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Final Review GC > Prenatal > Flashcards

Prenatal Flashcards

1
Q

HOW DO SERUM SCREENS WORK?

What do they measure?

What do they screen for?

What does a +VE test mean?

A

Serum screens measure non-DNA based information:

  • Proteins
  • Hormones

Various screens may include screening for:

  • Down syndrome
  • Trisomy 18
  • Open Neural Tube Defects

+ve is only a risk estimate (many women with increased risk will not have affected babies)

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2
Q

How is serum screening reported?

What is the standard value used?

A

MoM = Multiple of the median

Raw value

Median for the pt’s gestational age

  • Varies with gestational age, assay, and population tested
  • 1.0 MoM used as standard
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3
Q

What the origin of tested analytes?

A

Fetal origin

  • AFP (made by liver, pumped out by kidneys)
  • uE3 (in cholesterol synthesis pathway)- The fetal adrenal gland secretes dehydroepiandrosterone-sulfate (DHEAS), which is converted to E3 in the placenta and diffuses into the maternal circulation.

Placental Origin

PAPP-A,

hCG,

DIA,

ITA

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4
Q

Typical Patterns of Ist trimester:

A

Typical

PAPP-A: 1.0 MoM

bhCG: 1.0 MoM

NT 1.5mm

Down sx example

PAPP-A: 0.43 MoM -> low

bhCG: 1.98 MoM -> high

NT: 3mm. -> high

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5
Q

Typical Patterns of the 2nd Trimester :

A

Typical

AFP: 1.0 MoM

hCG: 1.0 MoM

uE3: 1.0 MoM

DIA: 1.0 MoM

Down sx

AFP: 0.74 MoM. -> low

hCG: 2.06 MoM -> high

uE3: 0.75 MoM -> low

DIA: 1.77 MoM -> high

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6
Q

What important intake should we check before reporting the results to the pt in addition to the analytes values?

A

INFO that can IMPACT RISK ESTIMATE:

Key information

1- Age

2- Gestational age (second-trimester screens)

3- Race

4- Diabetic status

5- # fetuses

6- Weight

7- Prior history DS, NTD, T18

8- Analyte values

9- Review NT results

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7
Q

Different Factors and Calculating Serum Screen
Factors with major weight
Factors with less weight

A

Factors with most weight in algorithm:

1- A priori risk (maternal age)

2- Specific analyte values

  • How far from median is each one
  • MUST be compared against same week in gestation reference point to be accurate

3- Ultrasound NT measurement if first trimester screen

Factors that influence, but less so

1- Ethnicity

2- Weight

3- Diabetic status

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8
Q

What is the importance of Gestational Age?

How do analytes levels change through 2nd Trimester?

AFP

uE3

hCG

Inhibin

A

A- Check gestational age

  • # 1 reason for abnormal results if no prior scan
  • Ask patient how due date was determined
  • FIRST TRIMESTER SCREENING INCLUDES GESTATIONAL AGE SO WILL NOT CHANGE

B- Medians for analytes vary throughout pregnancy

Second-trimester screening

  • AFP increases by ~15%/wk
  • uE3 increases by ~25%/wk
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9
Q

How do other factors affect interpretation?

  • Ethnicity, give an example? Which ethnicity has higher average values of AFP? what cut-off measure do labs apply to them?
  • Maternal Weight, how do analytes behave? are the cut-off levels adjusted according to weight?
  • Pregestational Diabetes - how do different analytes behave in diabetes? are cut-off levels are adjusted?
  • Mode of Conception (Natural vs IVF), how do analytes behave in IVF? are the cut-off levels adjusted?
A

A- Ethnicity

  • Higher MSAFP average value for African Americans
  • Some labs use a 2.8 cut-off, others adjust

B- Maternal Weight

  • Diffusion versus concentration based on mother’s blood volume
  • Decreased in heavier women, increased in lighter women
  • All MoMs adjusted

C- Pregestational Diabetes

  • AFP, uE3, and DIA values to be lower in diabetic pregnancies
  • Most labs tend to use lower cut-off (ex. AFP cut-off of 2.0 MoM)
  • Also have a higher background risk of ONTD if diabetic

D- Mode of Conception (Natural vs IVF)

  • hCG levels tend to be higher while uE3 levels are lower
  • Generally not adjusted for in calculation
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10
Q

What to do when you have incorrect screens?

When to recalculate? When not to recalculate?

When to repeat? When not to repeat?

A

A- Recalculate

  • Wrong dates (more than 10 days difference)
  • except Do NOT recalculate for dates if positive for T18
  • Wrong demographic and pregnancy information

B- Repeat

  • Do not repeat screens that have an NT measurement
  • Do not repeat a Down syndrome screen (unless original test uninterpretable)
  • Do not repeat a T18 screen (no exceptions!)
  • CAN REPEAT a +VE ONTD screen with a borderline value
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11
Q

What is regression to the mean?

A

In statistics, regression toward (or to) the mean is the phenomenon that if a variable is extreme on its first measurement, it will tend to be closer to the average on its second measurement

And if it is extreme on its second measurement, it will tend to have been closer to the average on its first.

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12
Q

Timeline of screening options

cfDNA

FTS

NT

Anatomy scan

CVS

Amnio

A

cfDNA -> by or > week 10
FTS -> 10- 13w6d
Quad -> 15-20w.6d

NT U/S screen -> 11- 14 ws
Anatomy scan -> 16-22 ws

CVS. -> 11- 14 ws
Amnio -> 16-22 ws

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13
Q

First Trimester

A
  • NIPT by 10th week
  • OTHER
  • FTS
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14
Q

FTS

GA

Analytes -> source, function

A

11w-13w6d*

  • analytes –> 10w0d-13w6d;
  • NT –> 11w0d-13w6d

PAPP-A

  • Glycoprotein produced by the placenta
  • Thought to be involved in local proliferative processes (ex. wound healing and bone remodeling)

Only useful in first trimester

βhCG

  • Dimeric (α and β subunits) glycoprotein produced by the fertilized ovum and then the placenta
  • Rises early in pregnancy, peaks by 10th wk, then decreases
  • β Subunit more accurate than whole molecule

NT

  • Measurement by ultrasound
  • 11w0d to 13w6d, CRL 45-84 mm
  • By certified provider for accuracy
  • Over 3.0 mm automatic problem, otherwise used in FTS equation
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15
Q

Abnormal FTS

Detection rate for DS and Tri 18

A
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16
Q

Stepwise Sequential

A

1st trimester

PAPPA + bhCG

NT

  • If <1 in 50 risk DS –>

2nd-trimester analytes: hCG, uE3, DIA

  • < 1in 270 risk

Screen Negative

  • If > 1/270 risk -> Screen Positive. -> Genetic Counseling offer further screening and diagnostic options
  • If > 1 in 50 risk DS

Screen positive

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17
Q

Contingent

A

1st trimester

PAPPA + bhCG

NT

  • If <1 in 300

Screen Negative

  • If a Borderline risk -> (between 1/50 and 1/300)

2nd-trimester analytes: hCG, uE3, DIA, AFP ->

*if < 1in 270 risk ->

Screen Negative

  • If > 1/270 risk -> Screen Positive -> Genetic Counseling, possible amnio or NIPT
  • If > 1in 50 risk DS ->

Screen positive -> Genetic Counseling, possible CVS or amnio or NIPT

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18
Q

Second Trimester Screening

How many analytes mention each, produced by, specific to

A

15w0d-20w6d

AFP

  • Glycoprotein produced by fetal GI tract and liver; pumped out by kidneys
  • Only analyte used in Open Neural Tube Defect Screening

hCG

  • Placental origin; good marker for placental function
  • Falls in second trimester

uE3

  • Estrogen hormone involved in cholesterol pathway
  • Precursor from fetal adrenal glands
  • Rises with growth of fetus

DIA

  • Glycoprotein hormone produced by the ovaries and placenta
  • Single best marker for DS; stable levels in second trimester

hhCG

  • Hyperglycosylated hCG (hhCG ) = invasive trophoblastic antigen (ITA)
  • Marked by Quest; no prospective studies showing increased efficacy
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19
Q

Abnormal Quad or Tetra

A
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20
Q 
ONTD Screening
What test do we use?
When is test positive?
When is it recommended to repeat the test?
What is the detection rate?
How the result is presented?
What is the relationship between test MOM and the severity?
What does it indicate?
A
  • Significantly increased AFP levels
  • 2.5 to 3.0 MoM as gray zone, may recommend repeat
  • 3.0+ MoM as automatic screen positive
  • Detection rates 80-90% for ONTDs
  • Presented as a risk figure
  • Greater MoM value, increased concern
  • Indicates

– Opening somewhere or

– cause of change in concentration somewhere

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21
Q

INCREASED AFP

A

CONCENTRATION PROBLEMS

  • Kidney Concerns (agenesis, cystic, oligo-hydramnios)
  • Placental Bleed, Pl insuffeciency
  • Multiples

Other

Wrong dates

Adverse Outcome -> IUFD

Maternal Malignancy

Normal Variation

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22
Q

INCREASED AFP 2

% of sensitivity for open spina bifida

% of sensitivity for anencephaly

A

70-85% sensitive for open spina bifida; >95% for anencephaly

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23
Q

Values of abnormal AFP

NTDs

A
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24
Q

Extreme AFP Elevations

What are the causes of extreme elevations?

When to suspect Congenital Finnish Nephrosis?

What is the anomaly?

How does show on U/S?

inheritance & progression

A

Maternal Liver Anomaly

Congenital Finnish Nephrosis

  • Suspected with significantly elevated MSAFP with extremely high AFAFP (>10 MoM) and negative ACHE
  • Abnormal renal tubule development with a normal appearance on ultrasound
  • “Lethal” condition

Genetic testing available (AR inheritance)

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25
Q

What to do when ONTD screen is abnormal?

What to do when the level is between 2.5-2.9? why?

How AChE is tested?

What will you target on The U/S?

A

I. Perform targeted ultrasound

– Confirm GA

– Rule out multiple gestations or fetal demise

– Observe fetal head and spine for defects

II. Amniocentesis to obtain amniotic fluid

  • Measure AF-AFP
  • Qualitative detection of acetylcholinesterase (AChE) -> Electrophoretic detection is 98% sensitive and >99% specific for ONTD

III. If AFP MoM 2.5 – 2.9 then may repeat screen from a new specimen to sort out false-positive results

– ~40%of false +VE become true-VE

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26
Q

When to repeat AFP test?

A

Okay to repeat if sample collected

  • at <11 weeks (1st tri) or
  • <14 weeks (2nd tri)
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27
Q

Aneuploidy screening: Multiple gestations

can be used for how many fetuses

How to screen for triplets?

What are the detection rates for 21 and 18? FTS/ QUAD

NTD detection rate

A

Twins only

  • no higher-order multiples
  • NT only for triplets, quads, etc

Adjusted MoM ->extrapolated risk for DS

Lower detection rates

FTS

  • DS: 70-89%
  • T18/T13: ?

Quad

  • DS: 50-63%
  • Tri 18: Insufficient data
  • NTD: 58%
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28
Q

Why is screening not as good with twins?

A
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29
Q

Aneuploidy Screening -Twins

Risk for dizygotic twins

Risk for monozygotic twins

Will the risk be provided to the whole pregnancy or to individual fetuses?

What kind of MSS is available for twins?

What to do if there is one twin’s demise?

A

Dizygotic twins

  • 2 different karyotypes -> each carries a risk similar to the mother’s adjusted risk
  • Increase in overall risk for aneuploidy

Monozygotic twins

Similar Karyotype

Risk is similar to the adjusted mother’s risk for a singleton

o The provided risks are for the whole pregnancy and not each individual fetus.

o First trimester, quad, and combined -> are all available for twin pregnancy.

o If a fetal demise or congenital abnormality in one gestation -> MSS should be

discouraged –> Pt is to be counseled and offered Dx testing.

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30
Q

Abnormal MSS and Adverse Pregnancy Outcomes

What is the relationship between the serum markers, placenta and pregnancy outcome?

A

Significant associations between serum markers and adverse obstetric outcomes

  • Markers are created by the placenta (mainly syncytiotrophoblast)
  • Several factors determine how these markers cross into the maternal bloodstream
  • Extreme analyte variations can reflect on the function of the placenta

Fetuses with aneuploidy may have funky placentas…

Analyte values are not diagnostic

  • Sensitivity and PPV too low
  • Most likely cause: normal variation
31
Q

Low MarkersuE3

uE3 special concerns

A

uE3 <0.5MoM

  • LBW (OR 1.79)
  • fetal loss before 24 weeks (OR 7.00)
  • *special concerns if <0.15 -> A serum uE3 <0.15 multiples of the gestational age median in women, who otherwise screen negative in the quad test, can indicate Smith-Lemli-Opitz syndrome and X-linked ichthyosis and contiguous gene syndrome (placental sulfatase deficiency disorders)
  • aromatase deficiency, and primary or secondary fetal adrenal insufficiency.
32
Q

Very low/Undetectable uE3

Cut- off level

Causes

A

Typically considered <0.15 MoM

  • Centers may use <0.25 or as low as <0.10

Deficient production of a precursor hormone by the fetal adrenal gland

  • Fetal Adrenal Hypoplasia
  • Anencephaly (AFP should also be ↑)

Deficient cholesterol synthesis

  • Smith Lemli Opitz
  • Antley Bixler syndrome

Deficient placental sulfatase activity

  • X-linked ichthyosis (steroid sulfatase deficiency)
33
Q

Antenatal Screening

When to perform?

What does it include?

A

Begin in the third trimester (after 28 weeks)

NST = non stress test

  • Monitor of fetal heart rate by external monitor
  • Monitor fetal movement & correlate to accelerations in heart rate

BPP = biophysical profile

  • Ultrasound
  • Measure (get up to 2 points for each)

1- Breathing (rhythmic breathing for 30 sec)

2- Movement/kicking (>3 in 30 min)

3- Tone (>1 flex/extension of limb or hand)

4- AFI (amniotic fluid index no less than 10 or one pocket 2)

5- +/- score from NST for either 8/8 or 10/10 score

Uterine Doppler Flow Studies

Evaluate changes in sound waves to determine direction and velocity of blood flowing through fetal vesse

34
Q

Screening performance

Let’s put them all togethe

A

Sensitivity = TP

TP +FN

Specificity = TN

TN+FP

PPV =. TP

TP+FP

FN Rate = FN

TP+FN

FP rate = FP

TN+FP

35
Q

What is cfDNA?

Description

What is formed of?

What is the source of the fetal cfDNA?

what is its %?

When can it be reliably detected? and what is its % by this time?

When it can be 1st detected?

What is the least detectable value?

When does it disappear?

A

o Short DNA fragments within the maternal blood, each segment is 150-200 bp

o Both maternal and fetal DNA are represented.

o Fetal DNA is:

  • Released from the placenta
  • constitute 3-20% of the total cfDNA in maternal blood
  • Reliably detected after 10 weeks (After 9 weeks Fetal DNA ACCOUNTS FOR 10% of all DNA in the plasma with a range of 4-20%)
  • Detectable after 7 weeks GA - It increases throughout the gestation
  • Disappears in hours post-partum.
  • Most studies require at least a 4% fetal fraction
36
Q

NIPS Techniques

Describe the three common techniques

What can and cannot the SNP technique detect?

A
  1. Massive Parallel Sequencing – Next Gen sequencing
    a. Amplified DNA pieces -> are tagged to know which chromosome they belong to -> count them.
    b. The whole genome is covered which increase sensitivity and specificity.
  2. Single Nucleotide Polymorphism SNP
    a. Differentiate between maternal and fetal DNA
    b. Number of informative SNPs differ in each pregnancy depending on the mother and the father genotypes
    c. Selective sequencing of loci for only chromosomes under investigation
    d. Poorly suited to consanguineous couples.
  3. Microarray Based NIPT:

Only to gather signals from custom probes. Specifically designed for NIPT that tiles the chromosome of interest

SNP can detect:

  • Aneuploidy for the two fetuses in twin pregnancy
  • used for surrogates and egg donor pregnancies
  • Triploidy and vanished twin

CAN NOT be used for :

  • Higher order multiples
  • Consanguinity
  • Hx of BM transplant
37
Q

ACMG

A

1- Informing all women that NIPS is the most sensitive screening option for screened aneuploidies (T21,13,18)

2- Referring patients with NIPS reported increased risk to a genetic professional

3- Offering Dx testing when +ve results are reported.

4- Provide balanced accurate up to date info at appropriate literacy when the fetus is dx with abnormality

5- The purpose is to educate the parents about the condition- cover both medical and psychosocial aspects

6- Laboratories should provide clearly stated:

–DR

–SPEC,

–PPV,

–NPV

for the screened conditions

7- Laboratorie should not offer screening for T21,18, or 13 if they cannot provide the above-mentioned values

38
Q

What conditions does NIPT screen for?

A
39
Q

NIPT and microdeletions

Mention the 5 most common detected CNVs?

A
40
Q

Limitations of NIPS

A
41
Q

Confined Placental Mosaicism

A
42
Q

Confined Placental Mosaicism, Mitotic vs meiotic

A
43
Q

Implications of CPM
What can it be associated with?
When CPM is seen in cvs, what is he possibility that it affect the fetus?
When. to consider amnio if CPM is detected in cvs?

A

a. Mosaic placenta can be associated with -> unfavored pregnancy outcomes e.g., SAB, IUGR, IUFD and preterm delivery.
b. Trisomy rescue can result

–in uniparental disomy. Imprinting effects (e.g. Prader Willi and Angelman syndrome associated with maternal and paternal UPD15)

c. When mosaicism is seen in the placenta (by CVS) –> it is most often confined to the placenta
d. The potential need for additional procedures

–Consider amnio for +VE Tri 13 and monosomy X

44
Q

What to do when +ve. NIPT?

During 1st trimester

During 2nd trimester

Why amnio is superior to CVS?

What is the drawback of amnio

A
  • cfDNA sequencing is superior to US, MSS
  • A +ve cfDNA screening -> should be confirmed by dx testing.
  • If +ve results during 1st trimester ->

o If tri 21 or 18 -> CVS -> there is 1-2% caveat for inconclusive results.

o If tri 13 or mono X with no US abnormalities -> preferably amnio -> to avoid CPM and associated false +ve results.

o Amnio is still a superior test for all aneuploidies

  • Analysis of amniocytes (more representative of the fetus) is superior to chorionic villi -> there could be a discrepancy between the trophoblasts and the pregnancy.
  • Mosaicism is much rarer in amniocyte
  • In some instances, however, -> waiting for the 15th week- > can be stressful to the couple and can delay dx.

CVS (11-14 ws) Drawbacks

  • False +ve due to CPM type iii
  • False -ve due to TFM type v if only trophoblasts were tested.
  • Amnio could be required to confirm the dx.
45
Q

What are the reasons for no call results?

A
  • Intrinsic increased risk for aneuploidy -> mainly triploidy and DS –> Warrants further evaluation
  • Maternal Obesity -> Low fetal fraction-> Active remodeling of adipose tissue in pregnant women with obesity results in an increased release of cfDNA of maternal origin
46
Q

How to manage no calls?

What is the average fetal fraction level in maternal bld between 9-19ws?

Will you repeat the test? why?

What is the least reported cfDNA with a result?

What does ACMG recommend?

What will you offer?

A
  • By 9-19 week -> fetal fraction % in maternal blood is ~10% (2-20%).
  • Don’t repeat the test: There is slight increase ->0.1% per week -> 10-21 weeks -> challenges the idea of repeating the test.
  • Significant increase after the 21st week -> 1% / week
  • Least reported cfDNA levels at which results were obtained is 4%
  • ACMG recommends that
  • labs report fetal fraction and not
  • to repeat the test
  • Offer Dx testing
47
Q

alculate Positive Predictive Value (PPV)

Definition

What variables PPV is dependent on?

When PPV is expected to be high?

What does Priori risk depend on?

A
  • Defined as the proportion of +ve results that are true positives.
  • Answers the question “what is the chance that abnormal cfDNA means the fetus has this condition?”
  • It depends on variables -> it’s a relative and not an absolute value.
  • It is dependent on the

o sensitivity and specificity of the test,

o prevalence of the condition (which varies from patient to patient with aneuploid)

· PPV will be higher in cases of higher prevalence –>+higher priori risk

· Priori risk is the risk before having the test.

· Priori risk depends on

–what is the condition,

–maternal age,

–GA,

–US,

–FH

o PPV= TP/TP+FP (all recorded +ves)

48
Q

NPV
Sensitivity- what does sensitivity assess?
Specificity-What does specificity assess?

A

o NPV= TN/TN+FN (all detected -ves)

o Sensitivity = TP/ TP+FN (all supposedly true +ve)

o Sensitivity / assesses how the test performs on the affected people in a target population.

o Specificity= TN/ TN+FP (All supposedly true-ve)

o Specificity assesses how the test performs on the unaffected people in a target population

49
Q

PPV calculator

Which calculator do we use?

What is included as default?

Why is the same data not included for CNVs?

In which aneuploidy, the maternal age has no impact?

What other factors can be of more importance than prevalence in some cases?

What are key points in testing cfDNA?

A

o NSGC website

o Sensitivity and specificity based on metanalysis and are included as default data.

o There is an option to enter lab-specific values of S&S.

o Default S&S are not available for CNV -> lack of metanalysis data

o Calculation utilizes Trisomy incidence at GA of 16th week.

o In monosomy X and CNV -> maternal age has no impact.

o The prevalence defaults may not be the best estimates for individual patient -> other factors can influence the priori risk :

  • US findings
  • Results of MSS
  • Personal or family hx of aneuploidy

Key points for cfDNA testing:

> > Sensitivity and specificity are important pretest info

> > PPV calculation is critical after +ve test results.

> > PPV is relative -> giving a figure depends on personalized risk assessment

> > Estimates provided by Labs based on age only may be falsely reassuring or falsely alarming

50
Q

Pre-Test Genetic Counseling

What are the main points you will discuss with pt?

When is cfDNA is not the test of choice?

A
  • Benefits
  • No risk
  • Highest detection rate of current screens

•

  • Limitations
  • Rare cytogenetic abnormalities are NOT detected
  • Microdeletions not routinely detected (screening on some assays) & PPV is low
  • May not be appropriate for multiple congenital anomalies or other indications
  • False reassurance
  • Possibility of no result or discordant result

•

•Is there time for a procedure post-results if necessary?

Termination not recommended based on screening

51
Q

Post Test Genetic Counseling

A
  • Analysis of negative results
  • Correlation to clinical information
  • Comparison of fetal sex to ultrasound
  • Discussion of abnormal results
  • Prenatal or postnatal confirmation of results
  • Correlation to clinical information (ultrasound abnormalities etc)
  • Follow up testing?
  • Parental chromosomes
  • CVS / amniocentesis

.Postnatal testing

52
Q

cfDNA for sex chromosomes aneuploidy

What is the overall PPV for sex chromosomes? What are the reasons?

What is the PPV for TS?

What can cause FP results of SCA?

A

There is limited data on test performance in SCAs

  • Overall PPV is ~50%
  • PPV in monosomy X is lower -> 20-30%
  • Reasons for the decreased PPV

o False -ve results cannot be determined -> Most children born with SCA do not have clinical features –> the number of newborns affected with an SCA that are missed by NIPT cannot be determined.

o False +ve results can be attributed to maternal X chromosome aneuploidy or CNV

  • There are professional concerns that encourage early dx of TS and Klinefelter

o Allows timely management of hormonal manifestations & associated structural abnormalities.

53
Q

Causes of false +ve cfDNA for monosomy X

What is the most common cause?

A
  1. Confined placental mosaicism -> one main reason.
  2. Cotwin demise (Vanishing Twin) with monosomy X, also ->
    a. the vanished twin DNA can be detected in the maternal serum. -> May be ~8 weeks.
    b. SNP based NIPT technique -> allows the detection of vanished twin haplotypes
  3. Maternal mosaicism which could be:
    a. Somatic loss of single X chromosome
    b. Mathers who are constitutionally mosaic -> 45, X/ 46, XX and fertile
54
Q

What to do after positive cfDNA for monosomy X?

A

1- dx testing

2- Follow up with Echo -> cardiac defects

3- Referral to pediatric Cardiologist

4- Ensure post-natal Karyotype or CMA

5- Advise to follow up for structural anomalies which include:

  • Renal US
  • Testing for hypothyroidism
  • Audiology ->Conductive or SNHL
  • Initiation of GH tx at age 4-6ys
55
Q

Fetal sex discordance

If US + Karyotype -> male / cfDNA -> female

A

If US + Karyotype -> male

cfDNA -> female

  1. Cotwin female demise
  2. Decreased fetal fraction
  3. Placental mosaicism -> 46, XX / 46, XY or 45, X/ 46, XY
56
Q

Fetal sex discordance

If US + Karyotype -> female / cfDNA -> male

A

If US + Karyotype -> female

cfDNA -> male

  1. Cotwin male demise
  2. Transplantation to the mother from a male donor -> organ or blood
  3. Placental 46XY/XX mosaicism
57
Q

Fetal sex discordance

If cfDNA + Karyotype -> female/ US -> male

A

If cfDNA + Karyotype -> female

US -> male

  1. XX male -> translocation of SRY gene on short arm of Y
  2. CAH, androgen producing tumors, exogenous androgens
58
Q

Fetal sex discordance

If Karyotype +cfDNA -> male / US -> female

A

If Karyotype +cfDNA -> male

US -> female

  1. Smith Lemli Opitz

Mutations in several sex development genes.

59
Q

Maternal causes of false +ve cfDNA results

A

Maternal constitutional or acquired genomic alterations

  • Maternal 47, XXX-> false +ve triple X
  • Age related loss of maternal sex chromosome -> False +ve monosomy X

Maternal malignancies

  • Can result -> whole chromosome / segmental gain or losses
  • Malignancies also release cfDNA into maternal circulation -> false +ve results
  • Very abnormal pattern - high risk for 2 chromosomes is suspicious

Maternal disease (non-malignant)

  • Uterine fibroids
  • Systemic Lupus
  • Severe maternal Vit B12 deficiency

Benign maternal de novo or inherited duplications or deletions

60
Q

Causes of false -ve cfDNA results

A

1- Decreased fetal fraction -> most common cause ->

causes of decreased ff include:

a. High maternal BMI-> increased adipose tissue-> increase release of maternal DNA.
b. Early gestational Age
c. Maternal anticoagulation therapy

2- Inadequate storage of the sample -> hydrolysis

3- Theoretically-> a vanished twin with normal DNA-> may mask a living fetus with aneuploidy

4- Maternal deletion on a target chromosome -> false -ve results of a fetus w/ a trisomy.

61
Q

Increased nuchal thickness

When it can be measured?

What is the cut-off measurement? why was it chosen?

What is the correlation between the measurement and the severity?\

Causes

What is the risk of fetal demise?

When can the outcome of pregnancy with increased NT be normal?

A

▪ Weeks 11-14

▪ 95th percentile 3.0mm

▪ The larger the measurement, the greater the likelihood of anomaly

Causes

▪ Chromosome abnormality

50% trisomy 21,

25% trisomy 13/18,

10% turner,

10% other

▪ Congenital heart disease – when 3.5mm or greater, 22.5x general population risk

▪ Single gene conditions, other anatomic anomalies

▪ Risk of fetal demise 5X (does not correlate with size)

When can the outcome of pregnancy be normal?

  • normal chromosomes and
  • normal 19week U/S and
  • Normal echo,
  • plus regression of NT,

up to 95% chance normal pregnancy outcome

62
Q

Abnormal nuchal translucency residual risk after normal cfDNA

A

Other causes as mentioned in previous card

  • When NT is > 3.5 mm > expect many genetic abnormalities especially in younger women
  • When NT is ≥ 3.5 mm, invasive testing should be strongly considered.
63
Q

NIPT in Clinical Practice -Professional Statements

A

I. International Society for Prenatal Diagnosis

○ NIPT screening as a primary test for all pregnant women

○ NIPT secondary to high-risk assessment based on US screening

II. ACOG (2015)

○ PPV differs between high and low-risk women even though sensitivity and specificity remain about the same in these populations

○ Should be offered to all pregnant women

○ If results are not reportable, indeterminate, or uninterpretable, send to GC due to increased risk of aneuploidy

○ Screening for microdeletions is not validated clinically

III. ACMG (2016)

○ Inform all pregnant women that

■ NIPT is the most sensitive screening option for aneuploidies

■ NIPT may be used to find SCAs

■ Availability of CNV screening if PPV can be provided

○ Do not screen for autosomal aneuploidies other than 13, 18, 21

○ Do not do genome-wide screening for CNVs

○ Do not repeat no-call NIPT

NIPT at UT MFM

I. Offered to

○ All pregnant women seen by a GC

○ AMA screen positive for T21, T18, or T13

○ Abnormal US

○ Low risk with GC

II. Offered after 10 weeks GA

III. Patients counseled that diagnostic testing is strongly recommended prior to TAB

IV. Results take 7-10 days

64
Q

NIPT Challenges

A

Higher-order multiples

  • Most not validated with egg donors
  • No call/ low fetal fraction
65
Q

Incidental Findings in NIPT

A
  1. Maternal CNVs
    - Easier to pick up than fetal CNVs
    - CNVs can have variable expressivity
    - Maybe on a reference chromosome, which can skew results
    - With SNP- based testing, benign CNVs will also be seen
  2. Maternal Mosaicism
    - 46% of women with Turner Syndrome are 45,X/46,XX
    - Normal loss of X chromosome

– 2%- 9% by age 40

  • 47,XXX in 1/1000 women

– 1% aneuploidy risk in these women as well as premature ovarian failure

  1. Maternal Malignancy
    - 68% of solid tumors and 60% of non-solid tumors are aneuploid
    - Circulating tumor DNA can be picked up in NIPT
    * ~82% of metastatic cases can be picked up
    - 50% of non-metastatic cases can be picked up
  2. Multiple Aneuploidies or Autosomal Monosomy
    - 0.16% of T21 fetuses have another sex chromosome aneuploidy
    - 5% of early SABs have multiple aneuploidies
  3. Fibroids (Leiomyomas)
    - Benign tumors, but can have chromosome abnormalities
  4. Women with Multiple Cell Lines
    - Transplants ->can cause issues with gender determination
    - Transfusions
    - Blood issues

Lovenox/heparin

66
Q

When can cystic hygroma be detected?

A

By the tenth week

67
Q

Primary Ciliary Dyskinesia (Kartagener Syndrome)

  • Gene
  • Types
  • Function
  • Inheritance
  • Symptoms
  • Age of onset
A

DNAI1 and DNAH5 (30%)
- many other genes also associated

Function in structure and function of cilia for organs/tissue
- Abnormal cilia and flagella

AR (mostly)
AD/XL (rare)

  • Chronic respiratory tract infections**
  • Difficulty breathing at birth/ respiratory distress
  • 50%: Abnormally positioned internal organs: situs inversus totalis
  • 12%: heterotaxy syndrome / situs ambiguus: structurally abnormal or improperly positioned heart, liver, intestines, or spleen.
  • Infertility
  • Recurrent ear infections (otitis media)> hearing loss
  • Hydrocephalus
68
Q

Isolated omphalocele on U/C, what could it be?

A

Think BWS

69
Q

Sausage toes and convex deformed toes

A

Turner Syndrome

70
Q

When will ring chromosomes will be mitotically stable?

A

When they have their centromere

71
Q

What treatment will improve the outcomes for pts with RPL and antiphospholipid syndrome?

A

Low molecular heparin

72
Q

What is gynogenetic conception?

A

Two maternal chromosomes (genomes)

Usually cause ovarian teratomas

73
Q

Elec trophoresis
Hb H
Hb Bart

A

Hb H:
Hb A. 60-90%
Hb H. 0.8-40%
Hb A. 2%

Hb Bart:
Hb Bart. 85%-90%
Hb H. 2-5%

Final Review GC (7 decks)

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