Serum and Ultrasound Based Screening Tests for Aneuploidy

What Is the History of Serum Screening?

Prenatal screening for aneuploidy has evolved dramatically over a short period of time. The purpose of prenatal screening for aneuploidy is to identify women who are at an increased risk for the most common aneuploidies. Down syndrome is the most common aneuploidy seen in live births. Chromosomal abnormalities occur in approximately 1 in 150 live births with Down syndrome being the most common with a prevalence of 1 in 800.

Screening tests for open neural tube defects started in the 1970s after the discovery that elevated levels of maternal serum alpha-fetoprotein (MSAFP) in the second trimester were associated with open spina bifida and anencephaly. The combination of reduced serum levels of second trimester AFP and maternal age was used to screen for Down syndrome beginning in 1984. Test performance improved with the introduction of other second trimester analytes namely unconjugated estriol (uE3), human chorionic gonadotropin (hCG), free beta hCG, and dimeric inhibin A, . Decreased maternal serum levels of uE3 and increased levels of hCG and inhibin A are associated with Down syndrome. Second trimester screening using maternal age and the quadruple serum markers alpha fetoprotein, total hCG, uE3, and inhibin A has been validated as an effective tool for Down syndrome.

First trimester maternal serum analytes were introduced in the mid-1980s, including pregnancy-associated plasma protein A (PAPP-A) and free beta hCG. Decreased levels of PAPP-A and increased levels of free beta hCG are associated with Down syndrome. The nuchal translucency (NT) is the most effective first trimester ultrasound marker for fetal aneuploidy and was first used in 1990. First trimester screening, using NT, combined with maternal age and serum analytes (the combined test) was found to be equivalent in performance to the second trimester quadruple test.

The integrated test was introduced in 1993 and includes first trimester NT and PAPP-A and the second trimester quad screen markers with the final interpretation provided only after analysis of the second trimester analyte levels. Integrated screening can also be performed using first and second trimester analytes without an NT. This may prove to be beneficial in cases in which women do not have access to first trimester NT assessment or in cases in which the NT is not obtainable.

Both the stepwise sequential and the contingent sequential screen are a type of integrated test. The results are available in the first trimester for both tests. In the stepwise sequential screen, the first trimester and the quadruple screen are performed with the results available after the first trimester screen. If a patient returns with a high risk for aneuploidy, this allows for earlier options. In the contingent screen, all women undergo the first trimester screen. They then get stratified into high-, medium-, and low-risk groups. The low-risk group does not require any further testing. The intermediate group is offered quadruple screening and the high-risk group is offered diagnostic testing.

Cell-free DNA (cfDNA) screening became commercially available in 2011 after Palomaki et al. conducted a blinded nested case–control study designed within a cohort of more than 4600 pregnancies at high risk for Down syndrome. The Down syndrome detection rate was 98.6% with a 0.8% false-positive rate. cfDNA screening is reviewed in Chapter 9 .

Who Should Be Offered Serum Screening for Aneuploidy?

All women should be offered the option of screening or diagnostic testing for aneuploidy regardless of age. There are identifiable risk factors that increase a woman’s risk of having a child affected with aneuploidy including advancing age ( Table 8.1 ). Other risk factors for aneuploidy are as follows: a history of a prior fetus with aneuploidy, a fetal anomaly or structural malformation, or a parental translocation. The decision to perform screening and/or diagnostic testing depends on the woman’s goals and desires for her pregnancy. Some women choose screening for knowledge, whereas others want to obtain information to make decisions regarding pregnancy continuation versus termination. Patients considering aneuploidy screening should have pretest counseling regarding the benefits, risks, and limitations of the test.

What Are the Different Serum Screening Tests? What Are the Benefits and Limitations of Each One?

Screening tests for aneuploidy include serum screening, ultrasound, and cfDNA. Fetal aneuploidy risk can be evaluated on the basis of maternal age, maternal serum results and ultrasound markers. No one screening test is superior for all testing characteristics, and not all tests are available in all centers. Factors to be considered in the choice of screening tests are the availably of NT assessment, gestational age at the time of presentation, cost, screening test sensitivity, and limitations. An overview of serum screening tests is described below and summarized in Table 8.2 . Detection rates and false-positive rates for common screening tests for aneuploidy are displayed. Each test has advantages and disadvantages that should be discussed with the patient before screening.