Prenatal Screening and Diagnosis

Diagnosis

Indications for Testing

  • Diagnostic testing for chromosome abnormalities and open neural tube defects (ONTD) should be offered to all 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] or trisomy 18 [T18])
      • Either parent is a known carrier of a genetic translocation or inversion
      • Maternal age ≥35 at estimated date of delivery (EDD)
      • Abnormal ultrasound or fetal findings
      • Increased risk of ONTD due to family history, patient 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
      • Examines fetal chromosomes only; uses placental tissue
      • Not appropriate for patients at increased risk for ONTD
    • Amniocentesis – ≥15weeks
      • Examines fetal chromosomes
      • Amniotic fluid alpha-fetoprotein concentration and acetylcholinesterase testing available to assist in the diagnosis of fetal ONTD

Screening

Serum screening (± nuchal translucency measurement) – singleton gestations
  • Can be done between 10-24 weeks gestation; diagnosis is available at ≥10 weeks gestation
  • Involves various combinations of pregnancy-associated serum markers (ie, placental protein A [PAPP-A], human chorionic gonadotropin [hCG], unconjugated estriol [uE3], alpha fetoprotein [AFP], dimeric inhibin A [DIA]) and/or ultrasound (US) for nuchal translucency (NT) with blood collections in the first or second trimester, or both
  • ACOG serum screening (± nuchal translucency measurement) recommendations, 2007
    • All women, regardless of age, should have the option of diagnostic testing
    • Maternal age of 35 years alone should no longer be used as a cutoff to determine who is offered screening vs. who is offered diagnostic testing
    • Patients seen early in pregnancy should ideally be offered aneuploidy screening that combines first- and second-trimester testing (integrated or sequential)
    • Options for women seen initially during the second trimester are limited to quadruple (quad) screening and ultrasound exam
  • Recommend any of the following screening tests based on patient and physician preference (see Test tab and Prenatal Screening table below for more details about these tests)
    • If low-risk patient presents in the first trimester and both CVS- and NT-certified sonographer are available
      • First-trimester (combined) screen for patient who accepts higher risk of a screen positive test (SPR)
      • Sequential screen for patient who prefers lower SPR, closer to that of the integrated test, but wants to know early if she is high risk
      • Integrated test for those patients who want the best possible detection rate (DR) coupled with the lowest SPR
    • If low-risk patient presents in the first trimester and neither CVS- nor NT-certified sonographer is available
      • Integrated screen
        • Available without an NT measurement (serum integrated)
        • Results available in the second trimester, so availability of CVS is not an issue
    • If low-risk patient presents in the second trimester
      • Quad screen
      • US
  • Follow-up
    • If screen indicates an increased risk for DS or ONTD (high AFP)
      • US to look for twins and fetal/placental abnormalities and to confirm dates
        • If EDD changes by ≥10 days based on second trimester US (or ≥7 days based on first trimester US) – contact lab to recalculate screening results
          • Normal – low risk for DS, T18, and ONTD; no further testing recommended
          • Abnormal – offer genetic counseling and either screening by noninvasive prenatal testing (NIPT) or diagnostic testing
          • If recalculated gestational age is <14 weeks (15 weeks at some labs) when sample was drawn, redraw sample and repeat test
        • If EDD is correct within 10 days based on second trimester US, offer genetic counseling and either screening by NIPT or diagnostic testing
    • If screen indicates a low risk for ONTD, DS, and T18, no further testing recommended
      • If EDD changes at scheduled second trimester US (18-22 weeks) by ≥10 days, contact lab to recalculate screening results
        • Do not redraw patient to repeat test
  • Ultrasound NT alone is usually inadequate for aneuploidy detection
    • If NT ≥3.5 mm
      • Patient is at high risk for fetal aneuploidy; additional serum screening is not indicated
        • Offer genetic counseling and either screening by NIPT or diagnostic testing by CVS or amniocentesis as well as targeted US and fetal echocardiogram in the second trimester
    • If NT ≥2.5 multiples of median (MoMs) after screening
      • Patient should be offered targeted ultrasound and fetal echocardiogram in the second trimester even if the screening results suggest a low risk for aneuploidy
    • Sonographers must be certified to perform NT measurements by the Fetal Medicine Foundation (FMF) or the Nuchal Translucency Quality Review Board (NTQR) 
    • For more test-specific information, refer to ARUP's First- and Second-Trimester Screening Options
Serum screening (± nuchal translucency measurement) – multiple gestations
  • Screening in twin pregnancies
    • In the case of twins, it is not possible to determine the relative contribution of each fetus to the measured concentrations of the serum markers
    • “Pseudo-risk” for DS and T18 can be determined by dividing the measured marker by the median value observed in twin gestations and calculating the risk as if the woman were carrying a single fetus
      • Decreases DR as compared to screening women with singleton gestations
      • Accurate NT measurements of both fetuses in the first trimester can increase DR for first trimester screens
  • Screening in higher order multiple gestations
    • Not recommended for DS and T18
      • Risk estimates generally not available
    • Screening for ONTD available in twin and triplet pregnancies, but DR is decreased
Screening by noninvasive prenatal testing (NIPT) using cell-free DNA
  • Noninvasive prenatal screening tests for DS and other numerical chromosome abnormalities (chromosomes evaluated depends on the laboratory performing testing)
  • Testing is performed on the small fraction of nonchromosomal, cell-free DNA that circulates in the maternal bloodstream; this DNA derives from both mother and fetus
  • Testing can be performed as early as 9-10 weeks gestation
  • Testing is available for DS, T18, and trisomy 13 (T13)
    • Other laboratories may
      • Report sex chromosome abnormalities
      • Screen for the presence of more common microdeletions/microduplications (eg, those that cause DiGeorge syndrome or Prader-Willi/Angelman syndrome)
      • Screen for triploidy
  • Currently, the American Congress of Obstetrics and Gynecology and the National Society of Genetic Counselors recommend offering this test only to patients at increased risk for T13, T18, DS, or Turner syndrome
    • High risk patients include
      • Maternal age ≥35 at time of delivery
      • Positive serum screening (± NT) test result for DS, T18, or T13
      • Fetus with ultrasound anomalies consistent with T13, T18, DS, or Turner syndrome
      • Patient had a previous pregnancy/child affected with a chromosome aneuploidy
  • Some labs report results as positive/negative while others report a post-test risk in a format that is similar for non-DNA based aneuploidy screening tests
  • Testing is more expensive than non-DNA based aneuploidy screening tests, however, the detection and false-positive rates are greatly superior to the non-DNA based tests

Although the reported DR-SPR for NIPT approaches that of a diagnostic test with an overall DR (including DS, T18, and T13) of 98.9% at a false-positive rate of 0.1%*, all positive NIPT results should be confirmed by fetal karyotype. 

  • False positive cases of T18 and T13 on NIPT have been encountered due to confined placental mosaicism (CPM)
  • If a CVS is used as follow-up for confirmation of positive NIPT cases, chromosome analysis should be performed on cultured cells established from the mesenchymal core of the villi

Rapid aneuploidy testing may only confirm the CPM and not reflect the fetal genotype. Ultimately, chromosome analysis on amniotic fluid may be required in an attempt to rule out true fetal mosaicism.

* These values are based on the testing of high-risk women in a controlled study; detection and false-positive rates in a low-risk, uncontrolled population may be lower.
NIPT specificity and sensitivity comparisons

Detection Rate

False Positive Rate

MPSS

Palomaki (2011 & 2012)

MPSS with SAFeR

Bianchi (2012)

Targeted Sequencing with FORTE

Ashoor; Nicolaides; Ashoor (2012)

The Panorama Test using NATUS

Trisomy 21

(Down Syndrome)

98.6-99.1%

0.2%

99.9%

0.2%

100%

0.1

>99%

0.0%

Trisomy 18

(Edwards Syndrome)

100%

0.3%

97.4%

0.4%

98%

0.1%

>99%

0.0%

Trisomy 13

(Patau Syndrome)

91.7%

0.9%

87.5%

0.1%

80%

0.05%

>99%

0.0%

45,X

(Monosomy X)

Not evaluated

95%

1.0%

Not evaluated

>99%

0.0%

Sex Chromosome Trisomies

Not evaluated

66-75%

Reported when identified

Not evaluated

>99%

  • Prenatal screening test information (see table below)

Prenatal Screening

TestRecommended forPurpose

First trimester (combined) screen

Maternal screen, first trimester

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

Crown-rump length (CRL) must be between 42-85 mm and an NT measurement must be obtained

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 specimen drawn between 11w0d and 13w6d gestation

CRL must be between 42-85 mm and an NT measurement must be obtained

Second specimen drawn between 15w0d and 24w6d

Specimen 1 measures PAPP-A and total hCG

Specimen 2 measures AFP, uE3, hCG, and DIA

Screens for DS, T18, ONTD

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

Patients who are 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 specimen drawn between 10w0d and 13w6d gestation

CRL must be between 32-85 mm (an NT measurement is optional for this test – must be obtained when the CRL is between 36-85)

Second specimen drawn between 15w0d and 24w6d

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

Specimen 1 measures PAPP-A

Specimen 2 measures AFP, uE3, hCG, and DIA

Screens for DS, 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 weeks gestation; however, reference medians are available from 14w0d to 24w6d

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

Screen for fetal risk of ONTD at 14-25 weeks

Quad Screen

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

ACOG recommends the quad for second trimester aneuploidy screening

Offer to patients 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 weeks gestation; however, reference medians are available from 14w0d to 24w6d

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

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

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

Best second trimester screen available

Noninvasive prenatal testing (NIPT) for fetal aneuploidy

Can be performed as early as 9.0 weeks gestation

Offer to patients who are considered to be at increased risk for one of the common fetal aneuploidy disorders: trisomy 13, 18, 21, or Turner syndrome (TS)

Women are considered to be at increased risk when

  • Patient age is ≥35 at EDD
  • Patient had a previous child with aneuploidy
  • Patient’s current fetus has US abnormalities associated with trisomy 13, 18, 21, or TS

Patient has screened positive by serum screening (± NT)

Highly sensitive screening test for specific fetal aneuploidies

Intended to identify women with a current pregnancy at risk for trisomy 13, 18, 21, or TS; may also identify fetuses with other sex-chromosome aneuploidies or triploidy

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

All positive NIPT results should be confirmed by fetal karyotype

  • Prenatal diagnosis – amniotic fluid and chromosome analyses (see table below)
Prenatal Diagnosis – Amniotic Fluid and Chromosome Analyses
TestRecommended forPurpose
Chromosome Analysis, Chorionic Villus Sampling (CVS)

Indications include

  • Patient desires diagnostic testing instead of screening
  • Advanced maternal age (patient age ≥35 at EDD)
  • Abnormal first trimester screen for DS or T18
  • Fetal US abnormalities
  • Family history of chromosome abnormality or genetic disorder
Prenatal diagnosis in pregnant patient at 11-14 weeks gestation
Chorionic Villus, 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
Chromosome Analysis, Amniotic Fluid

Indications include

  • Patient desires diagnostic testing instead of screening
  • Advanced maternal age (patient age ≥35 at EDD)
  • Abnormal maternal screen for ONTD, DS, or T18
  • Fetal ultrasound abnormalities
  • Family history of chromosome abnormality or genetic disorder

Prenatal diagnosis in patient >14 weeks gestation

Amniocentesis is discouraged <15 weeks 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 an abnormal fetal karyotype requiring further characterization
  • Abnormal ultrasound findings with a normal karyotype
  • Family history of a known or suspected chromosomal abnormality that is best evaluated by microarray
Detection of unbalanced chromosomal abnormalities (copy number gain/loss) and absence of heterozygosity in 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 week; use EDD to avoid clerical errors

Prenatal diagnosis for ONTD at 14-25 weeks 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 (see table below) 

Sensitivity and Initial Positive Rates for Down Syndrome

Screening Test

% DS Detection

% Initial PositiveDS 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  (see table below)

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 defects95%
Anencephaly

97%

Open spina bifida

99%

Abdominal wall defects

40-79%

  • Targeted ultrasound test results follow-up (see table below)

Targeted Ultrasound Test Results Follow-Up

Test ResultNext Action
Anomaly detected on US

Perform second-tier screening:

  • NIPT 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 Analysis FISH, Prenatal
  • Cytogenomic SNP Microarray - Fetal

OR

  • Chromosome Analysis, Chorionic Villus Sampling (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 weeks 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, patient is at risk for poor pregnancy outcome (prematurity, small-for-gestational-age infant, still birth)

  • Offer counseling
  • Monitor pregnancy
No anomaly on US, but hCG MoM* >3.5

Patient is at 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 (see table below)

Second Trimester Maternal Serum Screening Tests – Result Patterns

AFP

hCG

uE3

DIA

Pattern

L

H

L

H

Normal, overestimated gestation, and DS

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

Clinical Background

Because most families who have a child with an open neural tube defect (ONTD), Down syndrome (DS), or trisomy 18 (T18) have no prior family history of these disorders, prenatal screening should be discussed with all pregnant women.

Open neural tube defects (ONTD)

Epidemiology

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

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
  • Risk – independent of maternal age

Down syndrome (DS)

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 DS is ~1:1,500
    • 30s – risk rises dramatically
    • 40s – risk levels out to ~1:100
  • ~50% of babies with DS are born to mothers <35 years

Pathophysiology

  • Extra chromosome 21 found in all nucleated cells
  • Mosaic DS
    • Caused by an extra chromosome 21 in some, but not all, cells
    • Clinical phenotype
      • Usually milder than non-mosaic DS
      • 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

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 Presentations

  • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Maternal Serum Screening, Integrated, Specimen #1 0081062
Method: Quantitative Chemiluminescent Immunoassay

Screening test for DS, T18, and ONTD

Screen combines a first and second trimester blood specimen, with or without a first trimester NT measurement

Draw first sample between 10w0d and 13w6d gestation

CRL must be between 32-85 mm at time of NT measurement

First specimen measures PAPP-A

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 32mm) but NT, if done, must be measured when CRL is 36-85 mm)

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

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

When NT is included, this test yields the best detection rate and lowest false-positive rate of all prenatal screens

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

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

Screen combines first and second trimester blood specimens, with or without a first trimester NT measurement

Draw second sample between 15w0d and 24w6d gestation

Interpretation based on NT (if performed), PAPP-A, AFP, hCG, uE3, and DIA measurements

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

Genetic counseling for abnormal results recommended

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

Screening test for DS and T18 during the first trimester

Draw sample and obtain NT measurement (required) when CRL measures 42-85 mm

(Note: NT can be obtained when CRL ≥36mm)

If NT is unobtainable, order Maternal Serum Screening, Integrated, Specimen #1 in the first trimester and follow with Maternal Serum Screening, Integrated, Specimen #2 in the second trimester, which can be interpreted without an NT value

Interpretation based on NT, PAPP-A, and total hCG measurements

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

This test does not screen for ONTD

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

Screening test for DS and T18

Order test in the first trimester; must be followed by a Maternal Screening Sequential Specimen #2 test in the second trimester

Draw sample and obtain NT measurement (required) when CRL measures 42-85 mm

(Note: NT can be obtained when CRL ≥36 mm)

If NT is unobtainable, order Maternal Serum Screening, Integrated, Specimen #1 in the first trimester and follow with Maternal Serum Screening, Integrated, Specimen #2 in the second trimester, which can be interpreted without an NT value

Specimen 1 measures PAPP-A and total hCG

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)

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

Genetic counseling for abnormal results recommended

Patients 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 DS or T18; all patients receive a risk estimate after second sample is received

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

Screening test for DS, T18, and ONTD

Order if Maternal Screening Sequential Specimen #1 was ordered in the first trimester

Draw sample between 15w0d and 24w6d gestation

Specimen 2 measures hCG, AFP, uE3, and DIA

Interpretation based on NT, PAPP-A, AFP, hCG, uE3, and DIA measurements

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

Genetic counseling for abnormal results recommended

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

Screening test for DS, T18, and ONTD

Ideal time for ordering quad screening test is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d

Quad screen is the most economical prenatal screening test

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

Best second trimester screen available

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

Screen for fetal risk of ONTD

Order single screening test for mothers who have had early amniocentesis, CVS, or first trimester screening

Ideal time period is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d

Does not screen for DS or T18

If AFP is between 2.5 and 3.0 MoMs, repeat AFP test (no earlier than 2 weeks 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

Offer to patients who are considered to be at increased risk for one of the common fetal aneuploidy disorders –  trisomy 13, 18, 21, Turner syndrome, or triploidy

High sensitivity and specificity – >99%

Test available from 9w0d-term

Test not appropriate for

  • Women carrying >1 fetus
  • Women who are not the genetic mother of the fetus
  • Women who have undergone allogeneic bone marrow transplant

Screens only for chromosomes 13, 18, 21, X, and Y

Fetal mosaicism may not be detected

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

All positive NIPT results should be confirmed by fetal karyotype

Chromosome Analysis, Chorionic Villus 2002291
Method: Giemsa Band

Sample type – chorionic villus

Prenatal diagnosis at 11-14 weeks gestation, usually in high risk pregnancies

Indications include

  • Advanced maternal age
  • Abnormal first trimester screen for DS or T18
  • Fetal ultrasound abnormalities
  • Family history of chromosome abnormality or genetic disorder
  • Patient desires diagnostic testing instead of screening

Time-sensitive test

Patient may have a higher rate of spontaneous fetal loss post-procedure than with amniocentesis

Genetic counseling for abnormal results recommended

Chorionic Villus, FISH 0040203
Method: Fluorescence in situ Hybridization

Sample type – chorionic villus

Offered in conjunction with fetal chromosome study 

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

Preliminary results usually available within 48 hours

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

Genetic counseling for abnormal results 

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

Chromosome Analysis, Amniotic Fluid 2002293
Method: Giemsa Band

Sample type – amniotic fluid

Prenatal diagnosis after 14 weeks gestation, usually in high risk pregnancies

Indications include

  • Abnormal maternal screen results for DS, T18, or ONTD
  • Fetal ultrasound abnormalities
  • Family history of chromosome abnormality or genetic disorder
  • Patient desires diagnostic testing instead of screening
  • Advanced maternal age (patient age ≥35 at EDD)

Time-sensitive test

Genetic counseling for abnormal results 

Chromosome FISH, Prenatal 2002297
Method: Fluorescence in situ Hybridization

Sample type – amniotic fluid

Offered in conjunction with fetal chromosome study 

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

Preliminary results usually available within 48 hours

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

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)

Indications include

  • Clarification of an abnormal fetal karyotype requiring further characterization
  • Abnormal US findings with a normal karyotype
  • Family history of a known or suspected chromosomal abnormality that is best evaluated by microarray

Time-sensitive test

Will not detect balanced rearrangements, such as translocations, inversions, and balanced insertions

Most intragenic alterations, such as point mutations and very small deletions or duplications, are not detected

Imbalances of the mitochondrial genome, genomic imbalances below the resolution of this array platform, and aberrations in regions of the genome not represented on the array platform are not detected

Genetic counseling for abnormal results

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

Prenatal diagnosis of ONTD at 14-25 weeks gestation

Indications include

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

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

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

Genetic counseling for abnormal results

Additional Tests Available
 
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Test Name and NumberComments
Inhibin A (Dimer) 0070137
Method: Quantitative Chemiluminescent Immunoassay

Not a prenatal test; useful for infertility evaluation in nonpregnant patient

Maternal Serum Screen, Alpha Fetoprotein, hCG, and Estriol 0080108
Method: Quantitative Chemiluminescent Immunoassay

Screening test for DS, T18, and ONTD

Ideal time for ordering triple screening test is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d

ACOG recommends the quad for second trimester aneuploidy screening

Request recalculation only if ultrasound exam reveals a due date discrepancy of more than 10 days

Acetylcholinesterase and Fetal Hemoglobin, Amniotic Fluid 2006848
Method: Qualitative Gel Electrophoresis/Radial Immunodiffusion
Aneuploidy Panel by FISH 0040208
Method: Fluorescence in situ Hybridization