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Maternal serum screening has historically been used in obstetric care to identify pregnancies that may have an increased risk for certain birth defects, such as Down syndrome and trisomy 18. Screening in the second trimester has been available in some version (ie, alpha fetoprotein [AFP] test, triple screen, quad screen) for decades. Screening in the first trimester became an established alternative over the last decade.
More recently, sequential screening, which has an improved detection rate as compared to either first- or second-trimester screening, has become a standard option. Sequential screening has a higher detection rate because information about a pregnancy is collected in both trimesters, which provides a greater opportunity for detecting problems.
Sequential Maternal Screening, Part 1, Serum involves an ultrasound and a blood draw. The ultrasound measurement is of the back of the fetal neck, where fluid tends to accumulate in babies who have chromosome conditions, heart conditions, and other health problems. This measurement, referred to as the nuchal translucency (NT), is difficult to perform accurately. Therefore, NT data is accepted only from NT-certified sonographers. Along with the NT measurement, a maternal serum specimen is drawn and 1 pregnancy-related marker is measured (pregnancy-associated plasma protein A: PAPP-A). The results of the ultrasound measurement and blood work are then entered, along with the maternal age and demographic information, into a mathematical model that calculates Down syndrome and trisomy 18 risk estimates.
If the result from the first-trimester Sequential Maternal Screening, Part 1, Serum indicates a risk for Down syndrome that is higher than the screen cutoff, the screen is completed and a report is issued. In that event, the patient is typically offered counseling and diagnostic testing (ie, either chorionic villus sampling or amniocentesis). When the screen is completed after Sequential Maternal Screen Part 1, a neural tube defect (NTD) risk is not provided. For a stand-alone NTD-risk assessment, order MAFP / Alpha-Fetoprotein (AFP), Single Marker Screen, Maternal, Serum.
If the risk from the first trimester is below the established cutoff, an additional serum specimen is drawn in the second trimester for Sequential Maternal Screen, Part 2, which includes tests for AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A. Once that specimen is processed, information from both trimesters is combined and a report is issued. If results are positive, the patient is typically offered counseling and diagnostic testing (ie, amniocentesis).
Nuchal Translucency (NT):
The NT measurement, an ultrasound marker, is obtained by measuring the fluid-filled space within the nuchal region (back of the neck) of the fetus. While fetal NT measurements obtained by ultrasonography increase in normal pregnancies with advancing gestational age, fetuses with Down syndrome have larger NT measurements than gestational age-matched normal fetuses. Increased fetal NT measurements can, therefore, serve as an indicator of an increased risk for Down syndrome.
Pregnancy-Associated Plasma Protein A (PAPP-A):
PAPP-A is a 187-kDA protein comprised of 4 subunits: 2 PAPP-A subunits and 2 pro-major basic protein (proMBP) subunits. PAPP-A is a metalloproteinase that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4), dramatically reducing IGFBP-4 affinity for IGF1 and IGF2, thereby regulating the availability of these growth factors at the tissue level. PAPP-A is highly expressed in first-trimester trophoblasts, participating in regulation of fetal growth. Levels in maternal serum increase throughout pregnancy. Low PAPP-A levels before the fourteenth week of gestation are associated with an increased risk for Down syndrome and trisomy 18.
Prenatal screening for Down syndrome and trisomy 18
Prenatal screening for neural tube defects (this is only applicable to Part 2 [second trimester] of the test)
Maternal screens provide an estimation of risk, not a diagnosis. A negative result indicates that the estimated risk falls below the screen cutoff. A positive result indicates that the estimated risk exceeds the screen cutoff.
Sequential Maternal Screening, Part 1, Serum results are negative when the calculated risk is below 1/50 (2%). If Part 1 is negative, submit an additional specimen in the second trimester (order SEQF / Sequential Maternal Screening, Part 2, Serum).
Sequential Maternal Screening, Part 2, Serum results are negative when the calculated risk is below 1/270 (0.37%). Negative results mean that the risk is less than the established cutoff; they do not guarantee the absence of Down syndrome.
Results are positive when the risk is greater than the established cutoff (ie, > or =1/50 in Sequential Maternal Screening, Part 1, Serum and > or =1/270 in Sequential Maternal Screening, Part 2, Serum). Positive results are not diagnostic.
When both Sequential Maternal Screening Part 1 and Part 2 are performed with a screen cutoff of 1/270, the combination of maternal age, nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A has an overall detection rate of approximately 90% with a false-positive rate of approximately 3% to 4%. In practice, both the detection rate and false-positive rate vary with maternal age.
In Part 1, trisomy 18 results are only reported if the Down syndrome risk is positive.
In Part 2, the screen cutoff for trisomy 18 is 1 in 100 (1%). Risks that are > or =1% are screen-positive; positive results are not diagnostic. Risks <1% are screen-negative; negative results do not guarantee the absence of trisomy 18.
Use caution when revising positive results with earlier dating. Babies with trisomy 18 tend to be small, which can lead to underestimation of gestational age and an increased chance of missing a true-positive.
When both Sequential Maternal Screening Part 1 and Part 2 of sequential screening are performed with a screen cutoff of 1/100, the combination of maternal age, PAPP-A, AFP, uE3, and hCG has an overall detection rate of approximately 90% with a false-positive rate of approximately 0.1%.
Neural Tube Defect (NTD):
Risk assessment for NTD is only available after completion of Part 2 of the sequential maternal screen. See SEQF / Sequential Maternal Screening, Part 2, Serum for details.
Verify that all information used in the risk calculation is correct (maternal date of birth, gestational dating, etc). If any information is erroneous, contact the laboratory for a revision.
Screen-negative results typically do not warrant further evaluation.
If the results are positive, the patient is typically offered counseling, ultrasound, diagnostic testing, and possibly, referral to genetics counseling or a high-risk clinic.
Nuchal translucency (NT) measurements must be obtained from NT-certified sonographers. NT-measurement quality indicators will be monitored on a regular basis. Sonographers will be contacted if there is ongoing deviation in the quality indicators.
Incorrect or incomplete information may significantly alter results.
A negative screen does not guarantee the absence of fetal defects.
A positive screen does not provide a diagnosis, but indicates that diagnostic testing should be considered (an unaffected fetus may have a screen-positive result for unknown reasons).
The use of these markers to screen for Down syndrome or trisomy 18 is not an approved FDA procedure.
In twin pregnancies, the risk for Down syndrome is approximated, using twin-adjusted medians. A specific risk for trisomy 18 cannot be calculated. In cases where 1 twin has demised, results may be unreliable.
Results are not available for triplets or higher-multiple pregnancies
Each center offering maternal serum screening to patients should establish a standard screening protocol, which provides pre- and post-screening education and appropriate follow-up for screen-positive results.
An interpretive report will be provided. See Interpretation section for more details.
1. Malone FD, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005 Nov 10;353(19):2001-2011
2. Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No. 77. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:217-227
3. Wald NJ, Rodeck C, Hackshaw AK, et al: SURUSS in Perspective. Semin Perinatol 2005;29:225-235
4. Palomaki GE, Steinort K, Knight GJ, et al: Comparing three screening strategies for combining first- and second-trimester Down syndrome markers. Obstet Gynecol 2006 Feb;107(2 Pt 1):367-375
5. Palomaki GE, Neveux LM, Knight GJ, et al: Maternal serum-integrated screening for trisomy 18 using both first- and second-trimester markers. Prenat Diagn 2003 Mar;23(3):243-247