, Integrated, Specimen #1 0081062
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Ultrasound (US) for nuchal thickness is optional for this test; if an NT measurement is submitted to the lab, the sonographer must be FMF- or NTQR-certified

    Sample may be drawn as early as 10w0d (CRL of 34mm) but NT, if done, must be measured when CRL is 39-85 mm

    Sample draw and US do not have to be done on the same day

    Final interpretive report available only when the second sample test results are complete

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases, 15% of ONTD cases, and 10-20% of T18 cases, depending on the test and maternal age

    Follow Up

    When NT is included, this test yields the best detection rate and lowest false-positive rate of all biochemical (not cfDNA based) prenatal screens

    Final results are available after the second trimester sample is received by the lab

    Genetic counseling for abnormal results is recommended

    Maternal Serum Screening, Integrated, Specimen #2 0081064
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Requires a previously submitted first trimester sample, Maternal Serum Screening, Integrated, Specimen #1

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases, 15% of ONTD cases, and 10-20% of T18 cases, depending on the test and maternal age

    AFP false positives occur with multiple gestation pregnancies, underestimated gestational age

    Follow Up

    Genetic counseling for abnormal results recommended

    Maternal Serum Screen, First Trimester 0081150
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Requires NT measurement performed by an FMF- or NTQR-certified ultrasonographer

    This test does not screen for ONTD

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases and 10-20% of T18 cases, depending on the test and maternal age

    Follow Up

    Maternal Serum Screen, Alpha Fetoprotein (only) test is recommended in the second trimester to screen for ONTD

    Genetic counseling for abnormal results recommended

    Maternal Screening, Sequential, Specimen #1 0081293
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Requires an NT measurement that has been performed by an FMF- or NTQR-certified ultrasonographer

    Most expensive screening test (a combination of the required ultrasound, and the first- and second-trimester lab tests)

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases and 10-20% of T18 cases, depending on the test and maternal age

    Follow Up

    Interpretation is provided after first draw so pregnancies at very high risk for T21 can be identified in the first trimester

    Genetic counseling for abnormal results recommended

    Women at intermediate or low risk after first draw go on for second draw to complete the screen

    No risk estimate is provided after first sample unless patient is at very high risk for either T21 or T18; all patients receive a risk estimate after second sample is received

    Maternal Screening, Sequential, Specimen #2 0081294
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Requires a previously submitted first trimester sample (Maternal Screening, Sequential Specimen #1)

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases, 15% of ONTD cases, and 10-20% of T18 cases, depending on the test and maternal age

    AFP false positives occur with multiple gestation pregnancies, underestimated gestational age

    Follow Up

    Genetic counseling for abnormal results recommended

    Maternal Serum Screen, Alpha Fetoprotein, hCG, Estriol, and Inhibin A 0080269
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Better detection rate and lower false-positive rate than triple screen

    Best second-trimester screen available

    A screen interpreted as “normal” misses approximately 10-20% of T21 cases, 15% of ONTD cases, and 10-20% of T18 cases, depending on the test and maternal age

    AFP false positives occur with multiple gestation pregnancies, underestimated gestational age

    Follow Up

    Request recalculation only if ultrasound exam reveals a due date discrepancy >10 days

    Genetic counseling for abnormal results recommended

    Maternal Serum Screen, Alpha Fetoprotein (Only) 0080434
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Does not screen for T21 or T18

    Follow Up

    If AFP is between 2.5 and 3.0 MoMs, repeat AFP test (no earlier than 2 wks after original test was drawn) and offer targeted US and amniocentesis for chromosomes and AF-AFP

    If AFP ≥3.0 MoMs, offer US and amniocentesis

    Genetic counseling for abnormal results recommended

    Non-Invasive Prenatal Testing for Fetal Aneuploidy (Panorama) 2007537
    Method: Targeted sequencing with SNPs

    Limitations

    Inappropriate for women who

    • Are carrying more than one fetus
    • Are not carrying their biological offspring (eg, pregnancies resulting from an egg donor, or when the woman is a surrogate)
    • Have undergone allogeneic bone marrow transplant
    • In any of the above circumstances, cfDNA screening by alternative method may be available

    Aneuploidy for chromosomes other than 13, 18, 21, X, and Y will not be detected

    Fetal mosaicism may not be detected

    Low FF may occur normally in some pregnancies and can affect the ability to report a result

    • Women with elevated BMI are at increased risk of having a low FF
    • May result in increased chance of a false-positive, false-negative, or no-call test result

    Maternal factors (eg, BMI or current cancer diagnosis) may affect fetal fraction or cfDNA analysis

    Follow Up

    Women carrying a fetus with US abnormalities who screen negative by cfDNA should be offered diagnostic testing: fetal karyotype +/- fetal microarray by CVS or amniocentesis

    All positive cfDNA results should be confirmed by fetal karyotype

    Discuss positive predictive value with patient

    Genetic counseling for abnormal results recommended

    Non-Invasive Prenatal Testing for Fetal Aneuploidy with 22q11.2 Microdeletion (Panorama) 2013142
    Method: Targeted Sequencing with SNPs

    Limitations

    Inappropriate for women who

    • Are carrying more than one fetus
    • Are not carrying their biological offspring (eg, pregnancies resulting from an egg donor, or when the woman is a surrogate)
    • Have undergone allogeneic bone marrow transplant
    • In any of the above circumstances, cfDNA screening by alternative method may be available

    Aneuploidy for chromosomes other than 13, 18, 21, X, and Y will not be detected

    Fetal mosaicism may not be detected

    Low FF may occur normally in some pregnancies and can affect the ability to report a result

    • Women with elevated BMI are at increased risk of having a low FF
    • May result in increased chance of a false-positive, false-negative, or no-call test result

    Maternal factors (eg, BMI or current cancer diagnosis) may affect fetal fraction or cfDNA analysis

    Follow Up

    Women carrying a fetus with US abnormalities who screen negative by cfDNA should be offered diagnostic testing: fetal karyotype +/- fetal microarray by CVS or amniocentesis

    All positive cfDNA results should be confirmed by diagnostic testing

    Discuss positive predictive value with patient

    Genetic counseling for abnormal results recommended

    Non-Invasive Prenatal Testing for Fetal Aneuploidy (Panorama) with Microdeletions 2010232
    Method: Targeted Sequencing with SNPs

    Limitations

    Inappropriate for women who

    • Are carrying more than one fetus
    • Are not carrying their biological offspring (eg, pregnancies resulting from an egg donor, or when the woman is a surrogate)
    • Have undergone allogeneic bone marrow transplant
    • In any of the above circumstances, cfDNA screening by alternative method may be available

    Aneuploidy for chromosomes other than 13, 18, 21, X, and Y will not be detected

    Fetal mosaicism may not be detected

    Low FF may occur normally in some pregnancies and can affect the ability to report a result

    • Women with elevated BMI are at increased risk of having a low FF
    • May result in increased chance of a false-positive, false-negative, or no-call test result

    Maternal factors (eg, BMI or current cancer diagnosis) may affect fetal fraction or cfDNA analysis

    Follow Up

    Women carrying a fetus with US abnormalities who screen negative by cfDNA should be offered diagnostic testing: fetal karyotype +/- fetal microarray by CVS or amniocentesis

    All positive cfDNA results should be confirmed by diagnostic testing

    Discuss positive predictive value with patient

    Genetic counseling for abnormal results recommended 

    Chromosome Analysis, Chorionic Villus 2002291
    Method: Giemsa Band

    Limitations

    Time-sensitive test

    Rate of spontaneous fetal loss post-procedure may be higher than with amniocentesis

    Follow Up

    Genetic counseling for abnormal results recommended

    Chorionic Villus, FISH 0040203
    Method: Fluorescence in situ Hybridization

    Limitations

    Does NOT detect structural chromosome abnormalities, mosaicism or aneuploidy involving chromosomes other than 13, 18, 21, X, or Y

    Follow Up

    Genetic counseling for abnormal results 

    Irreversible therapeutic action should not be initiated on the basis of FISH results alone

    Chromosome FISH, Chorionic Villus with Reflex to Chromosome Analysis or Genomic Microarray 2011131
    Method: Fluorescence in situ Hybridization

    Limitations

    Will not detect base pair mutations, very small deletions/duplications; tetraploidy; balanced rearrangements, such as translocations, inversions, and balanced insertions; low-level mosaicism; imbalances of mitochondrial genome

    Failure of the array to detect an imbalance at any specific locus does not exclude the diagnosis of any disorder associated with that locus

    Duplications <2 MB and deletions <1 MB may not be reported if they contain only a few genes that have no compelling association with the disease

    Test results are often complex, and a CNV of uncertain clinical significance may be detected

    Chromosome Analysis, Amniotic Fluid 2002293
    Method: Giemsa Band

    Limitations

    Time-sensitive test

    Follow Up

    Genetic counseling for abnormal results 

    Chromosome Analysis, Amniotic Fluid, with Reflex to Genomic Microarray 2008367
    Method: Giemsa Band/Genomic Microarray (Oligo-SNP Array)

    Limitations

    Does not detect base pair mutations, very small deletions/duplications; tetraploidy; balanced rearrangements, such as translocations, inversions, and balanced insertions; low-level mosaicism; imbalances of mitochondrial genome

    Failure of the array to detect an imbalance at any specific locus does not exclude the diagnosis of any disorder associated with that locus

    Duplications <2 MB and deletions <1 MB may not be reported if they contain only a few genes that have no compelling association with the disease

    Test results are often complex, and a CNV of uncertain clinical significance may be detected

    Chromosome FISH, Prenatal 2002297
    Method: Fluorescence in situ Hybridization

    Limitations

    Does NOT detect structural chromosome abnormalities, mosaicism and other numerical chromosome abnormalities (excluding 13, 18, 21, X, and Y)

    Follow Up

    Genetic counseling for abnormal results

    Irreversible therapeutic action should not be initiated on the basis of FISH results alone

    Chromosome FISH, Amniotic Fluid with Reflex to Chromosome Analysis or Genomic Microarray 2011130
    Method: Fluorescence in situ Hybridization

    Limitations

    Will not detect base pair mutations, very small deletions/duplications; tetraploidy; balanced rearrangements, such as translocations, inversions, and balanced insertions; low-level mosaicism; imbalances of mitochondrial genome

    Failure of the array to detect an imbalance at any specific locus does not exclude the diagnosis of any disorder associated with that locus

    Duplications <2 MB and deletions <1 MB may not be reported if they contain only a few genes that have no compelling association with the disease

    Test results are often complex, and a CNV of uncertain clinical significance may be detected

    Follow Up

    Genetic counseling for abnormal results

    Irreversible therapeutic action should not be initiated on the basis of FISH results alone

    Cytogenomic SNP Microarray - Fetal 2002366
    Method: Genomic Microarray (Oligo-SNP Array)

    Limitations

    Time-sensitive test

    Does not detect base pair mutations; very small deletions/duplications; tetraploidy; balanced rearrangements (translocations, inversions, and balanced insertions); low-level mosaicism; imbalances of the mitochondrial genome

    To minimize variations of undetermined significance, duplications smaller than 2 MB and deletions smaller than 1 MB may not be reported if they contain only a few genes that have no compelling association with disease

    May reveal a biological relationship, including a close blood relationship (consanguinity or incest) between the mother and the father of the fetus

    Failure of the array to detect an imbalance at any specific locus does not exclude the diagnosis of any disorder associated with that locus

    Follow Up

    Genetic counseling for abnormal results

    Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase and Fetal Hemoglobin 0080427
    Method: Chemiluminescent Immunoassay/Electrophoresis

    Limitations

    AFP amniotic fluid test results are confounded by contamination with fetal blood which occurs in approximately 8% of samples collected

    AChE is much less affected by fetal blood

    Cannot be performed until second trimester

    Follow Up

    Positive tests will automatically reflex to testing that will check for the presence of ACHE and/or fetal blood

    Genetic counseling for abnormal results

    Related Tests

    Guidelines

    American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122(6): 1374-7. PubMed

    Benn P, Borell A, Chiu R, Cuckle H, Dugoff L, Faas B, Gross S, Johnson J, Maymon R, Norton M, Odibo A, Schielen P, Spencer K, Huang T, Wright D, Yaron Y. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. 2013; 33(7): 622-9. PubMed

    Committee Opinion Summary No. 640: Cell-Free DNA Screening For Fetal Aneuploidy Obstet Gynecol. 2015; 126(3): 691-2. PubMed

    Dondorp W, de Wert G, Bombard Y, Bianchi DW, Bergmann C, Borry P, Chitty LS, Fellmann F, Forzano F, Hall A, Henneman L, Howard HC, Lucassen A, Ormond K, Peterlin B, Radojkovic D, Rogowski W, Soller M, Tibben A, Tranebjærg L, van El CG, Cornel MC, European Society of Human Genetics, American Society of Human Genetics. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening Eur J Hum Genet. 2015; 23(11): 1438-50. PubMed

    Gregg AR, Gross SJ, Best RG, Monaghan KG, Bajaj K, Skotko BG, Thompson BH, Watson MS. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013; 15(5): 395-8. PubMed

    Practice Bulletin No. 162 Summary: Prenatal Diagnostic Testing for Genetic Disorders Obstet Gynecol. 2016; 127(5): 976-8. PubMed

    Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders Obstet Gynecol. 2016; 127(5): e108-22. PubMed

    Practice Bulletin No. 163 Summary: Screening for Fetal Aneuploidy Obstet Gynecol. 2016; 127(5): 979-81. PubMed

    Practice Bulletin No. 163: Screening for Fetal Aneuploidy Obstet Gynecol. 2016; 127(5): e123-37. PubMed

    Society for Maternal-Fetal Medicine (SMFM) Publications Committee. #36: Prenatal aneuploidy screening using cell-free DNA Am J Obstet Gynecol. 2015; 212(6): 711-6. PubMed

    Wilson KL, Czerwinski JL, Hoskovec JM, Noblin SJ, Sullivan CM, Harbison A, Campion MW, Devary K, Devers P, Singletary CN. NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Couns. 2013; 22(1): 4-15. PubMed

    General References

    Ashwood ER, Palomaki GE. A new era in noninvasive prenatal testing. N Engl J Med. 2013; 369(22): 2164. PubMed

    Bahado-Singh RO, Argoti P. An overview of first-trimester screening for chromosomal abnormalities. Clin Lab Med. 2010; 30(3): 545-55. PubMed

    Bianchi DW, Parker L, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ, CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014; 370(9): 799-808. PubMed

    Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP, MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012; 119(5): 890-901. PubMed

    Bornstein E, Lenchner E, Donnenfeld A, Barnhard Y, Seubert D, Divon MY. Advanced maternal age as a sole indication for genetic amniocentesis; risk-benefit analysis based on a large database reflecting the current common practice. J Perinat Med. 2009; 37(2): 99-102. PubMed

    Chetty S, Garabedian MJ, Norton ME. Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening. Prenat Diagn. 2013; 33(6): 542-6. PubMed

    Faas BH W, Cirigliano V, Bui T. Rapid methods for targeted prenatal diagnosis of common chromosome aneuploidies. Semin Fetal Neonatal Med. 2011; 16(2): 81-7. PubMed

    Greene MF, Mello MM, Morain S. A new era in noninvasive prenatal testing. N Engl J Med. 2013; 369(22): 2165. PubMed

    Gregg AR, Gross SJ, Best RG, Monaghan KG, Bajaj K, Skotko BG, Thompson BH, Watson MS. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013; 15(5): 395-8. PubMed

    Gregg AR, Van den Veyver IB, Gross SJ, Madankumar R, Rink BD, Norton ME. Noninvasive prenatal screening by next-generation sequencing. Annu Rev Genomics Hum Genet. 2014; 15: 327-47. PubMed

    Hung EC W, Chiu RW K, Lo YM D. Detection of circulating fetal nucleic acids: a review of methods and applications. J Clin Pathol. 2009; 62(4): 308-13. PubMed

    Krantz DA, Hallahan TW, Sherwin JE. Screening for open neural tube defects. Clin Lab Med. 2010; 30(3): 721-5. PubMed

    Mennuti MT, Cherry AM, Morrissette JJ D, Dugoff L. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol. 2013; 209(5): 415-9. PubMed

    Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn. 2011; 31(1): 7-15. PubMed

    Norton ME. First-trimester screening for chromosomal abnormalities: advantages of an instant results approach. Clin Lab Med. 2010; 30(3): 565-71. PubMed

    Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011; 13(11): 913-20. PubMed

    Pergament E, Cuckle H, Zimmermann B, Banjevic M, Sigurjonsson S, Ryan A, Hall MP, Dodd M, Lacroute P, Stosic M, Chopra N, Hunkapiller N, Prosen DE, McAdoo S, Demko Z, Siddiqui A, Hill M, Rabinowitz M. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort Obstet Gynecol. 2014; 124(2 Pt 1): 210-8. PubMed

    Sheppard C, Platt LD. Nuchal translucency and first trimester risk assessment: a systematic review. Ultrasound Q. 2007; 23(2): 107-16. PubMed

    The American College of Obstetricians and Gynecologists. Cell-free DNA Prenatal Screening Test . The American Congress of Obstetricians and Gynecologists. Washington, DC [Accessed: May 2016]

    Understanding a Down Syndrome Diagnosis developed by the National Center for Prenatal and Postnatal Down Syndrome Resources at the University of Kentucky https://lettercase.hdi.uky.edu/?product=understanding-a-down-syndrome-diagnosis-booklet

    van Lith JM M, Benacerraf BR, Yagel S. Current controversies in prenatal diagnosis 2: Down syndrome screening: is ultrasound better than cell-free nucleic acids in maternal blood? Prenat Diagn. 2011; 31(3): 231-4. PubMed

    Zhong Y, Tuuli M, Odibo AO. First-trimester assessment of placenta function and the prediction of preeclampsia and intrauterine growth restriction. Prenat Diagn. 2010; 30(4): 293-308. PubMed

    Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, Ryan A, Sigurjonsson S, Chopra N, Dodd M, Levy B, Rabinowitz M. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn. 2012; 32(13): 1233-41. PubMed

    References from the ARUP Institute for Clinical and Experimental Pathology®

    Burton BK, Leviton L, Vespa H, Coon H, Longo N, Lundy BD, Johnson M, Angelino A, Hamosh A, Bilder D. A diversified approach for PKU treatment: routine screening yields high incidence of psychiatric distress in phenylketonuria clinics. Mol Genet Metab. 2013; 108(1): 8-12. PubMed

    Chittamma A, Marin SJ, Williams JA, Clark C, McMillin GA. Detection of in utero marijuana exposure by GC-MS, ultra-sensitive ELISA and LC-TOF-MS using umbilical cord tissue. J Anal Toxicol. 2013; 37(7): 391-4. PubMed

    Erickson A, Ashwood ER, Gin CA. Evaluation of a dimeric inhibin-A assay for assessing fetal Down syndrome: establishment, comparison, and monitoring of median concentrations for normal pregnancies. Arch Pathol Lab Med. 2004; 128(4): 415-20. PubMed

    Furtado LV, Jama MA, Paxton CN, Wilson AA, Gardiner AE, Lyon E, Geiersbach KB. Aneuploidy detection in paraffin embedded tissue from products of conception by mini-STR genotyping. Fetal Pediatr Pathol. 2013; 32(2): 133-50. PubMed

    Owen WE, Rawlins ML, La'ulu SL, Roberts WL. Performance characteristics of the Access pregnancy-associated plasma protein-A assay. Clin Chim Acta. 2008; 398(1-2): 165-7. PubMed

    Paxton CN, Brothman AR, Geiersbach KB. Rapid aneusomy detection in products of conception using the KaryoLite™ BACs-on-Beads™ assay. Prenat Diagn. 2013; 33(1): 25-31. PubMed

    Pont-Kingdon G, Lyon E. Rapid detection of aneuploidy (trisomy 21) by allele quantification combined with melting curves analysis of single-nucleotide polymorphism loci. Clin Chem. 2003; 49(7): 1087-94. PubMed

    Rawlins ML, La'ulu SL, Erickson A, Roberts WL. Performance characteristics of the Access Inhibin A assay. Clin Chim Acta. 2008; 397(1-2): 32-5. PubMed

    South ST, Chen Z, Brothman AR. Genomic medicine in prenatal diagnosis. Clin Obstet Gynecol. 2008; 51(1): 62-73. PubMed

    Walker BS, Nelson RE, Jackson BR, Grenache DG, Ashwood ER, Schmidt RL. A Cost-Effectiveness Analysis of First Trimester Non-Invasive Prenatal Screening for Fetal Trisomies in the United States PLoS One. 2015; 10(7): e0131402. PubMed

    Wapner RJ, Martin CLese, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JLeigh, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367(23): 2175-84. PubMed

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    Last Update: June 2016