Prenatal Procedures and Diagnostic Testing

Practice questions based on prenatal procedures and diagnostic testing concepts.

When is the dating ultrasound typically done? what is the range?

8-12wks typically

6-14wks technically 

Between what gestational weeks is a Nuchal Translucency (NT) ultrasound performed?

A Nuchal Translucency (NT) ultrasound is performed specifically between 11w2d and 14w2d of gestation.

How is the NT measurement integrated with other markers for chromosomal abnormality risk assessment?

Integrated with maternal age and biochemical markers (PAPP-A and free \beta-hCG) to calculate an individualized risk assessment

What is the typical timeline for an anatomy ultrasound? What is the technical range?

Typically performed at 18-20 weeks of gestation

Can be as early as 16wk and as late as 22-24wk

What fetal structures are assessed during an anatomy ultrasound?

• Bone sizes

• Growth measurements

• Visualization of brain

• Face, etc. 

• Amniotic fluid volume

• Placental location/thickness/ and bleeding

• Umbilical cord flow

• Uteries, ovaries, and cervix

Name some conditions commonly detected by an anatomy ultrasound.

• Neural tube defects (e.g., spina bifida)

• Congenital heart defects

• kidney anomalies→ renal agenesis

• Abdominal wall defects (gastrochisis, omphalocele)

• Diaphragmatic hernia

• Limb anomalies (concerning for skeletal dysplasias)

• Severe cleft lift

• soft markers for chromosomal abnormalities → dont affect organs but seen commonly like choroid plexus cysts

Which chromosomal abnormalities are most commonly associated with an increased Nuchal Translucency (NT) measurement?

50% Down syndrome (Trisomy 21)

25% Trisomy 18 (Edwards syndrome), and Trisomy 13 (Patau syndrome)

10% turner

5% triploidy

5% Other chromosomal abnormalities

How is Turner Syndrome associated with increased NT measurements?

Often presents with significant nuchal thickening or cystic hygroma due to anomalies in the lymphatic system that can cause fluid accumulation.

What other genetic syndromes or structural defects can be indicated by an increased NT measurement?

Other genetic syndromes like Noonan syndrome, 22q11.2 deletion syndrome congenital diaphragmatic hernia, and abdominal wall defects

The degree of NT thickening typically correlates with the severity of potential underlying conditions.

What is the approximate risk for aneuploidy when an NT measurement is greater than 3.0 mm?

For an NT measurement greater than 3.0 mm, the risk for aneuploidy typically ranges from approximately 15-20%

Can be up to 50% or more for measurements exceeding 6.5 mm.

What are the screening steps recommended after an NT measurement greater than 3.0 mm?

Genetic counseling to discuss implications

offering cell-free DNA (cfDNA) screening as a further non-invasive screen

Which diagnostic tests are recommended after an NT measurement greater than 3.0 mm, especially if cfDNA is positive or there's high suspicion?

Chorionic Villus Sampling (CVS) or Amniocentesis for karyotype and/or chromosomal microarray.

What follow-up imaging is typically recommended after an NT measurement greater than 3.0 mm?

Typically a specialized fetal echocardiogram around 18-22weeks due to the increased risk of congenital heart defects

Detailed anatomy scan at 18-20 weeks to meticulously examine fetal structures

When is a fetal echocardiogram typically performed?

typically performed at 22-23 weeks

Can be done 20 weeks- 28 weeks

List some key indications for performing a fetal echocardiogram .

• Increased Nuchal Translucency (NT) measurement

• Suspected anomaly identified on a routine anatomy u/s

• Maternal diabetes (especially pre-gestational)

• a family history of congenital heart defects

• Positive cfDNA screen or diagnosed chromosomal abnormalities → down syndrome, turner syndrome

What specific cardiac issues can a fetal echocardiogram identify?

Ventricular septal defects (VSDs)

Atrial septal defects (ASDs)

hypoplastic left heart syndrome

Tetralogy of Fallot

Transposition of the great arteries.

What is the timeline for performing CVS?

Can be done 10-14 weeks of gestation.

UCI- 11w0d - 13w6d

What are the diagnostic capabilities of CVS?

Karyotyping (for chromosomal structural and numerical abnormalities)

Chromosomal microarray (for smaller deletions or duplications), Specific DNA testing for single-gene disorders, providing definitive genetic diagnosis.

What are the potential risks associated with Chorionic Villus Sampling (CVS)?

• Infection/ pregnancy loss: 1/450 risk

• Normal side effects: light spotting, cramping, abdominal tenderness, and bruising

• Confined placental mosaicism 

• Failure to obtain adequate sample which can delay results and decrease accuracy

• limb reduction defects if performed <9 weeks

What is amniocentesis, and what is its typical timing and procedure?

Typically performed after 16 weeks of gestation

• waiting for fusion of chorion and amnion (typically fuses around 14-16 weeks

What are the diagnostic capabilities of amniocentesis?

Contains fetal cells (shed from skin, urinary tract, GI tract)→ karyotyping and/or chromosomal microarray

What are the potential risks associated with an amniocentesis procedure?

Amniotic fluid leakage, infection, pregnancy loss 1/900 risk

mild vaginal spotting or bleeding, cramping, abdominal tenderness, and bruising

Missed mosaicism

Failure to obtain an adequate sample

why is the recommended window 16-20 weeks for an amniocentesis? What could happen if one was performed at 22 weeks?

Termination laws, latest is 24 weeks

if one done at 22 weeks, might not get the results on time

What are some of the risks is amniocentesis is performed in the 24-28 week period?

Could lead to very early labor resulting in very preterm

What specific types of genetic abnormalities does karyotype analysis detect?

Large-scale numerical abnormalities (aneuploidies like Trisomy 21)

Large structural rearrangements such as deletions, duplications (typically >5-10MB), translocations, and inversions.

Can detect triploidy

What is the clinical utility of detecting triploidy? What analysis can detect it?

most miscarry so imp to know

SNP microarray & karyotype

What are the limitations of karyotype analysis and its typical turnaround time?

Inability to detect small genetic changes (microdeletions/microduplications) or single-gene mutations.

Requires live & dividing cells→ products of conception may not grow, especially if SAb or IUFD then may not grow

Can miss low-level mosaicism (typically 20-25 cells, higher 35-50)

How does mosaicism detection change b/w a amniocentesis versus CVS

Amniocentesis: has some fetal cells so it is likelier to miss low-level mosaicism

CVS: only chorionic cells would miss placental mosaicism and low-level mosaicism

Can karyotypes detected unbalanced translocations? balanced translocations? What situation would this info be useful?

Balanced- if the translocation is large enough

Unbalanced- yes

Useful if parent has balanced translocation and want to see if fetus has unbalanced translocation

What is percutaneous umbilical blood sampling (PUBS) used for? what are some risks?

Can be used to dx chromosomal conditions, toxoplasmosis, Rh disease, nonimmune hydrops, and fetal thrombocytopenia

Rarely used now for genetic dx but TAT is 2-3 weeks 

Risks: infection, blood loss, premature membrane rupture 1-2/100, drop in fetal heart

What specific types of genetic abnormalities does SNP Chromosomal Microarray Analysis (CMA) detect?

Smaller submicroscopic duplications or deletions, known as copy number variants (CNVs)

Needs to be greater than 50Kb

What type of tests can be performed on CVS and amniocentesis?

• Karyotype

• microarray

• FISH (either targeted probes for specific del/dup or for common abnormalities)

• single-gene testing (targeted, common mutation panel, full-gene sequencing, and/or del/dup)

• multigene panel

• WES

• Only with Amniocentesis

  • AF-AFP

  • Fetal infection studies (PCR for CMV, toxoplasmosis)

What are the advantages of CMA over karyotype, and what are its limitations regarding balanced rearrangements?

Higher diagnostic yield for unexplained developmental disorders and congenital anomalies by detecting smaller CNVs. Does not require live cells

Cannot detect balanced translocations, only unbalanced

May miss low-level mosaicism detection is dep on size

TAT: 2-4weeks 

CMA are preferred for products of conception in most cases. What would be the exception?

If suspicious for unbalanced translocation, but want to know if parent had bal translocation or robertsonian translocation

Knowing limitations of SNP CMA for bal vs unbal translocationss. What situation might this be useful for?

If unk synd b/c it looks at a lot of genes

What type of UPD can be detected by SNP Microarray? what about triploidy?

Isodisomy detected, heterodisomy typically missed

Triploidy can be detected, but tetrapolidy may not be detected

What is the purpose and speed of Prenatal FISH (Fluorescence In Situ Hybridization) analysis?

Rapid screening NOT DIAGNOSTIC

TAT: 24-72 hours

Interphase analysis of Trisomy 21, 18, 13, X, Y)

Typically 50 cells analyzed and certain well-defined microdeletion syndromes.

How good is FISH at detecting abnormalities if: 

<10% w/ chromosomal abnormality

>60% w/ chromosomal abnormality

10-60% w/ chromosomal abnormality

<10% w/ chromosomal abnormality: Normal

>60% w/ chromosomal abnormality: Abnormal

10-60% w/ chromosomal abnormality: Uninformative

When is prenatal FISH diagnostic?

If used to detect specific familial deletion 

Rarely used

Requires lab to design probe for that region

If AF-AFP positive (>2.0 MoM), what would most labs do a reflex to?

Acetylcholinesterase (AChE)

If AChE detected→ suggests open NTD or AWD

if not detected, low risk for open NTD

When might single full-gene analysis be used clinically? Whats the TAT?

If known familial variant, like HD

TAT is 2weeks 

typically requires a positive control that is submitted w/ fetal sample

When might prenatal full-gene sequencing be used clinically? Whats the TAT?

If partner is not available and looking at a lot of possible sites/ areas that could be located to a syndro

TAT: 2-4wks

When might prenatal multigene panels be used? whats the TAT?

often ordered in context of specific fetal abnormalities

TAT; 3-4 weeks but sometimes longer

What test is ordered with or before a WES?

Microarray

What are limitations of WES?

TAT: changes for each lab, some 2 weeks, some 6-12 weeks

Insurance: may not cover, and high out of pocket cost

Specify some key indications for performing Whole Exome Sequencing (WES) in prenatal diagnostics.

Multiple fetal ultrasound anomalies that don’t point to a specific genetic disorder or group of disorders

What initial factors, regarding patient characteristics and gestational timing, should be considered when selecting prenatal genetic testing?

Maternal age, family history of genetic disorders, ethnic background (for carrier screening), and the current gestational age, as this dictates available test types.

What factors related to anomalies, invasiveness, and risks should guide the selection of prenatal genetic testing?

Selection of prenatal genetic testing should be guided by any abnormal findings on routine ultrasound (e.g., increased NT, structural anomalies), and the balance between the diagnostic accuracy of invasive procedures (CVS, amniocentesis) vs. their associated risks and the non-invasive nature of screening tests.

What should be considered when selecting CVS vs Amniocentesis?

What is the indication of testing→ cfDNA? u/s? specific conditions on differential?

What evaluations the patient had previously?→ cf DNA results?

Whats the patients gestational age? → TAT for karyotype vs microarray

What does the patient plan to use the information for?→ possibly for termination

Insurance→ authorizations, out of pocket cost