BRIEF REPORT |
First-trimester Screening : An Overview
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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Summary |
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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 [-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. 2001
).
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), 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) 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 (crownrump length 45 mm) to 1.5 mm in week 13 + 6 (crownrump 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. 1999
).
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. 2002a,b
). 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)(b
,c
,d
) 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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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. 1999). 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)
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) 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)
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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Acknowledgments |
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Footnotes |
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Received for publication May 25, 2004; accepted August 26, 2004
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Literature Cited |
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