The Sequential Screen is a two-part screening test that assesses the risk of a baby being born with Down syndrome, trisomy 18, and open neural tube defects (ONTDs). The risk for Smith-Lemli-Optiz syndrome (SLOS) is reported if the patient is high risk. The first part can be performed between 11 weeks and 13 weeks, 6 days gestation. The second part can be performed between 15 and 22 weeks of gestation.
In the first part, ultrasound is used to precisely determine the gestational age of the pregnancy (measure the crown-rump length (CRL)). The ultrasound, performed by a certified sonographer, is also used to measure the nuchal translucency (NT) and assess nasal bone development. A maternal blood sample is drawn to measure the levels of two serum analytes:
- Pregnancy-associated plasma protein (PAPP-A)
- Total beta-human chorionic gonadotropin (ß-hCG)
After the evaluation of the data from the first part, two risk groups are identified:
- High Risk (or Screen Positive) Results: Patients with a risk greater than or equal to one in 200 for Down syndrome or one in 46 for trisomy 18 receive a screen positive result. This is a final result and the second part of screening is not performed; and the patient is offered the option of genetic counseling and diagnostic testing.
- All Other Risks: Patients with a risk less than one in 200 for Down syndrome and less than one in 46 for trisomy 18 proceed to the second part of screening.
If the second part is done, a second maternal blood sample is taken to measure the levels of four serum analytes:
- Alpha-fetoprotein (AFP)
- Total beta-human chorionic gonadotropin (total ß-hCG)
- Unconjugated estriol (uE3)
After the evaluation of the data from the second part, a combined risk assessment is provided.
In pregnancies affected by Down syndrome, the levels of PAPP-A, AFP, and uE3 tend to be lower than normal while the levels of inhibin-A and total ß-hCG are elevated. The NT measurement may also be thicker than normal in an affected pregnancy and the nasal bone may be underdeveloped (hypoplastic).
In pregnancies affected by trisomy 18, the levels of PAPP-A, AFP, uE3, inhibin-A, and ß-hCG tend to be lower than normal.
In pregnancies affected by ONTDs, such as open spina bifida or anencephaly, the level of AFP tends to be elevated.
Two-part Risk Estimate
Using information from the first and second trimester yields a higher detection rate than a test using information from the first part alone. Additionally, a test using only information from the first trimester cannot assess risk for ONTDs.
What Does a Negative Result Mean After Completion of Both Parts of the Screening Protocol?
The result is considered screen negative if the risks for Down syndrome, trisomy 18 and ONTDs are lower than the cut-off used after completion of both parts. Typically, a cut-off of one in 270 is used for Down syndrome, a cut-off of one in 100 is used for trisomy 18, and a cut-off of one in 104 is used for ONTDs. A patient with a screen negative result is not considered at high risk to have a baby with either Down syndrome or trisomy 18. However, the chance to have a pregnancy with Down syndrome or trisomy 18 is not completely eliminated.
What Does a Positive Result Mean After Completion of both Parts of the Screening Protocol?
A screen positive result for Down syndrome by the Sequential Screen means that the patient’s risk of having a baby with Down syndrome is greater than or equal to one in 270. About 2.15% of patients who have the Sequential Screen receive a screen positive result. A screen positive result for trisomy 18 means that the patient’s risk of having a baby with trisomy 18 is greater than or equal to one in 100. A screen positive result for ONTDs means that the patient’s risk of having a baby with an ONTD is greater than or equal to one in 104.
A high-risk result for Smith-Lemli-Optiz syndrome (SLOS) will be reported if the patient has a risk of greater than or equal to 1 in 50. No risk assessment will be provided for this condition if the patient is low risk.
What is the Detection Rate for Down Syndrome, Trisomy 18, and ONTDs?
The Sequential Screen will detect about 95% of singleton pregnancies affected with Down syndrome after the second part, 95% of singleton pregnancies affected with trisomy 18 after the second part, and 85% of singleton pregnancies affected with ONTDs, after both parts.
What are the Other Tests that will be Offered if the Sequential Screen is Positive?
Depending on the results of the Sequential Screen, additional testing may be offered including a second trimester detailed anatomy ultrasound and prenatal diagnosis (chorionic villus sampling or amniocentesis). Genetic counseling is also recommended.
Why will Some Patients Have to Wait Until the Second Part of the Screening Protocol to Have a Risk Estimate?
Patients determined to be at elevated risk are identified in the first part and risk assessment ends for them as these patients will be offered prenatal diagnostic testing and/or other tests to better understand the results of the first part of the Sequential Screen. The remainder of patients will proceed to the second part. These patients will receive results using information from the first and second parts.