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BRIEF REPORT

First-trimester Screening : An Overview

Bernd Eiben and Ralf Glaubitz

Institute of Clinical Genetics North Rhine and Labor Wagner, Stibbe and Partners (Oberhausen, Hanover, Göttingen), Oberhausen, Germany

Correspondence to: Prof. Bernd Eiben, Institute of Clinical Genetics Nordrhein, Hum. Genet., Virchowstr. 20, D-46047 Oberhausen, Germany. E-mail: eiben{at}eurogen.de


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An improvement in prenatal screening for chromosomal defects has been achieved by combining sonography and biochemical markers. Analyzing markers taken from maternal blood such as pregnancy-associated plasma protein A and free ß-human chorionic gonadotropin in combination with the ultrasound marker nuchal translucency provides detection rates of 90% for the most important chromosomal anomalies. In addition, nuchal translucency is a marker for severe heart defects. This report discusses the potential of new markers such as the nasal bone. (J Histochem Cytochem 53:281–283, 2005)

Key Words: first-trimester screening • free ß-hCG • PAPP-A • nasal bone • trisomy 21 • chromosomal aberrations • sonography • NT • heart defects • maternal age

IN ALL DEVELOPED COUNTRIES, pregnant women take part in prenatal programs that screen for chromosomal disorders and major defects of the fetus. From the beginning, it has been a matter of discussion to whom invasive prenatal tests such as amniocentesis or corionic villi biopsy should be offered. A prerequisite for one of the first programs was the so-called advanced maternal age indication for all women aged 35 years and older. When this program was introduced in the early 1970s, ~30% of all women delivering a baby were in this age group; therefore, only 30% of all trisomy 21 pregnancies could be detected. This procedure focused maximum care on this age group, but younger women received less attention.

Fifteen years later, another screening program was introduced into feto-maternal medicine that assigned a more individualized risk to each woman. The risk of conceiving a child with Down syndrome, depending on maternal age, was determined via statistical calculations based on detecting specific biochemical markers [{alpha}-fetoprotein, human chorionic gonadotropin (hCG), and estriol]. The so-called triple test can be performed between gestational weeks 15 and 19. On the basis of an ~10% false-positive rate, 50% to 60% of all true trisomy 21 pregnancies could be classified as being in an elevated risk group (Eiben et al. 2001Go).

As a result of better education and sociological changes, the mean maternal age at delivery has increased steadily over the last 40 years. In Germany, the mean age is currently above 31 years. Because of this demographic change, the prevalence of Down syndrome has also changed, and not only in Germany. According to data presented by Cuckle (1999)Go, the prevalence changed from 1:722 in 1990 to 1:553 in 2000.

The first reports dealing with trisomy 21 sonographic markers in the first trimester were published in the early 1990s. Schulte-Valentin and Schindler (1992)Go reported on non-echogenic nuchal edema, which was later termed nuchal translucency (NT), serving as a marker for trisomy 21 screening. Today, we know that an NT can be detected in 99% of fetuses at the end of the first trimester. The 50th percentile NT increases from 1.2 mm in week 11 + 0 (crown–rump length 45 mm) to 1.5 mm in week 13 + 6 (crown–rump length 82 mm). The 95th percentile ranges from 2 mm in week 11 to 2.6 mm in week 13 + 6. The increase of an NT causes an increase in the risk for trisomy 21. In addition to trisomy 21 pregnancies (cutoff level 1:300), triploidies, trisomies 18 and 13, and monosomy X can also be categorized as being in a risk group (Nicolaides et al. 1999Go).

Combining sonography and biochemical markers constituted an improvement in screening techniques. Through first-trimester screening via analysis of biochemical markers taken from maternal blood [e.g., pregnancy-associated plasma protein A (PAPP-A) and free ß-hCG], a detection rate of 90% for the most important chromosomal abnormalities, with a false-positive rate of 5%, is attainable. This substantially elevated detection rate can only be achieved by using a high-quality analyte system (Kryptor; Brahms AG, Berlin-Henningsdorf, Germany), with a strict managing system and quality assessment. In Germany, this system is maintained by the Fetal Medicine Foundation (FMF) Deutschland (Eiben et al. 2002aGo,bGo). With FMF screening software, risk factors for maternal age, NT, and biochemical parameters can be combined for a likelihood analysis.

By combining the parameters for NT, PAPP-A, and free ß-hCG and incorporating the maternal risk factor, FMF-certified software calculates individual specific risk estimations for the most frequent aneuploidies with a false-positive rate of only 5%. As depicted in Table 1, Spencer et al. (2000a)Go(bGo,cGo,dGo) found distinct patterns (expressed as multiple of median) between different types of chromosomal aberrations such as trisomies 21, 18, and 13 and monosomy X, as well as the different types of triploidy.


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Table 1

Marker pattern in multiple of median and detection rates in different aneuploidies (Spencer et al. 2000aGo,bGo,cGo,dGo)

 
Table 2 lists the detection rates for trisomy 21 and 18 found in our laboratory. Using FMF software, it is feasible to alternatively calculate the risk figures for maternal age only, for both maternal age and biochemical markers combined, for maternal age and NT combined, and for the complete set of markers (maternal age, NT, and biochemical markers). The optimal risk value can only be achieved if all parameters are considered.


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Table 2

Parameters, detection rates, and number of trisomy 21 and trisomy 18 cases analyzed in the Institute of Clinical Genetics North Rhine

 
We also emphasize consideration of the individual biochemical or sonographic situation. In our study, seven cases of trisomy 21 showed normal NT but aberrant biochemical markers, and four cases presented with aberrant NT and normal biochemical markers. Our data also demonstrate the general practicability of this method in experienced hands.

Special attention should be given to those cases in which the NT is increased and the karyotype is normal. The NT is more than a marker for chromosomal disorders; when NT levels increase above the 95th percentile, the chance that a healthy baby will be born decreases. NTs above the 95th percentile and normal karyotypes are often associated with different malformations and genetic syndromes (Nicolaides et al. 1999Go). In a multicenter FMF study comprising 100,000 pregnancies, 161 of 4116 (3.9%) cases with a normal karyotype but with an NT above the 95th percentile showed structural defects or genetic syndromes. The most frequent defects were those of the heart and greater arteries. Hyett et al. (1999)Go found an increased NT (>95th percentile up to 3.4 mm) in 1507 out of 29,154 pregnancies, and major heart defects were found in eight of those cases (prevalence 5.3/1000 cases). On the other hand, in 66 cases with an NT between 4.5 and 5.4 mm, the prevalence was 90.9/1000 cases, while the prevalence for an NT above 5.4 mm was 195.1/1000 cases.

We also emphasize that an isolated, moderately increased NT is not a malformation, because in 90% of all pregnancies with an NT <4.5 mm the delivery of a healthy baby can be expected.

What will be the next steps in screening? Three years ago, Cicero et al. (2001)Go reported on the ossification of the os nasale, which can be detected via ultrasound in normal pregnancies at the end of the first trimester (Figure 1). In cases of trisomy 21, the nasal bone was not visible at this stage of pregnancy. Nicolaides (2003)Go conducted several studies on the nasal bone. In 3766 normal pregnancies, the nasal bone was visible in 97.2% of cases, but in 242 trisomy 21 pregnancies it was visible in only 33% of cases. Nasal bone could not be detected in 33% of 188 pregnancies with chromosomal defects other than trisomy 21. More multicenter studies need to be performed before this new marker can be introduced into prenatal medicine. A combination of nasal bone and first-trimester screening would elevate the trisomy 21 detection rate to 97% and decrease the false-positive rate to 3%. Analyzing nasal bone is a challenge for all sonographers, and, therefore, should only be performed by highly experienced clinicians.



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Figure 1

Nasal bone in a chromosomally normal fetus.

 
With the advent of first-trimester screening, a very powerful tool was introduced into prenatal medicine—one that has the potential to reassure pregnant women that they will give birth to a healthy baby. Very accurate risk estimations can now be offered, and invasive procedures such as amniocentesis or chorionic villi sampling can be performed with more reliability. For these reasons, it is extremely important to offer genetic counseling to women and their partners so that they understand the limits and risks of first-trimester screening.


    Acknowledgments
 
Special thanks to Dr Ingolf Böhm for a critical review of the manuscript.


    Footnotes
 
Presented in part at the 14th Workshop on Fetal Cells and Fetal DNA: Recent Progress in Molecular Genetic and Cytogenetic Investigations for Early Prenatal and Postnatal Diagnosis, Friedrich Schiller University, Jena, Germany, April 17–18, 2004.

Received for publication May 25, 2004; accepted August 26, 2004


    Literature Cited
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 Summary
 Literature Cited
 

Cicero S, Curcio P, Papageorhiou A, Sonek J, Nicolaides KH (2001) Absence of nasal bone in fetuses with trisomy 21 at 11–14 weeks of gestation. Lancet 358:1665–1667[CrossRef][Medline]

Cuckle H (1999) Maternal age-standardisation of prevalence of Down's syndrome. Lancet 354:529–530[CrossRef][Medline]

Eiben B, Alkier R, Denk R, Ellis A, Grunow G, Hackeloer B-J, Wagner H (2002a) On the perinatal risk precision in the first trimester of pregnancy in relation to nuchal translucency and biochemical analysis of maternal serum. Clin Lab 48:421–423[Medline]

Eiben B, Hackelöer B-J, Huesgen G, Kozlowski P, Merz E, Osmers R, Wagner H (2002b) Pränatale Risikopräzisierung im ersten Trimenon der Schwangerschaft über Messung der fetalen Nackentransparenz und biochemischer Analyse aus dem maternalen Serum. Ikon 11:2–8

Eiben B, Hammans W, Keuter S, Goebel R, Louwen F, Epplen JT (2001) Eine klinische Studie zur Wertigkeit der Trisomie 21. Risikopräzisierung im ersten Trimester der Schwangerschaft. Zeitschr Geburtsh Neonatol 205:94–98[CrossRef]

Hyett JA, Perdu M, Sharland GK, Snijders RJM, Nicolaides KH (1999) Using fetal nuchal translucency to screen for congenital cardial defects at 10–14 weeks of gestation: population based cohort study. Br Med J 318:81–85[Abstract/Free Full Text]

Nicolaides KH (2003) Screening for chromosomal defects. Ultrasound Obstet Gynecol 21:313–321[CrossRef][Medline]

Nicolaides KH, Sebire NJ, Snijders JM (1999) The 11–14-week Scan. The Diagnosis of Fetal Abnormalities. New York, London, The Parthenon Publishing Group

Schulte-Valentin M, Schindler H (1992) Non-echogenic nuchal oedema as a marker for trisomy 21 screening. Lancet 339:1053[Medline]

Spencer K, Heath V, Flack N, Ong C, Nicolaides KH (2000a) First trimester maternal serum AFP and total hCG in aneuploidies other than trisomy 21. Prenat Diagn 20:635–639[CrossRef][Medline]

Spencer K, Liao AW, Skentou H, Cicero S, Nicolaides KH (2000b) Screening for triploidy by fetal nuchal translucency and maternal serum free ß-hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 20:495–499[CrossRef][Medline]

Spencer K, Ong C, Skentou H, Liao AW, Nicolaides KH (2000c) Screening for trisomy 13 by fetal nuchal translucency and maternal serum free ß-hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 20:411–416[CrossRef][Medline]

Spencer K, Tul N, Nicolaides KH (2000d) Maternal serum free ß-hCG and PAPP-A in fetal sex chromosome defects in the first trimester. Prenat Diagn 20:390–394[CrossRef][Medline]





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