#163 Screening for Fetal Aneuploidy Flashcards
What is the definition of aneuploidy?
Having or or more extra or missing chromosomes, leading to an unbalanced chromosome number in a cell
How often do chromosomal abnormalities occur in live births?
1 in 150 live births
Is rate of fetal aneuploidy increased with certain race or ethnic groups?
No, not related to race or ethnicity
What factors increase risk of fetal aneuploidy?
Increasing age, history of prior aneuploid fetus, presence of fetal anomalies
What are the most common aneuploidies that are not related to sex chromosome disorders?
Trisomies
What is the prevalence of Down syndrome?
Approximately 1 in 800 live births
What is the most common sex chromosome aneuploidy? What is its prevalence?
Klinefelter syndrome (47, XXY) with prevalence of 1 in 500 males
What is the only viable monosomy?
Turner syndrome (45, X)
What is the most common cause of Down syndrome?
95% of cases resulted from nondisjunction involving chromosome 21 (remaining cases translocations or somatic mosaicism)
What is the clinical presentation of Down syndrome?
Associated with characteristic facial features, learning disabilities, congenital heart defects, intestinal atresia, seizures, childhood leukemia, early-onset Alzheimer disease
What percentage of pregnancies affected by Down syndrome do not survive between first trimester and full term?
Estimated 43% end in miscarriage or stillbirth
In economically developed countries, what is the median survival of individuals with Down syndrome?
Almost 60yo
Can prenatal assessment predict the severity of complications from Down syndrome?
No
What should you do for a woman with a positive aneuploidy screening test?
Offer option of diagnostic testing
What screening tests for aneuploidy are available?
First-trimester, triple, quad, and penta screens; cell-free DNA; and ultrasonographic screening (single screening tests). Integrated, sequential, and contingent screening (performed in first and second trimesters)
At what crown-rump length measurement range can you perform first-trimester screening?
Between 38-45mm and 84mm
At what gestational age range can you typically perform first-trimester screen?
10w0d to 13w6d. It really depends on CRL
What components are part of first-trimester screen?
Nuchal translucency measurement, serum free beta-hcg (or total hcg), pregnancy-associated plasma protein A (PAPP-A)
What is the definition of enlarged nuchal translucency?
3.0mm or more or above 99th percentile for CRL
True or false: enlarged nuchal translucency is independently associated with fetal aneuploidy and structural malformatinos?
True
During what gestational age range can you perform a quadruple (“quad”) screen? When is best time to run it and why?
15w0d to 22w6d. dependent on laboratory. Best time is from 16-18wks, optimizes screening for neural tube defects
What serum analytes are included in quad screen?
hcg, AFP, inhibin A, estriol
What is the detection rate for Down syndrome in first trimester screen? What percent of pregnancies screen positive?
82-87%. 5% screen positive.
What is the detection rate for Down syndrome in triple screen? What percent of pregnancies screen positive?
69%. 5% screen positive.
What is the detection rate for Down syndrome in quad screen? What percent of pregnancies screen positive?
81%. 5% screen positive.
What is the detection rate for Down syndrome in integrated screen? What percent of pregnancies screen positive?
96%. 5% screen positive
What is the detection rate for Down syndrome in sequential stepwise screen? What percent of pregnancies screen positive?
95%, 5% screen positive
What is the detection rate for Down syndrome in contingent screeningWhat percent of pregnancies screen positive?
88-94%, 5% screen positive
What is the detection rate for Down syndrome in serum integrated screen? What percent of pregnancies screen positive?
88%, 5% screen positive
What is the detection rate for Down syndrome in cell-free DNA screen? What percent of pregnancies screen positive?
99% (in patients who receive a result), 0.5% screen positive
At what gestational age can you run a cell-free DNA screen?
From 10wks to term
What is the detection rate for Down syndrome w/ nuchal translucency screen? What percent of pregnancies screen positive?
64-70%, 5% screen positive
What is the penta screen?
Aneuploidy screening during second trimester w/ hcg, estriol, AFP, inhibin A, and hyperglycosylated hcg (AKA invasive trophoblast antigen). Limited data available to compare accuracy with other second-trimester screens
What analytes are in the triple screen?
hcg, AFP, unconjucated estriol. Lower sensitivity than quad and first-trimester screening
What are the protocols for combined first- and second-trimester screening?
Integrated, sequential, or contingent
What is integrated aneuploidy screening?
Patient undergoes a first-trimester nuchal translucency and analyte screening followed by second-trimester quad screen and receives single result in second trimester
What is stepwise sequential aneuploidy screening?
Patient is given a preliminary risk estimate after completion of first-trimester screen. If screen positive, patient offered diagnostic test or cell-free DNA screening and screening protocol discontinued. If negative screening, proceed to quad screen in second trimester
What is contingent sequential screening?
Aneuploidy risk after first-trimester screen classified as high, intermediate, or low. High risk are offered cell-free DNA screen or diagnostic testing. Low risk given no further screening. Intermediate risk offered quad screen.
Is it recommended for patients to undergo multiple aneuploidy screening tests performed independently (unlinked)?
No, will result in unacceptably high positive screening rate
What is the name of syndrome with trisomy 13?
Patau syndrome
What is rate of Patau syndrome (trisomy 13)?
1 in 10,000 births
What is the name of syndrome with trisomy 18?
Edwards syndrome
What is rate of Edwards syndrome (trisomy 18)?
1 in 6,000
What chromosome abnormality is associated with Patau syndrome?
Trisomy 13
What chromosome abnormality is associated with Edwards syndrome?
Trisomy 18
What are the major structural anomalies associated with fetal Down syndrome?
Cardiac anomalies (septal defects, tetralogy of Fallot, AV canal defects), duodenal atresia
What are soft ultrasonographic markers for aneuploidy?
Thickened nuchal fold, renal pelvis dilation, echogenic bowel, intracardiac echogenic focus, choroid plexus cyst, shortened humerus or femur length, hypoplastic or absent nasal bone, cystic hygroma, ventriculomegaly
What soft ultrasonographic marker for aneuploidy has the highest risk of aneuploidy as an isolated finding?
Increased nuchal skinfold thickness
What isolated soft ultrasonographic marker has the lowest risk of fetal aneuploidy?
Isolated echogenic intracardiac focus
For prenatal ultrasound, which isolated ultrasonographic soft markers require follow up?
renal pelvis dilation, echogenic bowel, shortened humerus or femur length
Where does fetal cell-free DNA come from?
Fetal component is released into maternal circulation primarily from placental cells undergoing apoptosis
What is the normal fetal fraction of cell-free DNA?
3-13%, increases throughout gestation
How soon after delivery do you expect fetal cell-free DNA to be cleared from maternal circuluation?
Within hours after childbirth
True or false, women with “no reportable result” with cell free DNA screening are at increased risk of fetal aneuploidy?
True
Does increased nuchal translucency increase risk of anything beyond aneuploidy?
Yes. Increased risk of genetic syndromes and isolated anomalies, such as congenital heart defects, abdominal wall defects, and diaphragmatic hernia
What should you offer patient’s with increased nuchal translucency?
Genetic counseling. Diagnostic genetic testing. Targeted ultrasound exam and fetal echo in second trimester
What does a cystic hygroma look like in first trimester?
Increased nuchal translucency extending along the length of the fetus in which septations are clearly visible
What percentage of pregnancies with cystic hygroma will result in healthy live-born infants at term?
Less than 20%
What additional screening should be offered to women who undergo first trimester screen?
Second-trimester assessment for open fetal defects by ultrasound, MSAFP screening, or both
What can a positive screening test result from cell-free DNA screening represent apart from fetal aneuploidy?
Confined placental mosaicism, a resorbing twin, maternal malignancy or maternal aneuploidy
What is the positive predictive value of cell-free DNA testing for down syndrome, trisomy 18, trisomy 13, and sex chromosome aneuploidy?
Down - 93%
Trisomy 18 - 64%
Trisomy 13 - 44%
Sex chromosome - 39%
What factors contribute to low fetal fraction on cell-free DNA screen?
Sampling before 10 wks, high maternal BMI, fetal aneuploidy
What percent of cell-free DNA screens that fail to obtain a result are aneuploid?
22%, according to one study of more than 1,000 analyzed samples
How should you manage a low fetal fraction result on cell-free DNA screening?
Repeat cell-free DNA screening or do diagnostic testing
What is the recommendation after positive cell-free DNA screening result?
Diagnostic testing. Not recommended to pursue pregnancy termination based off cffDNA results
Does cffDNA screening offer information regarding potential for open fetal defects?
No. Patients should undergo ultrasound, MSAFP screening, or both
What is the residual risk of a chromosomal abnormality with a normal cffDNA screening after an abnormal traditional screening test?
2%
What obstetrical complications are associated with a PAPP-A level below 5th %tile in first trimester?
Spontaneous fetal and neonatal loss, fetal growth restriction, preeclampsia, placental abruption, preterm delivery
In second trimester, elevated hcg, AFP, and inhibin A levels in pregnancies without structural anomalies are associated with what?
Increased risk of fetal death, IUGR, and preeclampsia
If a patient conceives and has undergone preimplantation genetic screening, should prenatal aneuploid screening be offered?
Yes, because false-negative results can occur with preimplantation genetic screening
Is the risk of having aneuploid fetus higher in monozygotic twins or dizygotic twins?
Dizygotic. Each fetus carries risk of aneuploidy similar to mother’s age-adjusted risk, but mother carries increased risk of having a fetus with aneuploidy because there is more than one fetus. Monozygous typically is all or none.
Are aneuploidy screening tests as accurate in twin gestations as singletons?
No, but can still be used for twin gestations (do not use for higher-order multifetal gestations). Nuchal translucency allows for each fetus to be independently screened.
What can a single enlarged nuchal translucency in monochorionic twins of discordant size indicate?
Early sign of twin-twin transfusion , rather than aneuploidy
In multifetal gestation, if fetal demise or anomaly is identified in one fetus, can you use serum-based aneuploidy screening?
Should be discouraged, significant risk of an inaccurate test result
Are cell-free DNA screening tests useful for assessing for microdeletions?
Has not been validated clinically and not recommended at this time
