Maternal Serum Screen Flashcards
What is a Screening Test?
-it is a ____ ________, and not a diagnostic test
-the result is a ________, and not a certainty
——-_________= higher likelihood/ risk of the disease
——-________=lower likelihood/ risk of the disease
The screening procedure itself does not diagnose the illness
risk assessment
likelihood
Positive
Negative
____________
-Identification, from among apparently healthy individuals, of those sufficiently at risk of a specific disorder to justify a subsequent diagnostic test or procedure
-Screen with a less-invasive test: followed by a more invasive test to confirm diagnosis
Screening
What is sensitivity and specificity?
Sensitivity and specificity are measures of a test’s ability to correctly classify a person as having a disease or not having a disease.
___________-is the ability to assign an individual with the disease as positive. A highly sensitive test means that there are few false _________ results, and thus fewer cases of disease are missed.
__________- is the ability to assign an individual who does not have the disease as negative. A highly specific test means that there are few false ________ results.
Sensitivity
Negative
Specifity
Positive
Criteria for Screening (True or False)
-you don’t screen for diseases that are not severe or diseases of high incidence
True
Criteria for Screening (True or False)
-disorder should be well-defined, with known prevalence
-severity of disease (high) vs. prevalence (low)
True
Criteria for Screening (True or False)
-disorder should represent a substantial public health burden
True
Criteria for Screening (True or False)
-there may not be an effective remedy for the disorder
True
Criteria for Screening (True or False)
-tests should be simple, safe, stable
True
Criteria for Screening (True or False)
-cost effective: cost of health care (high) vs. cost of screen (low)
True
Criteria for Screening (True or False)
-Ethical: follow-up diagnostic procedures in place
True
Criteria for Screening (True or False)
-made available to the most of population
True
Criteria for Screening (True or False)
-distribution of test values in affected populations is known
True
Criteria for Screening (True or False)
-degree of overlap with unaffected populations is small, and the cut-off (or decision point) is defined
True
Criteria for Screening (True or False)
-follow up testing: risk of miscarriage, use of therapeutic abortion is an ethical issue, parent’s choice in Canada
True
Limitations of Screening Tests (1 of 3)
1.Cut off values for populations of unaffected & affected overlap
—–screening “cut off” point used to determine negative and positive values refer to marker concentrations
- False negative: below the cut-off there is a segment of the affected population who will be screen-negative.
3.False positive: above the cut-off there is a segment of the unaffected population who will be screen-positive
Limitations of Screening Tests (2 of 3)
- detection rate (Sensitivity)
——-the fraction of the affected population that is screen positive - false positive rate (Specificity)
——the fraction of the unaffected population that is screen positive
Note: No screening tests have a 100% detection rate; all screening tests have some false positives.
Ideally?
Sensitivity = detection rate = does the screen detect ALL those affected?
Specificity vs. false positive rate = does it detect ONLY those who are affected?
Limitations of Screening Tests (3 of 3)
- Can we change the screening cut-off?
—–Increase cut off:
decrease false positive rate, decrease detection rate
—–decrease cut off:
increase detection rate, increase false positive rate
Must have a huge amount of data before changing cut-off!
__________ screening:
To determine the likelihood the baby may havetrisomy 21 (Down syndrome)ortrisomy 18.
Anyone may have a pregnancy with trisomy 21 or trisomy 18, regardless of their family history.
-This chance increases with the age of the mother or the age of egg donor.
-Prenatal screening poses little risk to the pregnancy as it involves ultrasound and blood work.
—–enhanced first trimester screening(eFTS)
—–maternal serum screening(MSS)
—–Non-invasive prenatal testing(NIPT)
Pre-natal
__________ _________ Screen
-Testing the serum of the mother
-goal is to identify fetus at risk for a specific disorder
-blood test for certain biochemical markers is a good preliminary test
Maternal Serum
_______ ________ _________(NSO)
-screens newborn blood spot samples for groups of diseases.
Newborn Screening Ontario
Newborn Screening Ontario
__________ Diseases - where the body is unable to break down certain substances in foods, like fats, proteins or sugars
Metabolic
Newborn Screening Ontario
__________ Diseases - where the body produces too much or too little of certain hormones
Endocrine
Newborn Screening Ontario
________ _________ Disease (SCD) - which affects the movement of oxygen in the blood
Sickle Cell Disease
Newborn Screening Ontario
_________ ________ - which causes problems with breathing and growth
Cystic Fibrosis
Newborn Screening Ontario
________ __________ ________ _________(SCID) - which affects the body’s ability to fight infections
Severe Combined Immune Defficiency
Newborn Screening Ontario
________ __________ _________ (SMA) - which causes muscle weakness and wasting
Spinal Muscular Atrophy
Newborn Screening Ontario
______ _________ ________ ________ (CCHD) - which affects the quantity of oxygen in the blood.
Critical Congenital Heart Disease
Newborn Screening Ontario (NSO)
Specimen: small blood sample if place on a paper slide. About 3-5 drops of baby’s blood is needed for all these tests
Tandem Mass Spectrometry (flow-injection):
—-Amino acidopathies (i.e. phenylalanine, tyrosine etc.)
—Organic acidopathies and fatty acid oxidation defects (i.e. C3, C8, C14:1, acylcarnitines etc.)
Tandem Mass Spectrometry (LC-MSMS):
—Congenital adrenal hyperplasia (2nd tier steroid profile)
—Organic acidopathies (2nd tier methylcitrate assay)
Immunoassay:
—Congenital adrenal hyperplasia (17OHP)
—Congenital hypothyroidism (TSH)
—Cystic Fibrosis (IRT)
Enzymatic assays:
—Biotinidase
—Galactosemia
HPLC:
—Hemoglobinopathies
DNA:
—Severe Combined Immunodeficiency
_______ _________ _________ (NTDs)
-all or part of the neural tube fails to close completely during fetal development.
-defects of spinal cord & brain derived from a structure in the developing embryo called the neural tube
-Canadian incidence: 1/2000 births (does not vary with maternal age)
Neural Tube Defects
Neural Tube Defects (NTDs)
open defect (most common)
_______ ______: failure of spinal cord to close
___________: failure of skull to close, and neural tissue left exposed
_______ defect
–defect covered with bone & skin
–less impairment
Spina bifida
Anencephaly
Closed
________ ________
Pathophysiology:
–paralysis of lower limbs
–loss of motor control of bladder, bowels
–hydrocephalus (water on brain)
–mental disabilities (variable)
Spina Bifida
Spina Bifida
______________:
the spinal cord is involved & protrudes from a hole in the bone of the spine
____________:
the spinal cord does not leave the protective bone tube (less severe)
Myelomeningocele
Meningocele
___________
Complete or partial absence of the cranial vault, the forebrain, the midbrain, membranes & skin & possibly spinal cord
newborns with severe form die shortly after birth
Anancephaly
NTDs cont’d
exact cause of NTDs is not clear:
-__________ component
—–family history, previous affected birth
—–likely a genetic mutation: folic acid may prevent a genetic mutation
-__________ component
—–higher frequency in Caucasians of Celtic Irish, Scots and Welsh descent
-_________ component
—–daily intake of folic acid one month before conception & during pregnancy has been shown to reduce the risk
genetic
ethnicity
dietary
How do we detect NTDs?
-fetal proteins leak into amniotic fluid
-proteins enter maternal circulation by transfer & diffusion across placental membranes
-alpha-fetoprotein (AFP) detectable in both amniotic fluid & maternal serum
-open NTDs: levels of AFP are increased in both amniotic fluid & maternal serum
_______ __________
-the first marker used for MSS
-protein: MW 70kDa, 591 aa
-synthesized initially by fetal yolk sac & later by fetal hepatocytes
-elevated amniotic fluid AFP concentration crosses the placenta, and leads to increased amounts in the maternal blood
-fetal blood levels peak 10-13 weeks gestation & then decline until term
-maternal serum levels peak at 28-32 weeks gestation, & then decline until term
Alpha-fetoprotein
Analysis of Maternal Serum AFP (MSAFP)
Maternal blood at __-___ weeks gestation
16-20
MSS Markers: Reporting & Interpretation
MSS Markers are reported in units called ____________ ___ ___ __________ (MoM)
-units correlate to the risk of NTDs
-units more reliable & allow for inter-laboratory variation / comparisons
-it is the maternal serum marker conc’n (ug/L) median reference for serum marker for gestational age
-increased AFP MoM levels above the cut-off indicate presence of NTD
-Correction factors used to account for maternal age, race, weight, gestational age, level of nutrition, diabetes
Multiples of the Median
Interpretation of MSAFP Results
-MSAFP cut-off is ___ - ___ MoM
-levels above the cut-off is a _____ screen and require further investigation
-MSAFP detects most NTDs:
—-open spina bifida ___-___% of cases
—-anancephaly > ___% cases
-follow up testing more invasive, but more conclusive
2.0-2.5
positive
70-80
90
Follow-up Testing for Screen Positive MSAFP
_____________
-ultrasound used to guide needle
-collect ~20 mL
-risk: up to 0.5% (1:200) spontaneous miscarriage
-measure AFP, AchE
Amniocentesis
________ _________ (_______ __)
-extra copy of long-arm of chromosome 21
-mental retardation, low muscle tone, congenital heart defects, flat facial profile, larger protruding tongue
-incidence increases with maternal age: 1:1300 age 25, 1:365 age 35, 1:100 age 40, 1:30 age 45
-maternal age alone is a screening test
-most common serious disorder resulting from a chromosomal abnormality in live born babies
-A correlation between decreased MSAFP levels & DS first identified in 1984
-decreased maternal serum AFP levels
< 0.5 MoM are suggestive of DS
Problem: too much overlap
Down syndrome (Trisomy 21)
Down Syndrome (Trisomy 21)
Confirmation test: ________ chromosome Cytogenetics analysis
—–amniocentesis (___-___ wks)
—–chorionic villus sampling (CVS) (__-___ wks)
—–percutaneous umbilical cord blood sampling (PUBS) (__-___ wks): high risk
_____- contains fetal cells from chorion that is placental tissue derived from fetal side of placenta
______-needle guided by Ultrasound through abdomen & uterine wall to umbilical cord: small sample of fetal blood obtained for testing
Karyotyping
15-20 weeks
10-13 weeks
18-20 weeks
CVS
PUBS
________ ________ Screen
-3 markers in maternal serum measured by immunoassay during 2nd trimester: AFP, hCG, uE3
-Screens for NTDs and Down Syndrome
-test offered to all pregnant women in Ontario regardless of their age
-one blood sample taken at 16-18 wks
An ________ levels of hCG and ________ levels of unconjugated estriol (uE3) associated with Down Syndrome
Triple Marker
increased; decreased
______ __________ ______________
-maternal serum marker for detection of fetus with Down syndrome, but not NTD
-hCG MoM of 2.5 or higher associated with DS
-only detects 40% of DS pregnancies if used alone (poor sensitivity if used alone)
Human Chorionic Gonadotropin
________ ________
-early in second trimester, fetus begins to synthesize large amounts
——a complex series of enzymatic reactions involving fetal liver, fetal adrenal glands, & placenta
—-rises progressively throughout gestation
—-A decreased level in maternal serum is a predictor of DS & NTD
Unconjugated Estriol
Interpretation: Triple Marker Screen
suspected NTDs
1. refer to Genetics
2. Level II ultrasound
3. amniocentesis: analyze amniotic fluid AFP & acetylcholinesterase
suspected DS
1.refer to Genetics
2.Ultrasound
3.confirm with karyotyping (amniocentesis, CVS, PUBS, )
Laboratory Considerations
Calculating Risk & Reporting
A “screen positive” result means fetus has an increased chance of having one of the screened conditions
Confirmation testing may conclude that baby does not have one of the conditions (i.e., false positive rate or specificity of the screen)
A “screen negative” result means chance for having a baby with the condition screened for is lower than the standard screening cut-off and is not considered to be at an increased risk
does not guarantee birth of a baby without problem
for every pregnancy, there is a 2-3% chance for having a baby with some problems at birth
Quad Screen- Dimeric Inhibin A (DIA)
-Ontario’s screening programs have added 4th serum marker:
-_________- are glycoprotein hormones secreted by ovaries in non-pregnant women, and by the placenta
-In a non-pregnant state, it suppresses the secretion of FSH
——–function in pregnancy is unknown
-levels ________ in both NTD and DS
——–measurement of additional markers has been shown to increase detection rate & decrease false positive rates
inhibin
increased
_______ _________ _________
Performed at 11-14 wks gestation (earlier than triple screen), measurement of 2 serum markers AND Ultrasound:
- free-beta subunit hCG (in serum: is not protein bound)
———–__________ in DS - pregnancy associated plasma protein A (PAPP-A)
———-___________ in DS - includes a fetal ultrasound: nuchal translucency (NT)
————NT __________ with DS and some other birth defects
First Trimester Screening
1.increased
2. decreased
3. increased
_________ ____________
-measure fluid accumulation at the back of the fetal neck (nuchal region between back of spine and skin)
-measurements greater than 3.0 mm need further investigation (usually no greater than 1 or 2 mm thick)
Nuchal Translucency
First Trimester Screening
More Recent Screening
Trisomy 18
cell free- DNA
Review Questions
