Maternal Screening
A European Perspective

Maternal screening is a valuable tool for determining high-risk pregnancies. It offers a safe, economical means of identifying pregnant women at risk for giving birth to babies with chromosomal and other defects. In the event that significant risk is indicated by screening, a confirmed diagnosis can be obtained by karyotyping amniotic fluid or by chorionic villi sampling (CVS). Screening provides statistical risk assessment for two of the most common chromosomal anomalies: Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18). Atypical biochemical profiles may be observed in these as well as other chromosomal and nonchromosomal anomalies. For example, high alpha-fetoprotein (AFP) values have been used for many years in second-trimester screening for neural tube defects (NTD). The table summarizes median MoM (multiples of the median) values observed in fetuses who are chromosomally affected.

Screening strategies vary worldwide due to lack of consensus among practitioners, differences in levels of medical care, and financial and political issues. Although a great deal of confusion exists among doctors on the benefits, maternal screening has become a standard component of prenatal care worldwide.

Historical perspective

The original method for Down syndrome screening was introduced in 1970; it addressed the association between trisomy 21 and advanced maternal age. Amniocentesis was initially reserved for women at least 40 years old, due to its high cost and the associated risk of miscarriage. Over time, the cutoff was reduced to 35 years of age. If this screening approach were still in use today, it would result in 10 percent of all pregnant women undergoing amniocentesis. To reduce this number to a more acceptable level of 5 percent, the cutoff age has since been changed to 37 years, which corresponds to a maternal age-related risk for Down syndrome of 1 in 250 at term.

In the late 1980s, the "double" and "triple" tests were introduced for second-trimester screening (14 to 22 weeks' gestation). They combine maternal age with measurements of AFP and human chorionic gonadotropin (HCG). In the triple screen, unconjugated or "free" estriol (uE3) is also measured. Values are expressed as MoMs.

Current screening strategies

Currently, the double and triple tests are the most widely used screening algorithms in Europe for the second trimester. These methods are far more effective than maternal age alone: at a false-positive rate (FPR) of 5 percent, between 60 and 70 percent of Down syndrome cases are detected. Since their introduction, these algorithms have been improved by correcting the MoM values for variables that influence biochemical results. These include maternal weight, ethnic origin, twins, IVF procedures, diabetes and smoking. Adding inhibin A to the second trimester panel has been shown to increase the detection rate by 3 to 9 percent, depending on whether it is used as a substitute for uE3 or as a fourth marker (quadruple test).

Ultrasound was initiated as a component of first-trimester maternal screening in 1990, after it was observed that an increased accumulation of fluid in the neck of the fetus at 11 to 14 weeks occurs in a high percentage of cases involving either chromosomal or nonchromosomal disorders. The swelling or thickening at the back of the fetal neck was termed nuchal translucency (NT); and a new algorithm, based on NT measurements and maternal age, was introduced. This first-trimester screening method has proven capable of detecting approximately 75 percent of Down syndrome cases at a 5 percent FPR.

The high detection rate and the psychological advantages of first-trimester screening to the patient prompted researchers to investigate the possibility of formalizing this approach.

Today, first-trimester maternal screening in Europe combines maternal age, NT measurements and biochemical levels for free b-HCG and pregnancy-associated plasma protein-A (PAPP-A). This combination yields a detection rate for Down syndrome of approximately 85 percent at a 5 percent FPR. A recent report from a UK medical center applying this algorithm has confirmed the high detection rate. It also illustrates how a sufficiently rapid turnaround of free b-HCG and PAPP-A results on a random access analyzer can provide patients with both timely answers and the option to pursue CVS during the same office visit.

One limitation of first trimester screening is that it takes place too early in the gestational process to constitute a screen for neural tube defects (NTD). Possible solutions include taking another blood sample for AFP in the second trimester at approximately the 15th week or searching by ultrasound for typical intracranial signs. Recently, a new screening approach, called the "integrated" test, was proposed. It combines 6 to 7 tests performed in the first and second trimesters. Proponents of the integrated test state that this algorithm yields a 95 percent detection rate with a 5 percent FPR, when employing the standard cutoff (corresponding to the 1-in-250 maternal age risk of a 37-year-old woman at term). Increasing the cutoff would result in sending only 0.9 percent of all screened women for an amniocentesis, but would decrease the detection rate for Down syndrome to 85 percent.

Future developments

Further developments in prenatal screening are expected to come from new biochemical parameters, of which hyperglycosylated HCG shows great potential as a first- or second- trimester serum or urine marker. New ultrasound parameters are also being considered. For example, researchers have concluded that the absence of a nasal bone at the time of the NT measurement increases the risk for Down syndrome 146-fold. When combined with NT, free b-HCG and PAPP-A, this algorithm resulted in a
93 percent detection rate with a 1 percent FPR.

Clinical observations and research findings of the last 12 years have substantially improved the efficiency of both first- and second-trimester maternal screening. Continued research is expected to further enhance performance and could possibly extend the application to aneuploidies other than Down and Edwards syndromes. In addition, new biochemical parameters could bring cost-effective serum screening to women lacking access to high-quality ultrasound diagnostics. Clearly, the field of maternal screening is still evolving, and it is sure to undergo plenty of dynamic growth and discovery along the way.

Suggested Reading

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Cuckle H. Biochemical Screening for Down syndrome. Eur J Obstet Gynecol Reprod Biol 2000;92(1):97-101.

Cuckle H. Time for total shift to first-trimester screening for Down's syndrome. Lancet 2001;358(9294):1658-9.

Cuckle HS, Holding S, Jones R, Groome NP, Wallace EM. Combining inhibin A with existing second-trimester markers in maternal serum for Down's syndrome. Prenat Diagn 1996;16(12):1095-100.

Cuckle HS, Sehmi IK, Jones RG, Mason G. Low maternal serum PAPP-A and fetal viability. Prenat Diagn 1999;19(8):788-90.

Cuckle HS, van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn. 1999;19(6):505-12.

Cuckle HS. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study. J Pediatr. 2002;140(5):632-3.

Nicolaides KH, Heath V, Cicero S. Increased fetal nuchal translucency at 11-14 weeks Prenat Diagn 2002;22(4):308-315.

Spencer K, Spencer CE, Power M, Moakes A, Nicolaides KH. One stop clinic for assessment of risk for fetal anomalies: a report of the first year of prospective screening for chromosomal anomalies in the first trimester. BJOG 2000;107(10):1271-5.

Spencer K, Tul N, Nicolaides KH. Maternal serum free beta-hCG and PAPP-A in fetal sex chromosome defects in the first trimester. Prenat Diagn 2000;20(5):390-4.

Wald NJ, Densem JW, George L, Muttukrishna S, Knight PG. Prenatal screening for Down's syndrome using inhibin-A as a serum marker. Prenat Diagn 1996;16(2):143-53.

Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome. J Med Screen 1997;4(4):181-246.

Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Eng J Med 1999;341(7):461-7.

Weinans MJ, Butler SA, Mantingh A, Cole LA. Urinary hyperglycosylated hCG in first trimester screening for chromosomal abnormalities. Prenat Diagn 2000;20(12):976-8.