Prenatal Diagnosis

Question 1

What is the definition of screening?

Answer 1

The identification, among apparently healthy individuals, of those who are sufficiently at risk of a specific disorder to justify a subsequent diagnostic test or procedure

Question 2

What three criteria are needed for a screening test?

Answer 2

1. Should identify women who are at increased risk, prior to having definitive diagnostic test
2. Should be offered to all pregnant women who are considered to be only at population risk
3. Should be beneficial to those who receive it

Question 3

At what point should all mothers have amniocentesis?

Answer 3

When the risk of all diagnosable chromosomal abnormalities exceeds the reported risk of miscarriage, commonly around 35 years maternal age.

Question 4

What is used for first trimester chromosomal abnormality screening? What would be found in abnormal?

Answer 4

PaPP-A - Pregnancy-associated plasma protein A - decreased in all chromosomal abnormalities

hCG - human chorionic gonadotropin - DECREASED in all chromosomal abnormalities, but INCREASED in Down’s syndrome

Nuchal translucency - thickness behind fetus’ neck - increased in all chromosomal abnormalities

Question 5

What are the two tests for second trimester chromosomal abnormality screening?

Answer 5

1. Triple test (MSAFP, hCG, estriol)

2. Quad test (MSAFP, hCG, estriol, inhibin)

Question 6

What is MSAFP and when is it increased vs decreased?

Answer 6

Maternal Serum Alpha Feto Protein

Increased in Neural Tube Defects
Decreased in Down Syndrome

Question 7

What are typical quad test findings for a Down syndrome baby?

Answer 7

MSAFP - low
hCG - high
estriol - low (fetal-placenta unit not well intact)
inhibin - high (produced in placenta)

Question 8

What are the ultrasound findings for a baby with Down syndrome?

Answer 8

1. Nuchal translucency is increased (skin of neck separation from underlying tissue)
2. Nasal bone - reduced in length or absent
3. AV cardiac defect
4. Duodenal atresia - DOUBLE BUBBLE sign

Question 9

What is the correct series of screening / diagnostic tests for Down syndrome?

Answer 9

1. Run first trimester screening for PaPP-a, NT, hCG.
2. If results indicate Down’s syndrome -> immediate diagnostic testing. If results are negative, proceed to second trimester screening (quad test)
3. If second trimester screening is positive -> diagnostic testing

Make sure to test fetus if first semester screen was positive even if second semester was negative.

Question 10

If MSAFP is high, which is amniocentesis checking for?

Answer 10

High acetylcholinesterase, which indicates a neural tube defect.

Question 11

What does folic acid reduce the risk for?

Answer 11

Both orofacial clefting and neural tube defects

Question 12

What are potential ultrasound findings for trisomy 18 (Edward)?

Answer 12

1. Omphalocele - intestines not returning to body properly
2. Rocker bottom feet
3. Clenched hands
4. Polyhydramnios
5. Cystic hygroma
6. CNS defects or neural tube defect

Question 13

What are potential ultrasound findings for trisomy 13?

Answer 13

1. Omphalocele as well
2. Echogenic kidneys
3. Polydactyly
4. Cleft lip / palate
5. Holoprosencephaly or microcephaly

Question 14

What are potential ultrasound findings for Turner syndrome?

Answer 14

1. Cystic hygroma
2. Cardiac defects - coarctation of the aorta
3. Horseshoe kidneys
4. Hydrops - accumulation of fluid

Question 15

How does ffDNA work? Is this considered diagnostic or screening?

Answer 15

Free fatal DNA - derived primarily from syncytiotrophoblasts in the placenta, fetal DNA appears as early as 5-7 weeks and is 5-25% of circulating DNA in mother’s serum. Next generation sequencing makes detect of chromosomal abnormalities 99% of the time and requires only a blood draw.

Considered a SCREENING test. Need to confirm definitively with appropriate diagnostic procedure

Question 16

What is chorionic villous sampling, what are its two routes, and its major advantage? Disadvantage?

Answer 16

Sample the chorionic villous either transcervically or transabdominally.

Advantage: available early in pregnancy
Disadvantage: Quite difficult to do, and there may be some placental mosacism which makes it wrong

Question 17

What is the biggest fetal risk of CVS?

Answer 17

Increased risk for hemangioma

Question 18

What are the advantages and disadvantages of amniocentesis?

Answer 18

Advantage: easiest to perform, highly reliable cytogenetic results
Disadvantage: Results are not available til later (16-18 weeks), fetal trauma and Rh- blood types are at risk.

Question 19

Why is early amniocentesis (10-13 weeks) no longer done?

Answer 19

Higher rate of fetal loss, since the 20 mL of amniotic fluid needed is a larger proportion of the amniotic fluid at that time

Question 20

What is PUBS, and what are the advantages and disadvantages?

Answer 20

Percutaneous umbilical blood sampling
Advantage: Full fetal karyotyping + hamtology and serology, can assess CVS mosacism
Disadvantage: Must be done later in gestation, hardest to do, higher fetal loss

Question 21

What is the bane of prenatal diagnosis?

Answer 21

Mosaicism

Question 22

What is pseudomosaicism vs constitutional vs confined placental mosacisim?

Answer 22

Pseudomosaicism: Mutation arose during cell culture

Constitutional: Recognized in amniocentesis only, a true mosaicism of the embryo

Confined placental: Mosaicism of placenta only, encountered via chorionic villous sampling

Question 23

What two things are at higher risk when mosaicism is present?

Answer 23

1. Uniparental disomy

2. Fetal growth restriction

Question 24

What are some uncommon teratogens?

Answer 24

1. Phenytoin - epileptic drug
2. Retinoic acid - vitamin A
3. Tetracycline
4. Lithium - bipolar
5. Carbamazepine - epileptic, bipolar

Question 25

What are some infectious teratogens?

Answer 25

TORCH
Toxoplasmosis
Rubella
Cytomegalovirus

Also: Varicella

Question 26

Are pre-gestational diabetes associated with chromosomal abnormalities? What is it associated with?

Answer 26

No, but is at increased risk for major malformations, including:
Cardia anomalies
Neural tube defects
Renal anomalies
Most specific: Caudal regression syndrome

Question 27

What is caudal regression syndrome?

Answer 27

Most specific major anomaly detected with pregestational diabetes (not gestational)

Sacral agenesis / abnormal fetal development of lower spine

Question 28

What maternal hemoglobin A1c level is the threshold for congenital malformation increased risk?

Answer 28

<7%. Massive risk increase at >10%

Question 29

What does maternal obesity put the baby at risk for?

Answer 29

NTD, orofacial clefts, cardiac malformations, anorectal atresia, hydrocephaly

Question 30

When is preimplantation genetic testing used?

Answer 30

For IVF - remove 1-2 cells of trophoectoderm on blastomere

Question 31

What is preimplantation genetic screening vs diagnosis?

Answer 31

It is only considered diagnosis if the parents are known to carry a mutation or balanced chromosomal rearrangement

Question 32

When is gender selection used in IVF?

Answer 32

If there are X-linked mutations the baby is at risk of inheriting

Question 33

What is the mechanism by which maternal diabetes increases congenital malformations?

Answer 33

Hyperglycemia-induced oxidative stress

Question 34

What is the increased risk for congenital malformations with assisted reproductive technologies? Why?

Answer 34

30%!!!!

ART may interfere with epigenetic mechanisms, like imprinting of genes

Question 35

What disease has the greatest relative risk of occurring with assisted reproductive technologies?

Answer 35

Beckwith-Wiedemann Syndrome - imprinting error on chromosome 11 - sixfold increase in relative risk. An overgrowth syndrome often associated with paternal uniparental disomy