First-Trimester Aneuploidy Screening A Combined Approach

Prenatal testing for Down syndrome has gained importance--and urgency--as more women delay pregnancy into their later reproductive years. A first-trimester screening technique that combines use of maternal serum markers with ultrasonographic assessment may offer reliable answers sooner than do other available tests.

The prospect of maternal serum screening for fetal aneuploidy in the first trimester of pregnancy, with subsequent karyotyping when indicated, offers distinct advantages over current protocols and has inspired a lot of research lately. Under the current system, whereby screening is not undertaken until the second trimester, pregnant women have little time for decision-making regarding possible termination of an affected fetus. An earlier warning would offer women valuable time to make decisions, as well as an opportunity for earlier and safer termination of the pregnancy if desired.

Until recently, with the exception of maternal serum free b-human chorionic gonadotropin (b-hCG), none of the second-trimester markers--including a-fetoprotein (AFP), hCG, a-hCG, unconjugated estriol (E3), and inhibin--have been found useful for first-trimester screening.^1-4 Now, though, researchers have identified an additional first-trimester biochemical marker: pregnancy-associated plasma protein A (PAPP-A).^3,5 When combined, free b-hCG and PAPP-A can detect 63% of Down syndrome cases in the first trimester, with a fixed false-positive rate of 5%.^3-5 Indeed, this double test, when performed in the first trimester, is as good as or better than the routine triple test (AFP, hCG, and E3) that is done in the second trimester.

Ultrasonography is performed routinely during the second trimester of pregnancy, and has long been an effective tool for identifying structural malformations. Because of technologic advances, ultrasonographic evaluation of fetal nuchal translucency in the first trimester is showing great promise with regard to aneuploidy; up to 70% of Down syndrome cases have been detected with use of this measurement alone.^5-8

Screening protocols for fetal aneuploidy can be optimized by combining use of independent maternal serum markers that offer the best discrimination between normal and affected pregnancies (i.e., free b-hCG and PAPP-A1,3,8) with ultrasonography. Incorporation of the findings into a single risk-calculation algorithm can identify 90% of Down syndrome cases, again with a 5% false-positive rate.^5,9

RESEARCH FINDINGS

Pandya and associates have reported on the use of fetal nuchal translucency screening for aneuploidy at 10 to 13 weeks' gestation in two maternity units that perform 6000 deliveries per year.^10-12 Prior to the introduction of first-trimester screening, only 2 of 11 fetuses with Down syndrome were identified prenatally (the policy at that time was to offer amniocentesis to women older than 35). After implementation of first-trimester testing, increased nuchal translucency measurements were detected in 3.6% of pregnancies, and all four abnormal fetuses were diagnosed prenatally.

Taiple and colleagues studied nuchal translucency as a potential marker for chromosomal defects using transvaginal ultrasonography.¹³ They examined more than 10,000 pregnant women at 10 to 16 weeks' gestation. Increased nuchal translucency (³3 mm) was detected in 0.8% of the fetuses. Test sensitivity was 66%, and the screen-positive rate was 0.9%.

Orlandi and coworkers presented statistical data on first-trimester screening for fetal aneuploidy using a combination of maternal serum markers and nuchal translucency.⁵ By itself, nuchal translucency measurement detected 57% of aneuploidy cases. After modeling for the age distribution of live births, with a 5% false-positive rate taken into consideration, Down syndrome detection efficiency was 61% for maternal serum markers alone, 73% for nuchal translucency measurement alone, and 87% for both methods used together. These data suggest that combined biochemical and ultrasonographic evaluation for chromosomal abnormalities in the first trimester of pregnancy yields a detection capability that may exceed that of current second-trimester screening protocols.

However, it is possible that some researchers investigating first-trimester markers for aneuploidy might have been overly optimistic. For example, when Komman et al screened for nuchal translucency in 923 low-risk fetuses, the nuchal fold could not be measured accurately in 48% of cases.¹⁴ The authors detected only two of seven affected fetuses prenatally. These findings also underscore the importance of the skills of the sonographer in terms of obtaining consistent, reproducible measurements.

RISK DETERMINATION

Ultrasonographic Evaluation
First-trimester screening for fetal aneuploidy using the combined technique begins with a high-resolution ultrasound examination between 10 weeks, 4 days and 13 weeks, 5 days of gestation.⁵ First, crown-rump length (CRL) is measured for precise pregnancy dating. Next, fetal nuchal translucency is examined as a specific marker for chromosomal aneuploidy.⁶

The keys to success in this stage of testing are high-level training for the sonographer and strict application of quality-control standards. Although the technique of nuchal translucency measurement is relatively easy to master, population-based prenatal screening programs depend on consistent determinations of normal marker distributions versus affected marker distributions.⁷

Nuchal translucency can be measured successfully using the transabdominal approach in about 95% of cases; in the remainder, it may be necessary to perform transvaginal ultrasonography. Equipment must be of good quality, and each fetal scan should take at least 10 minutes. The sonographer must be able to obtain an accurate, reproducible CRL and a proper sagittal view of the fetal spine. Given these qualifications, most sonographers can learn to measure nuchal translucency thickness competently in a few hours. To ensure the uniformity of results, all sonographers must meet these criteria for each assessment:

• Obtain a sagittal section of the fetus, as in CRL evaluation
• Magnify the image such that the fetus occupies at least 75% of it
• Take care to distinguish between fetal skin and amnion
• Measure maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine by placing the calipers on the lines (Figure)
• Take three measurements per scan and record maximum thickness.

Maternal Serum Markers
Screening continues with collection of a dried blood sample via finger stick. The maternal serum is analyzed for free b-hCG and PAPP-A. (Free b-hCG is not the same as hCG, the compound measured in pregnancy tests.) In pregnancies affected by Down syndrome, free b-hCG is roughly twice the normal value, whereas PAPP-A is less than half the normal level.⁹

Data Interpretation
Specific risk for Down syndrome in a given pregnancy is based on the patient's age-related risk, the fetal nuchal translucency measurement, and maternal serum levels of free b-hCG and PAPP-A. Consistency is imperative in determining each patient's values, not only because of the effect on specific individual risk assessment but also because of the effect on population parameters used to calculate future risk.

DIAGNOSTIC PROCEDURES

Patients found to be at increased risk for carrying a child with Down syndrome can be offered fetal karyotyping by chorionic villi sampling or early amniocentesis. In the second trimester, AFP testing is still indicated to screen for neural tube defects, and multimarker Down syndrome testing can be performed as well. However, two important factors should be considered when weighing the merits of second-trimester rescreening in women who have undergone prior first-trimester testing: 90% of Down syndrome cases are detected with first-trimester screening (false-positive rate, 5%); and second-trimester screening will incur an additional 5% false-positive rate while detecting only about 60% of the remaining 10% of cases.

CONCLUSION

First-trimester Down syndrome screening using a combination of biochemical markers (maternal serum free b-hCG and PAPP-A) and a biophysical parameter (fetal nuchal translucency) can achieve 90% detection, with a false-positive rate of 5%. This exceeds the detection rate offered by any second-trimester protocol, and offers a major advantage of earlier diagnosis.

References:

REFERENCES

1. Wald NJ, George L, Smith D, et al. Serum screening for Down syndrome between 8 and 14 weeks of pregnancy. Br J Obstet Gynecol. 1996;103:407-412.

2. Aitken DA, McCaw G, Crossley JA, et al. First-trimester biochemical screening for fetal chromosome abnormalities and neural tube defects. Prenat Diagn. 1993; 13:681-689.

3. Krantz DA, Larsen JW, Buchanan PD, Macri JN. First-trimester Down syndrome screening: free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Am J Obstet Gynecol. 1996;174:612-616.

4. Haddow JE, Palomaki GE, Knight GJ, et al. Screening of maternal serum for fetal Down's syndrome in the first-trimester. N Engl J Med. 1998;338:955-961.

5. Orlandi D, Hallahan TW, Krantz DA, Macri JN. First-trimester screening for fetal aneuploidy: biochemistry and nuchal translucency. Ultrasound Obstet Gynecol. 1997;10:301-386.

6. Nobel PL, Abraha HD, Snijders RJM, et al. Screening for fetal trisomy 21 in the first trimester of pregnancy: maternal serum free beta-human chorionic gonadotropin and fetal nuchal translucency thickness. Ultrasound Obstet Gynecol. 1995;6:390-395.

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

8. Berry E, Aitken DA, Crossley JA, et al. Screening for Down syndrome: changes in marker levels and detection rates between first and second trimesters. Br J Obstet Gynaecol. 1997;104:811-817.

9. Brizot ML, Snijders RJM, Bersinger NA, et al. Maternal serum pregnancy-associated plasma protein A and fetal nuchal translucency thickness for the prediction of fetal trisomies in early pregnancy. Obstet Gynecol. 1994;84:918-922.

10. Pandya PP, Snijders RJM, Johnson SJ, et al. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. Br J Obstet Gynaecol. 1995;102:957-962.

11. Pandya PP, Goldberg H, Walton B, et al. The implementation of first-trimester scanning at 10-13 weeks' gestation and the measurement of fetal nuchal translucency thickness in two maternity units. Ultrasound Obstet Gynecol. 1995;5: 20-25.

12. Pandya PP, Hilbert F, Snijders RJM, Nicolaides KH. Nuchal translucency thickness and crown-rump length in twin pregnancies with chromosomally abnormal fetuses. J Ultrasound Med. 1995;14: 565-568.

13. Taiple P, Hillesmaa V, Salonen R, Ylostalo P. Increased nuchal translucency as a marker for fetal chromosomal defect. N Engl J Med. 1997;337:1654-1657.

14. Komman LH, Marssink LP, Beekhuis JR, et al. Nuchal translucency cannot be used as a screening test for chromosomal abnormalities in the first trimester of pregnancy in a routine ultrasound practice. Prenat Diagn. 1996;16:797-781.

Boris Petrikovsky, MD, PhD, is a Professor and Chairman, Department of Obstetrics and Gynecology, Nassau County Medical Center, East Meadow, NY. Terrence W. Hallahan, PhD, is Research Director, and James N. Macri, PhD, is Laboratory Director, both at NTD Laboratories, Inc, East Meadow, NY.

*David A. Krantz, BS, Director of Biostatistics, NTD Laboratories, Inc, East Meadow, NY, contributed to this article.

Originally published in The Female Patient -- November, 1999

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