Exam 2: Lecture 35

Question 1

What is prenatal testing?

Answer 1

• pregnancy- specific risk assessment
• 3-5% chance regardless of family history

Question 2

Why prenatal testing goals?

Answer 2

• expectant maanagement (Grief, family time to prepare)
• may considere options for terminations or adoption
• shoudl balance ethical principles of autonomy and distributive justice in terms of patient backgroun and test cost

Question 3

Prenatal Testing Recommendations

Answer 3

• prenatal testing should be offered to ALL pregnant people early in pregnancy.. like the first visit –> regardless of age or prior risk (aneuploidy screenings)

Question 4

List reasons for testing/ referals

Answer 4

• trisomy increases with maternal age
• microdeletions is not associated with maternal age
• reason for testing: single gene disorder, environmental agents, or multifactorial etiology: combo of genetics and environment

Question 5

Prenatal vs Postnatal diagnnosis

Answer 5

• can have inutero intervention
• may influence neonatal team approach
  pallative care consultation
• delivery location and planning
• adoption vs psychological preparation

Question 6

Multifactorial: open neural tube defects

Answer 6

• abnormal closing of neural tube
• typically completed by the end of gestational week 4
• spectrum diagnosis: spinal bifida with or without myelomeningocele, anencephaly, encephalocele, prognosis dependent on location and size of lesion
• no genetic test for it

Question 7

Aneuploidy Screening

Answer 7

• identifying who is at high risk
• can be applied to anyone and should be offered to ALL

Question 8

Screening test of aneuploidy with Maternal Info

Answer 8

• calculation using maternal factors: maternal age, prior history of aneuploidy, weight, and number of fetuses

Question 9

First Trimester Screening for aneuploidy

Answer 9

• first trimester US ( Pregnancy dating, # of fetuses, nuchal translucency, fetal nasal bone)
• NB–> absence is associated with aneuploidy
• NT –> specific measurement–> too much is abnormal

Question 10

2ND Trimester US

Answer 10

• Recommended fetal anatomy (18-20 wks)
• cannot detect 100% anomalies

Question 11

US findings in Aneuploidy

Answer 11

• 50% sensitive with down syndrome
• major structural abnormalities: cardiac anomalies ( septal defects, tetralogy of fallot, and atrioventricular canal defects)
• duodenal atresia (double bubble sign in the abdomen)
• minor sonographic “soft markers” (may come and go during the pregnancy): echogenic bowel, intracardiac focus, absent fetal nasal bone, short long bones
• > 90% sensitivity for Trisomy 13, 18, ONTDs
• dependent on maternal habitus, fetal position, etc. (how much body is there between fetus and transducer on the belly)

Question 12

Screening Test results

Answer 12

• low risk result or high risk result
• never diagnostic or zero risk

Question 13

First trimester biochemical screening (10-13.6 wks)

Answer 13

• cell free DNA
• SERUM FREE BETA hcg
• Total human chorionic gonadotropin (hCG)
• pregnancy-associated plasma protein A
• nuchal translucency measurement
• can give you risk for Trisomy 21, 18, and maybe 13

Question 14

2nd trimester serum analytes

Answer 14

• Quad screen
• produced by fetus and placenta
• certain patterns represents different risks
• poor dates can result in reports of down syndrome (less pregnant than expected)

Question 15

What does a quad screen measure?

Answer 15

• alpha- fetoprotein (detectable in 6 wks; peak levels in 12-14 wks)
• Human chorionic gonadotrophin (hCG) (Placenta)
  -Unconjugated estradiol
• Dimeric Inhibin A (placenta)

Question 16

What patterns are associated with increased/decreased alpha-fetoprotein?

Answer 16

• elevated in neural tube defects
• decreased in fetal down syndrome

Question 17

What patterns are associated with increased hCG?

Answer 17

• increased in fetal down syndrome

Question 18

What patterns are associated with decreased unconjugated estradiol(uE3)?

Answer 18

• decreased in pregnancy affected by fetal down syndrome

Question 19

What patterns are associated with increased dimeric inhibin A?

Answer 19

• FETAL DOWN SYNDROME

Question 20

What patterns can you see with down syndrome, trisomy 18, neural tube defects/omphalocele, and undiagnosed twins?

Answer 20

• down syndrome: AFP- LOW , UE3-LOW, hCG- HIGH, Inhibin- HIGH
• Trisomy 18: AFP- LOW , UE3- LOW, hCG- LOW, Inhibin- N/A
• neural tube defect/omphalocele: AFP- HIGH , UE3- N/A, hCG-N/A, Inhibin-NA
• undiagnosed twins: AFP- HIGH , UE3- HIGH, hCG- HIGH, Inhibin- HIGH

Question 21

Types of Aneuploudy screening

Answer 21

-

Question 22

Cell-free DNA (cfDNA) screening

Answer 22

• trisomy 21, 18, 13
• sex chromosome aneuploidies
• select chromosomal microdeletion syndromes like DiGeorge or Velocardiofacial
• select single gene conditions

Question 23

How does cDNA work?

Answer 23

• DNA derived from apoptotic cells
• floating in plasma
• in pregnancy, certain portion from trophoblastic cells ( placenta)
• not a diagnostic test
• can use in general risk population
• 10 weeks gestation to term
• 3-13% of cfDNA from placenta
• false negative: may result from low “fetal” fraction –> maternal obesity has highest association with low fetal fraction… diluted
• false positives: may result from confined placental mosaicism–> usually placenta has the same complement as the fetus, but 1-2% cases may have abnormality that does not represent the fetus

Question 24

cfDNA screening for microdeletion and single gene changes

Answer 24

• Recommendation: 22q11.2 deletion syndrome should be offered to all patients
• fetal RBC antigen genotyping–> for RhD (immuno-globulin); negative and negative will not need Rhogam

Question 25

Prenatal diagnostic testing

Answer 25

- defined as a medical test performed to aid in the detection of a suspected disease or condition -invasive - chorionic villus sampling (CVS) amniocenteses - fetal blood sampling (PUBS)

Question 26

Chorionic Villus Sampling (CVS)

Answer 26

- 10-13 weeks gestation - if earlier, will have limb reduction defects - placental villi via transcervical (flexible catheter) or transabdominal placental access (needle) - tissue aspiration--> negative pressure with a syringe - transcervical: anterior placenta - abdominal: anterior placenta

Question 27

Amniocentesis

Answer 27

- usually between 15-20 weeks - cells cultured and analyzed - cytogenetic results highly reliable - disadvantage: many results take 2-4 weeks (timing is important... if you'd like to abort) - find pocket of amniotic fluid, away from fetal parts and umbilical cord - use needle to collect fluid ( get rid of first mm because it may be mom's)

Question 28

Percutaneous Umbilical Blood Sampling (PUBS)

Answer 28

- US guided sampling from fetal umbilical vessel--> usually when you could not get anything from the other two - advantages: able to perform fetal hematology and serology; utility in assessing CVS mosaicism - disadvantages: 1-2% fetal loss risk; later in gestation >18 weeks - FEWER PRACTITIONERS PERFORM THIS

Question 29

Prenatal diagnostic lab test

Answer 29

- FISH--> quick assessment of common aneuploidies (13, 18, 21, X, Y) - Chromosomal analysis - chromosomal microarray - single gene or known familial variant testing - prenatal whole exome (goal: look at all of the genes, 95%-- for suspicion of muti-system diseases) - pre-implantation genetic diagnosis

Question 30

Chromosomal microarray and fetal anomalies

Answer 30

- patient and reference DNA hybridized to assess gains and losses (specific locations) - highest detection rates for isolated: cerebella hypoplasia, holoprosencephaly, club feet or hands, skeletal anomalies - specific anomalies seen with anomalies in other organ systems, highest detection rates were: hypoplastic left heart, posterior fossa defects, tetralogy of fallot, cystic hygroma - is not diagnostic!!

Question 31

Prenatal whole Exome sequencing

Answer 31

- pulling every book that tells you how to make a product or a cookbook.... scanning cover to cover - need pre and post test counseling

Question 32

Prenatal genetic carrier testing

Answer 32

- preconception screening is ideal vs prenatal - autosomal recessive and x linked conditions - if patient is a carrier, test partner if applicable - no need to re-screen genes in later pregnancies unless aneuploidies

Question 33

Carrier screening recommendations

Answer 33

- cystic fibrosis, spinal muscular atrophy, hemoglobin electrophoresis - fragile x for people with history of ovarian insufficiency - based on fam history or ethnicity - screen regardless of ethnicity

Answer 34

1:200 carrier frequency--> offer to everyone (tier 3 screening)

Question 35

Genetic counseling and decision making

Answer 35

- pre- and post test counseling - individualized risk assessment of conditions of concern - post-test: interpretation of results - residual risk--> - difference between genotype vs phenotype --. cannot use genomic results as a crystal ball to predict the future