First Trimester Screening
by Karen V. Valdez, MS, March 2000

The current standard of practice for screening for Down syndrome in pregnant women under age 35 years is by second trimester maternal serum screening. The test is usually referred to as the triple screen, and is based on measuring the concentrations of alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin in maternal serum between 15 and 22 weeks of pregnancy. Based on the concentrations of these substances, and by also considering maternal age and gestational age, a risk is estimated for the fetus to have Down syndrome, Trisomy 18, or a neural tube defect. By using these parameters, about 60-70% of Down syndrome pregnancies can be detected, as well as approximately 60% of Trisomy 18 pregnancies and approximately 80% of pregnancies with open neural tube defects. Despite the benefits of the test, it has certain limitations. One of the main disadvantages of the triple screen is the timing of the test. By the time a definitive diagnosis is made via amniocentesis (after a positive triple screen result), it is often late in the second trimester. The option of termination of pregnancy can be difficult for women at this point. Because of these factors, researchers have been trying to develop earlier and more accurate forms of screening.

First trimester screening involves the combination of serum screening and ultrasonography. This methodology was developed by Kypros Nicolaides. (Epstein, 1998). The markers that are routinely measured in the first trimester are PAPP-A and free Beta hCG. Pregnancy associated plasma protein A (PAPP-A) is the single best marker yet discovered for first trimester screening for Down syndrome. PAPP-A is detectable by about the 30th day in gestation and is produced mainly by the placenta. (Casals, 1999). In pregnancies with Down syndrome, PAPP-A levels are decreased by more than half between the 8th and 13th week of gestation. (De Graaf, 1999). Low PAPP-A may also be associated with Trisomy 18. After the 14th week in pregnancy, PAPP-A loses its effectiveness. The second marker, free beta hCG is one of the two subunits of the glycoprotein hormone hCG. It is doubled in pregnancies with Down syndrome and is decreased in pregnancies with Trisomy 18. Other serum markers, such as AFP, have also been used in clinical trials, but were found to be of less discriminatory value.

The second part of the first trimester screening procedure is a high resolution ultrasound. This test is performed between 10 and 15 weeks gestation. On ultrasound the nuchal translucency of the fetus is measured. Nuchal translucency refers to the subcutaneous space between the skin and the cervical spine in the fetus. (Devine, 1999). It is the measurement of fluid accumulation behind the neck. An increased nuchal translucency measurement is known to be associated with an increased risk for aneuploidy, such as Trisomy 21 and Trisomy 18. Nuchal translucency measurement between 10 and 15 weeks gestation can detect 54% of Trisomy 21 cases, 62% of trisomies, and 69% of cases with any aneuploidy. (Taipale, 1997). It can also be an indicator for a structural anomaly or genetic syndrome present in the fetus, such as diaphragmatic hernia, cardiac defects, exomphalos, body-stalk anomaly, fetal akinesia syndrome, or certain skeletal dysplasias. (Souka, 1998). A normal ultrasound alone is thought to reduce the maternal age-related risk for Down syndrome by 50%. (Epstein, 1998). The maternal age is also taken into consideration with first trimester screening. With the combination of serum screening, ultrasound screening, and maternal age, an overall assessment of the woman's chance to have a baby with Down syndrome can be determined.

Studies have been carried out to determine the detection rate of serum screening alone in the first trimester. With the combination of PAPP-A and free beta hCG, detection rate for Down syndrome ranges between ~50-65% with a 5% false positive rate. Nuchal translucency measurement alone between 10 and 14 weeks gestation and maternal age can identify between 68-75% of cases of Down syndrome. (De Graaf, 1999). The combination of nuchal translucency measurement and the serum markers together have been reported to have a detection rate as high as 85%. Detection rate for Trisomy 18 has been reported to be ~75%. Based on these results, the Royal College of Obstetrics/Gynecology Study Group (1997) recommended that there is sufficient evidence to consider that specific serum markers for Down syndrome between 9 and 13 weeks gestation may be as effective as those used between 15 and 22 weeks gestation.

One of the advantages of screening during the first trimester is that it is early enough in pregnancy, so women can decide whether they would like to pursue diagnostic testing such as CVS or amniocentesis. Pregnancy termination options that would be available are considered safer. It would also allow couples more privacy if an abnormality is detected. In the first trimester, pregnancy may not be readily apparent to others. The disadvantages are that the test will not detect neural tube defects, so an AFP test will still need to be done. The ultrasound portion of the screening protocol needs to be performed by a skilled physician or ultrasound technician with high resolution equipment. Earlier assessment of risk and prenatal diagnosis preferentially identifies those chromosomally abnormal pregnancies that are destined to miscarry. (Snijders, 1998).

REFERENCES

Casals E, Aibar C, Martinez JM, Borrell A, Soler A, Ojuel J, Ballesta AM, Fortuny A: "First trimester biochemical markers for Down syndrome" Prenatal Diagnosis 19: 8-11,1999.

De Biasio P, Siccardi M, Volpe G, Famularo L, Santi F, Canini S: "First trimester screening for Down syndrome using nuchal translucency measurement with free B-hCG and PAPP-A between 10 and 13 weeks of pregnancy - the combined test" Prenatal Diagnosis 19: 360-363, 1999.

De Graaf IM, Oajkrt E, Bilardo CM, Leschot NJ, Cuckle HS, Van Lith JMM: "Early pregnancy screening for fetal aneuploidy with serum markers and nuchal translucency" Prenatal Diagnosis 19: 458-462, 1999.

Epstein RH: "Great news about prenatal testing" Parents 75-78, 1998.

Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH: "UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation" The Lancet 352: 343-346, 1998.

Snijders RJM, Johnson S, Sebire NJ, Noble PL, Nicolaides KH: "First trimester screening for chromosomal defects" Ultrasound Obstet Gynecol 7: 216-226, 1996.

Souka AP, Snijders RJM, Novakov A, Soares W, Nicolaides KH: "Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10-14 weeks of gestation" Ultrasound Obstet Gynecol 11: 391-400,1998.

Taipale P, Hiilesmaa V, Salonen R, Ylostalo P: "Increased nuchal translucency as a marker for fetal chromosomal defects" The New England Journal of Medicine 337: 1654-1658, 1997.

Tsukerman GL, Gusina NB, Cuckle HS: "Maternal serum screening for Down syndrome in the first trimester: experience from Belarus" Prenatal Diagnosis 19: 499-504, 1999.