Day 15, Lecture 1: (Sept. 13): Prenatal Development Defects: Genetic and Other Causes of Fetal Abnormalities Flashcards
% of major structural anomalies of liveborn infants
2-3%
Define Birth Defects
- Congential malformations
- Structural, behavioral, functional, and metabolic disorders present at birth
Brith defects prenatal identification
- U/S sensitivity varies depending on
- type of anomly
- population screened (obesity is a limitation)
- Site of ultrasound (tertiary center vs. community-based facility)
- Contemporary number is 80% of major anomalies in a tertiary MFM practice
__% of newborns are born with minor anomalies
15%
Some minor anomalies are associated with major anomalies. Give the relative risk for one, two, and three minor anomalies
- one minor
- 3% risk major
- two minor
- 10% risk major
- Three minor
- 20% risk major
____ is the study of congenital anomalies
Dysmorphology
Teratogens
- increase frequency of adverse fatal effect
- Dose-Response relationship
- Period of greatest sensitivity typically organogenesis
- Often a genetically more susceptible group
- Exogenous teratogens:
- Coumadin (Warfarin)
- Alcohol
- Dilantin
- Accutane
- Thalomid
- Endogenous Teratogens:
- Elevated blood glucose
- Elevated Phenylalanine
What is the familial recurrence in Multifactorial inheritance
about 2-5%
What is the most common fetal aneuploidy after first trimester
Down Syndrome
What is the typical IQ for Down Syndrome patients
<70; MR can range from mild to severe
Chance of cardiac defects in Down syndrome patients
>50%
___% of Down Syndrome patients survive to 1 y/o; and over ___% survive to 50 y/o
- 85-90% survive to 1 y/o
- 50% survive to 50 y/o
Types of Prenatal Tests
- screening tests
- identify high-risk patients
- results should be thought of as “low-risk” vs. “high-risk” not “negative” vs. “postive”
- identify high-risk patients
- Diagnostic tests
- Identify abnormality
- results “normal” or “negative vs. “abnormal” or “postive”
- Identify abnormality
___ is the major fetal colloid in the first half of pregnancy.
Alpha-Fetoprotein (AFP)
Causes of elevated maternal serum AFP (MSAFP)?
- Spina Bifida
- Gastroschisis
Aneuploidy Screening second trimester
- initial screening test for aneuploidy was maternal age (high-risk>or equal to 35 y/o)
- Lower MSAFP values associated with fetal aneuploidy (primarily T21)
- Initial Strategies used maternal age combined with fixed cut-offs (e.g. <0.5 MoM)
- Now use likelihood ratio (LR) determined from Gaussian distributions
- you take affected relative probablity at that level divided by relative probability of unaffected at that AFP level.
- then you multiple this ratio with the RR of the persons age
- using a 1:270 second trimester Down syndrome cut-off (equal to risk at 35 y/o), MSAFP allowed identification of an additional 20% of affected prgnancies
-
Triple Screen
- similar LRs, hCG, and UE3 added to MSAFP
-
Quadruple screen
- Similar LRs, hCG, UE3, and Inhibin-A added to MSAFP
- test for T21 and T18
- Low-risk (negative) screen not a guarantee of normalcy
- Most patients with a high-risk (positive) screen have normal fetus
- Those with positive screens will be offered additional testing
- e.g.
- Genetic amniocentesis
- e.g.
What is the quadruple screen?
- MSAFP, LRs, hCG, UE3, and Inhibin-A
- can test for T21 and T18
- can be done at 14-22 weeks Gestational age
- Results affected by GA and must be adjusted based on maternal weight, diabetic or not, and race
- For twin pregnancies
- a “pseudo-risk” will be calculated
- detection rates lower in twins and essentially worthless in higher-order multiples
First Trimester screening for aneuploidy
- Nuchal Translucency (NT)
- NT measurement between 11 and 13 weeks GA associated with aneuploidy
- Aneuploidy risk increases as a continuous function of the NT
- Age plus NT plus serum markers
- Pregancy-associated plasma protein-A (PAPP-A)
- hCG
- Sensitivity for T21 of 80-85% at a 5% false positive rate
Newest Aneuploidy Screening tests
- Cell-free fetal DNA (cffDNA)
- About 10% of the DNA framents in a pregnant woman’s serum is fetal in origin
- Isolated using various methods (different companies’ tests)
- Though a screening test, detection rates very high
- In high-risk groups (35 y/o or older, u/s anomaly, prior infant with aneuploidy)
- T21 and T18 99%
- T13 about 90%
- Sex chr abnl 95-99%
- other chr microdeletions/duplications 90-98%
- If normal 99.5%
- Performance is not as good in low-risk patients (concept of prevalence affecting PPV and NPV)
cffDNA is not as good in low-risk patients as it is in high -risk patients because prevalence effects PPV and NPV
Ultrasound as a Diagnostic Test
- Used for
- Confirming/determining gestational age
- Determining number of fetus(es)
- confirming live fetus(es)
- Looking for structural malformations (e.g. detect 95-98%) of ONTD)
- Aiding in performance of diagnostic and therapeutic fetal procedures
Ultrasound as a Screening Test
- Increased risk of aneuploidy/other genetic abnormalities if structural anomalies (AV canal detect-fetus has T21 until proven otherwise)
- Also, increased risk of aneuploidy if ultrasound “markers”
Ultrasound Aneuploidy Markers
- Echogenic intracardiac focus
- Echogenic bowel
- Thickened nuchal fold
- Pyelectasis
- Short femur/humerus
- Absent nasal bone
why and why not to do prenatal screening
- Why to screen
- More information about the pregnancy
- Reassurance
- Planning
- Decision-making, continue?
- Utility of information is patient-specific
- More information about the pregnancy
- Why not screen for more
- Expanded carrier screening panels on the market-can screen for > 90 conditions
- Pre- and post-test counseling recommended; resources not available
- Range of symptoms, severity, treatment availability, life expectancy
- not cost-efective
