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Disease Categories > Perinatal Disease

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Prenatal Screening and Diagnosis

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 the same.

Age is a known risk factor for DS; however, half of DS children are born to women less than 35.

Open neural tube defects

Incidence varies
- With racial background
- With geographical location
Incidence has decreased from approximately 1 in 1000 to 1 in 1,700 due to fortification of the food supply with folic acid
Most common types include spina bifida (a developmental defect of the spine and overlying skin) and anencephaly (failure of proper development of the brain, skull and overlying skin)
- Lesions of spina bifida include:
  - Simple meningocele
  - Lipomyelomeningocele
  - Diastematomyelia
  - Myelocystocele
  - Neuritic cyst
  - Intraspinal and intrapelvic meningoceles
Spina bifida often results in the following sequela, but clinical severity depends on the location and the size of the lesion, among other things
- Paralysis of the lower limbs
- Difficulty with bowel and bladder control
- Cerebral ventriculomegaly requiring shunt placement
Anencephaly associated with limited lifespan
- 50% of the infants are stillborn
- Remainder of newborns die within hours or days of birth

Down syndrome

Incidence of 1 in 700 births regardless of race or geographical location
Caused by the presence of an extra chromosome 21 in every cell of the body
Clinical manifestations
- Moderate mental retardation
- Characteristic facial features
  - Down-slanting palpebral fissures
  - Epicanthic folds
  - Depressed nasal bridge
- Cardiac abnormalities
  - Ventricular Septal Defect (VSD)
  - Endocardial cushion defect
The risk for DS increases with maternal age, but using a maternal age cutoff of 35 to determine who will be offered diagnostic testing will only identify approximately 50% of cases

Trisomy 18

Caused by the presence of an extra chromosome 18 in every cell of the body
Survival
- 50% are stillborn
- 5% of infants who survive delivery will be alive at 1 year
Clinical manifestations
- Severe mental retardation
- Nonambulatory
- Nonarticulate
  - Survivors can learn sign language

Screening and Diagnosis

Prenatal screening using maternal serum allows recognition of these disorders in a large portion of patients
Chorionic villus sampling/amniocentesis allows further differentiation of these disorders

Prenatal Screening
Test	Recommended for	Purpose
First trimester screen Maternal Serum Screen, First Trimester	Order this screening test during the 1st trimester (between 11w0d and 13w6d gestation) CRL must be between 42-79 mm	Use when mother wants to know the DS risk prior to 14 weeks Does not detect ONTD
Sequential screen combines 1st and 2nd trimester screening results	First specimen drawn between 11w0d and 13w6d gestation Crown rump length (CRL) must be between 42-79 mm and a nuchal translucency measurement must be obtained Second specimen drawn between 15w0d and 22w6d Most expensive screen	Specimen 1 measures PAPP-A and total hCG Specimen 2 measures hCG, AFP, uE3 and DIA An interpretation is provided after the first draw so that pregnancies at very high risk for DS can be identified in the 1st 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 1st and 2nd trimester screening results	First specimen drawn between 10w3d and 13w6d gestation Crown rump length (CRL) must be between 36-79 mm (a nuchal translucency measurement is optional for this test) Second specimen drawn between 15w0d and 22w6d	Specimen 1 measures PAPP-A Specimen 2 measures hCG, AFP, uE3 and DIA When combined with a 1st trimester certified ultrasound for nuchal translucency (NT), 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) Ideal time period is 16-18 weeks gestation; however, reference medians are available for 14w0d and 24w6d	Mothers who have early amniocentesis, chorionic villus sampling or 1st trimester screening	Screen for fetal risk of open neural tube defects (ONTD, i.e., spina bifida) in the 2nd trimester
Triple Screen Maternal Serum Screen, Alpha Fetoprotein, hCG, & Estriol Ideal time period is 16-18 weeks gestation; however, reference medians are available for 14w0d and 24w6d	Patients who present to care in the 2nd trimester, who do not wish to have 1st trimester screening, or for whom 1st trimester screening is not available. The quad and the triple are the most economical prenatal screening tests to use.	Triple screen for fetal risk of Down syndrome (trisomy 21), trisomy 18, and open neural tube defects (ONTD, i.e., spina bifida)
Quad Screen Maternal Serum Screen, Alpha Fetoprotein, hCG, Estriol, & Inhibin A Ideal time period is 16-18 weeks gestation; however, reference medians are available for 14w0d and 24w6d	Patients who present to care in the 2nd trimester, who do not wish to have 1st trimester screening, or for whom 1st trimester screening is not available. The quad and the triple are the most economical prenatal screening tests to use.	Quad screen for fetal risk of Down syndrome (trisomy 21), trisomy 18, and open neural tube defects (ONTD, i.e., spina bifida) Better detection rate at a lower false-positive rate than the triple screen Best 2nd trimester screen available

Prenatal Diagnosis – Amniotic Fluid and Chromosome Analyses
Tests	Recommended for	Purpose
Chromosome Analysis, Chorionic Villus Sampling (CVS)	Indications include: - Advanced maternal age (patients 35 or older at EDD) - Abnormal 1st trimester maternal serum screen for DS or T18 - Fetal ultrasound abnormalities - Family history of chromosome abnormality or genetic disorder	Prenatal diagnosis in pregnant patient at 10-13 weeks gestation
Chromosome Analysis, Amniotic Fluid	Indications include: - Abnormal maternal screen for DS or T18 - Fetal ultrasound abnormalities - Family history of chromosome abnormality or genetic disorder - Advanced maternal age (patients 35 or older at EDD) Final results in about 12 days	Prenatal diagnosis in pregnant patient after 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 Chromosome Analysis, Chorionic Villus Sampling (CVS)
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 Chromosome Analysis, Amniotic Fluid testing
Amniotic Fluid AFP with Reflex to Acetylcholinesterase	Indications include: - Abnormal MSAFP screen - Family history of ONTD - Patient taking valproic acid or carbamazepine	Prenatal diagnosis for open neural tube defects at 14-25 weeks gestation

Additional Information

Indications for Ordering

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 Screen, First Trimester 0081150 Method: Chemiluminescent Immunoassay/Enzyme-Linked Immunosorbent Assay	Order this screening test during the 1st trimester (between 11w0d and 13w6d) Crown-rump length (CRL) must be between 42-79 mm) and an NT measurement performed by a certified ultrasonographer must be obtained If an NT is unobtainable, order Maternal Serum Integrated Screen (0081062 and 0081064), which can be interpreted without an NT value	This test does not screen for open neural tube defects (ONTD)	The MSAFP test is recommended in 2nd trimester to screen for open neural tube defects (ONTD) (Maternal Serum Screen, Alpha Fetoprotein (Only) 0080434)
Maternal Screening, Sequential, Specimen #1 0081293 Method: Enzyme-Linked Immunosorbent Assay/Chemiluminescent Immunoassay	Order this test along with maternal screening sequential specimen #2 First specimen drawn between 11w0d and 13w6d gestation Crown-rump length (CRL) must be between 36-79 mm, and an NT measurement performed by a certified ultrasonographer must be obtained If an NT is unobtainable, order Maternal Serum Integrated Screen (0081062 and 0081064), which can be interpreted without an NT value Specimen 1 measures PAPP-A Most expensive screening test		An interpretation is provided after the first draw so that pregnancies at very high risk for DS can be identified in the 1st trimester Patients who are at intermediate or low risk after the first draw go on for the second draw and the complete screen
Maternal Screening, Sequential, Specimen #2 0081294 Method: Chemiluminescent Immunoassay/Enzyme-Linked Immunosorbent Assay	Order this test along with maternal screening sequential specimen #1 for patients with a very high risk for DS Specimen is drawn between 15w0d and 22w6d gestation Most expensive screening test Specimen 2 measures hCG, AFP, uE3 and DIA	Requires a previously submitted 1st trimester specimen (Maternal Screening, Sequential 0081293) Requires a nuchal translucency (NT) measurement that has been performed by a certified ultrasonographer
Maternal Serum Screening, Integrated, Specimen #1 0081062 Method: Enzyme-Linked Immunosorbent Assay	First specimen drawn between 10w3d and 13w6d gestation Crown-rump length (CRL) must be between 36-79 mm The first specimen of an Integrated Maternal Serum Screening is used to measure PAPP-A	An ultrasound for nuchal thickness is optional for this test. It does require a 2nd trimester specimen	Draw second specimen between 15w0d and 22w6d gestation (Maternal Serum Screening, Integrated, Specimen #2 0081064)
Maternal Serum Screening, Integrated, Specimen #2 0081064 Method: Chemiluminescent Immunoassay/Enzyme-Linked Immunosorbent Assay	This screen combines a 1st trimester and 2nd trimester blood specimen with or without a 1st trimester ultrasound exam (NT). When NT is included, it yields the best detection rate and lowest false-positive rate of all prenatal screens Second specimen drawn between 15w0d and 22w6d gestation	Requires a previously submitted 1st trimester specimen, Maternal Serum Screening, Integrated, Specimen #1 (0081062) Final interpretative report only available when the second specimen test results are complete
Maternal Serum Screen, Alpha Fetoprotein (Only) 0080434 Method: Chemiluminescent Immunoassay	Screen for fetal risk of open neural tube defects (i.e., spina bifida) Order the single screening test for mothers who have early amniocentesis, chorionic villus samplings or 1st trimester screening Ideal time period is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d		If the AFP is between 2.5 and 3.0 MoMs: 1) repeat the AFP test (no sooner than 2 weeks after original test was drawn); 2) offer targeted US and amniocentesis for chromosomes and AFAFP If the AFP ≥3.0 MoMs, offer US and amniocentesis
Maternal Serum Screen, Alpha Fetoprotein, hCG, Estriol, & Inhibin A 0080269 Method: Chemiluminescent Immunoassay	Ideal time for ordering the quad screening test is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d Screen for fetal risk of Down syndrome (trisomy 21), trisomy 18, and open neural tube defects (ONTD, i.e., spina bifida) The quad and the triple are the most economical prenatal screening tests to use Better detection rate at lower false-positive rate than the triple Best 2nd trimester screen available		If abnormal, request recalculation only if ultrasound exam reveals a due date discrepancy more than 10 days
Maternal Serum Screen, Alpha Fetoprotein, hCG, & Estriol 0080108 Method: Chemiluminescent Immunoassay	Ideal time for ordering the triple screening test is 16-18 weeks gestation; however, reference medians are available for 14w0d-24w6d Screen for fetal risk of Down syndrome (trisomy 21), trisomy 18 and open neural tube defects (ONTD, i.e., spina bifida) The quad and the triple are the most economical prenatal screening tests to use		If abnormal, request recalculation only if ultrasound exam reveals a due date discrepancy more than 10 days
Chromosome Analysis, Chorionic Villus Sampling (CVS) 0097610 Method: Giemsa-Band Analysis	Prenatal diagnosis in pregnant patient at 10-13 weeks gestation Indications include: - Advanced maternal age - Abnormal 1st trimester screen for DS or T18 - Fetal ultrasound abnormalities - Family history of chromosome abnormality or genetic disorder	Time sensitive test Higher rate of spontaneous fetal loss postprocedure than amniocentesis	Genetic counseling for abnormal results
Flourescence in Situ Hybridization, CVS 0040203 Method:	Offered in conjunction with a fetal chromosome study for 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 Irreversible therapeutic action should not be initiated on the basis of FISH results alone
Chromosome Analysis, Amniotic Fluid 0097601 Method: Giemsa-Band Analysis	Prenatal diagnosis in pregnant patient after 14 weeks gestation Indications include: - Abnormal maternal screen results for DS or T18 or ONTD - Fetal ultrasound abnormalities - Family history of chromosome abnormality or genetic disorder	Time sensitive test	Genetic counseling for abnormal results
Chromosome Analysis, Prenatal FISH 0097779 Method: Fluorescence in situ Hybridization	Offered in conjunction with a fetal chromosome study for 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 Irreversible therapeutic action should not be initiated on the basis of FISH results alone	Genetic counseling for abnormal results
Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase 0080427 Method: Chemiluminescent Immunoassay/Electrophoresis	Prenatal diagnosis in pregnant patient at 14-25 weeks gestation Indications include: - Abnormal MSAFP screen - Family history of open neural tube defects - Patient taking valproic acid or carbamazepine - Patient is an insulin-dependant 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 2nd trimester	Genetic counseling for abnormal results

Additional Information

Second trimester maternal serum screening is optimally performed at 16-18 weeks gestation, although risk estimates are given for tests performed anytime between 14 and 24 completed weeks gestation.

When specifying the gestational age at the time of the screen, use completed weeks and days. Do not round the gestational age to the nearest week because ARUP uses day-specific medians to calculate risks. It is better to use the estimated due date (EDD) than the gestational age because there are fewer clerical errors when EDD is used.

Note: Detection and false-positive rates for DS and T18 are affected strongly by the age of the women undergoing the testing. Older women would best benefit from the quad (2nd trimester) and integrated (1st trimester) tests due to their better initial positive rates. The rates listed in the table are actual initial positive rates and estimated detection rates.

Sensitivity and Initial Positive Rates for Down Syndrome
Screening Test	% DS Detection	% Initial Positive	DS cutoff
Triple	80	5.4	1/190
Quad	81	4.9	1/150
Integrated	85	1.0	1/110
Sequential	85	2.0	1/25 (1st) 1/110 (2nd)
First	85	5.0	1/230

Amniotic Fluid AChE Specificity and Sensitivity Rates for Open Neural Tube Defects (0080427: Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase)
	Specificity	Sensitivity
Open Neural Tube Defects	99.7%
Anencephaly		97%
Open Spina Bifida		99%
Abdominal Wall Defects		94%

Targeted Ultrasound Test Results Follow-Up
Test Result	Next Action
Anomaly detected on ultrasound	Confirm with follow up tests: Alpha Fetoprotein (Amniotic Fluid) with Reflex to Acetylcholinesterase 0080427 and Chromosome Analysis, Amniotic Fluid 0097601 Chromosome Analysis, Prenatal FISH 0097779 or Chromosome Analysis, Chorionic Villus Sampling (CVS) 0097610
No anomaly on ultrasound, but MSAFP MoM* >2.5	Confirm with amniotic fluid tests (Alpha Fetoprotein [Amniotic Fluid] with Reflex to Acetylcholinesterase 0080427) 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 ultrasound, but hCG MoM* >3.5	Patient is at risk for poor pregnancy outcome (preeclampsia and 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 insulin-requiring diabetes.

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

Guidelines

ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217-227. (Link to PubMed)

DoD/VA clinical practice guideline for management of uncomplicated pregnancy. Department of Defense - Federal Government Agency [U.S.]Department of Veterans Affairs - Federal Government Agency [U.S.] Veterans Health Administration - Federal Government Agency [U.S.]. 2002 Oct. Various pagings. NGC:003062. (Link to NGC)

Neural tube defects. American College of Obstetricians and Gynecologists - Medical Specialty Society. 2001 (revised 2003 Jul). 11 pages. NGC:003131. (Link to NGC)

General References

Canick JA, Kellner LH, Bombard AT. Prenatal screening for open neural tube defects. Clin Lab Med. 2003;23(2):385-94, ix. (Link to PubMed)

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005;353(19):2001-2011. (Link to PubMed)

Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen. 2003;10(2):56-104. (Link to PubMed)

Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med. 1999;341(7):461-467. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Erickson JA, 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):415-420. (Link to 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):1087-1094. (Link to PubMed)

Reviewed by

Ashwood, Edward R., M.D. Senior Vice President, Director of Laboratories and Chief Medical Officer at ARUP Laboratories; Professor of Pathology, University of Utah

Chen, Zhong , M.D. Medical Director, Cytogenetics at ARUP Laboratories; Professor, Pediatrics and Pathology, University of Utah

LaGrave, Danielle, M.S., C.G.C. Licensed Genetic Counselor, Maternal Serum Screening and Cytogenetics at ARUP Laboratories

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Comprehensive Review: November 2007
Last Update: July 2008