가정의학회지 2003;24:775-780 J Korean Acad Fam Med

◇ 종 설 ◇ Prenatal Screening

Department of & Gynecology, College of Medicine, Korea University

Min Jeong Oh, M.D. ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Down syndrome is known as one of the most common causes of mental retardation. Screening for Down's syndrome in the second trimester of , based on the concentrations of various markers in serum and maternal age, has become widely used in the past decade. Down's syndrome is associated with low maternal serum alpha-fetoprotein and unconjugated concentrations and high maternal serum human chorionic gonadotropin and inhibin A concentrations. Measurements of the first three markers, in addition to age, constitute the widely used triple test; measurements of all four markers with age make up the quadruple test. The triple test shows 62% of detection rate and the quadruple test was substantially better than the triple test (70%). Also several sonographic markers, especially nuchal translucency and nasal bone apprears to be a highly effective method to screen for Down syndrome. ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ

INTRODUCTION and over 50% will be expected to survive beyond 50 years.3) This disorder is therefore one of the most important potential Screening has been defined as 'the systematic application of causes of mental retardation in the population. Women with a test or inquiry, to identify individuals at sufficient risk of a a Down syndrome affected frequently choose to terminate specific disorder to benefit from further investigation or direct their pregnancy. However, this is not the goal of prenatal preventative action, among persons who have not sought screening and diagnosis. The aim of genetic screening programs medical attention on account of symptoms of the disorder. and prenatal diagnosis should be to maximize the options Criteria for worthwhile screening programs include a well- available to families rather than to reduce the prevalence of the defined medically important disorder with known prevalence disease. and tests that are cost-effective, safe, accessible, and have TRIPLE TEST (MSAFP+uE3+hCG) well-defined performance.1) Identification of women who are at high risk for fetal Down syndrome is consistent with this 1. Alpha-fetoprotein definition. In 1984, Merkatz et al. reported that maternal serum alpha- Down syndrome is clinically characterized by mental fetoprotein (MSAFP) levels were lower in in which retardation, birth defects, and specific physical features that are fetal chromosomal abnormalities (primarily Down syndrome) identifiable at birth. Mental retardation ranges from mild to were present.4) The maternal age-specific risk is multiplied by severe with most cases showing a moderate level. At birth, a likelihood ratio determined by the heights of the MSAFP cardiac defects are present in approximately 56% of Down Gaussian distributions in affected and unaffected pregnancies. syndrome individuals, 11% show digestive tract anomalies and Fig. 1 illustrates the principle of using Gaussian distributions a diverse group of other anatomical defects may also be to modify risk. Using a 1：270 second trimester Down present.2) Approximately 85∼90% of individuals born with syndrome risk cut-off (equivalent to maternal age 35 in the Down syndrome can be expected to survive to 1 year of age absence of serum screening), it was estimated that MSAFP screening would allow an additional 20% of all affected 교신저자: 오민정 pregnancies to be identified. The biological function of AFP Tel: 02-818-6347, Fax: 02-838-1560 in the fetus remains poorly defined and the reason why MSAFP E-mail: [email protected] levels are lower in Down syndrome pregnancies is also unclear.

Vol. 24, No. 9 775 Min Jeong Oh : Prenatal Down Syndrome Screening ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Table 1. Expected detection rates for second trimester tests when the false positive rate is held at 5%. ꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧ Screening test Detection rate (%) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Maternal age alone ≥38 years at delivery 32 Maternal age, plus MSAFP 36 Total hCG 49 uE3 48 INH-A 45 MSAFP+hCG 63 MSAFP+uE3+hCG 71 MSAFP+uE3+hCG+INH-A 79 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Figure 1. Use of Gaussian distributions to adjust risk. In this Detection rates for maternal age plus serum tests are based on example, the test result is 1.5 MoM. The relative probability that pregnancies dated by ultrasound, with correction for maternal the result is from the unaffected population is given by the height, weight. n, of the unaffected distribution at 1.5 MoM and the relative probability that the result is from the affected population is given by the height, d, of the affected distribution. The likelihood ratio little advantage over those that measure total hCG. is d/n=3.2/1.1=2.91. If the maternal age specific risk for Down syndrome is 1：500, the risk following the screening test is 2.91： 3. Unconjugated estriol 500 or 1：172. Likelihood ratios derived from independent tests can be multiplied together. When tests are not completely Isolated case reports and an early study noted lower than independent, the correlation factors need to be factored into the normal levels of estriol in maternal urine when fetal Down calculations. syndrome was present. Subsequent analysis of second trimester maternal serum indicated that a reduction of unconjugated uE3 High levels of AFP have been found in the placentas of affected is nearly as useful as hCG and is more powerful than MSAFP pregnancies suggesting a defect in the secretion of AFP into in distinguishing between affected and unaffected pregnancies the maternal circulation. (Table 1).6) UE3 is produced by the placenta from the fetal precursor mol- 2. Human chorionic gonadotropin ecule 16 alpha-hydroxydehydroepiandrosterone sulfate (DHEAS). Bogart et al. showed that second trimester maternal serum In Down syndrome pregnancies, both uE3 and DHEAS appear human chorionic gonadotropin (hCG) levels are generally to be lower than normal in the fetal liver, placental tissue, and higher in maternal serum when fetal Down syndrome is maternal serum. This indicates that Down syndrome preg- present.5) They noted that hCG appeared to be superior to nancies are characterized by a diminished supply of DHEAS. MSAFP in detecting fetal chromosome abnormalities. HCG is The concentration of uE3 rises very rapidly during the a glycoprotein composed of two dissimilar subunits, α and β, second trimester and this analyte may therefore be particularly produced by the placenta. In addition to intact hCG, maternal sensitive in identifying those pregnancies where the fetus is serum contains free α, free β, and degradation products small or underdeveloped at the time of screening. (nicked hCG). Intact hCG and free β-hCG show peak concentrations at 8∼10 weeks gestation while free α-hCG QUADRUPLE TEST does not peak until much later in pregnancy. In the second (MSAFP+uE3+hCG+Inhibin-A) trimester, assays to both α- and β-subunits will help identify Down syndrome pregnancies. However, testing with an The use of inhibin as an additional marker for Down antibody that identifies all β-subunits (intact hCG and free syndrome screening was first suggested by Van Lith et al.7) β-hCG combined) appears to be superior. Assays also exist Inhibins are dimeric glycoproteins synthesized by gonads and that identify only the free β-hCG but these appear to have placental tissue. There are two subunits, α and β, the latter

776 가정의학회지 오민정 : 산전 다운증후군 선별검사 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ existing in two forms, βA and βB, to form inhibin-A or (14%), ad the odds of being affected in those with a positive inhibin-B. It is the inhibin-A (INH-A) form that has been result less favourable (1：147) than those obtained with the shown to have the greatest practical utility in Down syndrome quadruple test (Table 2). screening. INH-A and hCG secretions appear to be in- Tabel 3 shows detection rates for a 5% false-positive rate terdependent, with increased production of INH-A by placental for all methods, before and after adjustment for the trophoblasts in pregnancies complicated by Down syndrome. spontaneous fetal loss of affected pregnancies after about 16 There is a moderately strong correlation between the maternal weeks of gestation. The adjusted detection rates show that the serum concentrations of hCG and INH-A in both affected and quadruple test was substantially better than the double test unaffected pregnancies.8) Nevertheless, INH-A still provides (70% vs 57%) and moderately better than the triple test (70% good distinction between affected and unaffected pregnancies, vs 62%). The additional advantage of the quadruple test over alone, or in combination with other tests and this can include the triple test is that, at the same 5% false-positive rate, it hCG (Table 1).9) detected 21% of the cases missed by the triple test. Procedures for performing the INH-A immunoassay were The quadruple test meets or exceeds performance ex- initially complex, limiting its practical adaptation to a routine pectations and appears to represent an improvement over the clinical chemistry setting. However, the availability of widely used triple test. simplified procedures and commercially available kits has facilitated its introduction. In the second trimester, INH-A SONOGRAPHIC MARKERS concentrations vary less with than those seen 1. Nuchal translucency for many other markers making risks based on this test somewhat less susceptible to gestational age inaccuracy.10) Considerable pregress has been made in using first trimester Quadruple screening was undertaken and maternal age ultrasound markers in screening for Down syndrome. Most recorded 46,193 pregnancies by Wald, et al.11) Of 88 observed important of these markers is the measurement of nuchal Down's syndrome pregnancies, 71 (81%) had a positive translucency (NT), the thickness of the subcutaneous fluid- screening result (81% detection rate, 95% CI 72∼89), and of filled space at the back of the neck of the developing fetus.12) 46,105 unaffected pregnancies, 3200 tested positive (7% false- Using NT measurements and age alone, it was estimated that positive rate). The odds of being affected in those with a 73% of affected pregnancies would be identified if the positive screening result were 1：45. With maternal age alone, false-positive rate is set at 5%.13) The ultrasound examination the detection rate would have been much lower (51%, 95% is carried out at 10∼14 weeks gestational age. CI 41∼62%), the false-positive rate more than twice as high

Table 2. Results of antenatal screening for Down's syndrome with quadruple test (including maternal age) and with maternal age alone. ꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧ Odds of being Number of pregnancies Number of screen Detection False-positive affected given screened positives rate rate a positive result ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ With With All Down's Unaffected All Down's Unaffected SD SD ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Screening method Quadruple 46,193 88 46,105 3,271 71 3,200 71 of 88 3,200 of 46,105 1：45 (71：3,200) test*† (81%) (7%) Maternal 46,193 88 46,105 6,659 45 6,614 45 of 88 6,614 of 46,105 1：147 (45：6,614) age (51%) (14%) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ *Risk at term ≥1 in 300, †≥35 years

Vol. 24, No. 9 777 Min Jeong Oh : Prenatal Down Syndrome Screening ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Table 3. Detection rates (DR) and adds of being affected given a positive result (OAPR) for a flxed 5% false-positive rate by method of screening. ꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧ Observed Adjusted* ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ DR (95% CI) OAPR DR OAPR ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Screening method Maternal age alone 26% (17∼35) 1：104 24% 1：135 Double test† 61% (51∼72) 1：43 57% 1：56 Triple test‡ 66% (56∼76%) 1：40 62% 1：52 Quadruple test§ 75% (66∼84) 1：35 70% 1：45 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ 88 Donw's syndrome pregnancies observed. *Allowing for spontaneous fetal loss of Down's syndrome pregnancies after about 16 weeks gestation, †Alphafetoprotein and hCG, ‡Alphafetoprotein, hCG, and unconjugated oestriol, §Alphafetoprotein, hCG, unconjugated oestriol, and inhibin A. All tests include maternal age.

2. Nasal bone bone absence was again noted to be very low (0.5%). The absence of a fetal nose during the 15∼20-week scan was noted Prenatal nasal bone evaluation with ultrasound is proving to to increase the risk of DS 83 times. The actual NBL has been be an exceptionally powerful marker for Down syndrome. This found to play an important role as well. These investigators is not surprising given the fact that the Down Syndrome looked at the utility of biparietal diameter (BPD)/NBL ratios. phenotype has been known to be associated with nasal bridge This ratio increases as the nasal bone becomes shorter. They abnormalities ever since its original description by Langdon found that a discriminatory BPD/NBL ratio of ≥10 would Down in 1866. However, the striking abnormalities of the give this test a sensitivity of 81% with a false-positive rate of nasal bone appearance as seen by prenatal sonography were not 11%. Bromley et al.15) also confirmed that NBL increases recognized until early 2001. linearly with gestational age in euploid . However, the The first of these studies was published in 2001.14) In this NBLs in DS fetuses were found to be remarkably uniform (3.5 study, a remarkable difference in the incidence of nasal bone ±0.47 mm) over the gestational period investigated. absence in fetuses with DS and in euploid fetuses was found Another study looking at the utility of nasal bone evaluation during the 11∼14-week scan. The incidence of nasal bone in the second trimester (15∼22 weeks' gestation) was absence in DS fetuses was 73% whereas only 0.5% fetuses with reported.16) A total of 62% of DS fetuses were noted to have normal chromosomes were noted to have an absent nasal bone. absent or hypoplastic nasal bones (＜2.5 mm) during this The presence or absence of the nasal bone was found to be gestational period. The incidence of nasal bone hypoplasia in independent of other fetal and maternal variables. This large trisomy 18 fetuses was 7%. Euploid fetuses were found to have difference in the incidence of nasal bone absence not only an incidence of nasal bone hypoplasia of 1.2% during the same increased the sensitivity of the early (11∼14 weeks) preg- time period. A difference between Caucasian and Afro-Carib- nancy-screening test but also decreased the false-positive rate. bean populations in the incidence of nasal bone hypoplasia was In this way, the addition of nasal bone evaluation increases the noted, suggesting that racial adjustments need to be made correct identification of DS fetuses whilst decreasing the when using the nasal bone for screening. exposure of euploid fetuses to the risk of invasive procedures. The importance of a standardized view of the nasal bone The benefit of nasal bone evaluation in screening for DS in cannot be overstated. The fetus must be imaged facing the the early- and mid-second trimester has now been confirmed transducer. The fetal face is viewed longitudinally and strictly in larger trials. The absence vs. presence of the nasal bone in the midline. In this view, a normal nasal bone is identified continues to be very important. In a publication by Bromley, as a thin echogenic line within the bridge of the nose. The et al.15), nasal bone absence in DS fetuses between 15 and 20 skin over the nasal bridge can be as echogenic as the nasal weeks' gestation was noted to be 43%. Among the fetuses with bone itself. This is especially true during the 11∼14-week a normal chromosomal complement, the incidence of nasal

778 가정의학회지 오민정 : 산전 다운증후군 선별검사 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Figure 3. A diagrammatic representation of the fetal skull. Angles Figure 2. Ultrasound image showing the two parallel horizontal of insonation with respect to the longitudinal axis of the nasal bone echogenic lines in the nose, the top one representing the skin and are shown. the bottom one representing the nasal bone and cartilage. A third line, almost continuous with the skin, but at a higher level, represents the tip of the nose. the lateral resolution of the ultrasound equipment is often not sufficient to image the nasal bone and the diagnosis of nasal bone absence can be made in error. scan. Therefore, the nasal bone must be clearly identified as Finally, in common with the evaluation of NT and other a second echogenic line beneath the skin. A second surface ultrasound markers whose effectiveness depends on a consistent echogenic line in front of the nasal bridge is usually seen. This and standard approach, care must be taken to implement nasal represents the skin over the tip of the nose. An echogenic line bone evaluation in clinical practice only when there is the or lines can also often be seen within the tip of the nose. These expertise and equipment to do so. Optimally, formal training lines probably represent the cartilage and/or parts of the and ongoing quality assurance audit should be a part of vomeral bones. This view was proposed and described by The implementing such a program. Fetal Medicine Foundation (Fig. 2).14) One source of some confusion is the angle of insonation with 3. Other soft markers which the nasal bone should be imaged. For example, the Second trimester ultrasound may identify specific "markers" method proposed by The Fetal Medicine Foundation uses an that have been associated with Down syndrome. These markers angle of insonation of 45. with respect to a reference line, include increased nuchal fold thickness, short femur and which connects the fetal forehead and the chin. The angle of 17) humerus, echogenic cardiac foci, renal pyelectasis, echogenic insonation described in the paper by Minderer et al. is also bowel and presence of choroid plexus cysts.19) 45. but the reference line here connects the forehead and the tip of the fetal nose. In practice, the actual angle of insonation CONCLUSION only roughly approximates to the 45˚ proposed in these two descriptions. A much simpler way to describe the angle of The second trimester triple and quadruple tests provides a insonation is to use the longitudinal axis of the nasal bone as useful tool for Down syndrome screening. The combination of the reference line, i.e. the nose should be viewed with the sonographic finding and new test development should lead to longitudinal axis of the nasal bone being at 90. to the greater efficacy in screening for Down syndrome. insonating beam (Fig. 3).18) Absence of the nasal bone is best demonstrated in the same view with the angle of insonation being perpendicular to the echogenic skin over the nasal REFERENCES bridge. Care must be taken to avoid imaging the nasal bone with the angle of insonation approaching either 0. or 180. 1. Wald NJ. Guidance on terminology. J Med Screen 1994;1:76. Since the nasal bone is very thin, when it is viewed 'on end' 2. Torts CP. Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med

Vol. 24, No. 9 779 Min Jeong Oh : Prenatal Down Syndrome Screening ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Genet 1998;77:431-8. 361:835-6. 3. Baird PA, Sadovnick AD. Life tables for Down syndrome. 12. Benn PA. Advances in prenatal screening for Down syndrome: Hum Genet 1989;82:291-2. II. first trimester testing, integrated testing, and future direc- 4. Merkatz IR, NitowskyHM, Macri JN, Johnson WE. An tions. Clinica Chimica Acta 2002;324:1-11. association between low maternal serum alpha-fetoprotein and 13. Nicolaides KH, Snijders RJ, Cuckle HS. Correct estimation of fetal chromosomal abnormalities. Am J Obstet Gynecol 1984; parameters for ultrasound nuchal translucency screening. Pre- 148:886-94. nat Diagn 1998;18:519-23. 5. Bogart MH, Pandian MR, Jones OW. Abnormal maternal 14. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. serum chorionic gonadotropin levels in pregnancies with fetal Absence of nasal bone in fetuses with trisom 21 at 11∼14 chromosome abnormalities. Prenat Diagn 1987;7:623-30. weeks of gestation: an observational study. Lancet 2001;358: 6. Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal 1665-7. screening for Down's syndrome. J Med Screen 1997;4:181- 15. Bromley B, Lieberman E, Shipp T, Benacerraf B. Fetal nasal 246. bone length: a marker for Down syndrome in the second 7. Van Lith JM, Pratt JJ, Beekhius JR, Mantingh A. Second- trimester. J Ultrasound Med 2002;21:1387-94. trimester maternal serum immunoreactive inhibin as a marker 16. Cecero S, Sonek J, McKenna D, Croom C, Johnson L, Nicol- for fetal Down's syndrome. Prenat Diagn 1992;12:801-6. aides K. Nasal bone hypoplasia in fetuses with trisomy 21. 8. Wald NJ, Densem JW, George L, Muttukrishna S, Knight Ultrasound Obstet Gynecol 2003;21:15-8. PG. Prenatal screeningfor Down's syndrome using inhibin-A 17. Minderer S, Gloning KP, Henrich W, Stoger H. The nasal as a serum marker. Prenat Diagn 1996;16:143-52. bone in fetuses with trisomy 21: sonographic versus path- 9. Benn PA. Advances in prenatal screening for Down syndrome: omorphological findings. Ultrasound Obstet Gynecol 2003;22: I. General principles and second trimester testing. Clinica 16-21. Chimica Acta 2002;323:1-16. 18. Sonek JD. Nasal bone evaluation with ultrasonography: a 10. Watt HC, Wald NJ, Huttly WJ. The pattern of maternal marker for fetal . Ultrasound Obstet Gynecol 2003; serum inhibin-A concentrations in the second trimester of 22:11-5. pregnancy. Prenat Diagn 1998;18:846-8. 19. Drugan A, Johnson MP, Evans MI. Ultrasound screening for 11. Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening for fetal chromosome anomalies. Am J Med Genet 2000;90:98- Down's syndrome with the quadruple test. Lancet 2003; 107.

780 가정의학회지