부산대병원학술지통권제 33 호, 2013 태아의염색체이상을발견하기위한산전선별검사 양산부산대학교병원산부인과 이동형 Antenatal screening methods for fetal chromosomal abnormalities Dong Hyung Lee, M.D. De

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1 부산대병원학술지통권제 33 호, 2013 태아의염색체이상을발견하기위한산전선별검사 양산부산대학교병원산부인과 Antenatal screening methods for fetal chromosomal abnormalities Dong Hyung Lee, M.D. Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Yangsan, Korea Abstract * Noninvasive screening based on biochemical analysis of maternal serum or fetal ultrasound measurements allows estimates of the risk of a pregnancy being affected, and provides information to guide decisions about definitive testing. Screening options in the first trimester include nuchal translucency testing in combination with measurement of pregnancy-associated plasma protein-a(papp-a) and human chorionic gonadotropin(hcg). Screening options in the second trimester include serum screening using triple or quadruple screening, and ultrasonography. Patients may also choose a combinationof first- and second-trimester screening in an integrated, stepwise sequentialor contingent sequential fashion. However, as * 본연구는 2011 년도양산부산대학교병원임상연구비지원으로이루어졌음

2 more complex options for risk assessment become available, it is more difficult to compare the performance of different screening tests conductedat different times during pregnancy. This article reviews first- and second-trimester screening tests and estimatesthe most effective prenatal screening test at present. In addition, introduces the current study of non-invasive chromosomal approach of screening method using cell-free DNA. Key words: Down syndrome, nuchal translucency, maternal serum screening test, aneuploidy 서론 염색체이상은전체출생아의약 0.4% 를차지하며사산이나신생아사망의 6-7% 를차지한다. 1 또한신생아기형의약 10-15% 에서염색체이상을동반하는것으로알려져있다. 2 선천기형을가진태아의출산은당사자뿐만아니라가족에게도심각한경제적, 사회적문제를일으킬수있다. 하지만홀배수체를산전에진단하기위하여시행되는양수검사, 융모막생검은침습적검사방법으로검사자체에의한태아소실률이약 1-2% 정도로보고되고있다. 3 따라서이러한침습적검사전에염색체이상이있는태아를조기에발견하여불필요한침습적인검사로인한임산부와태아의합병증발생위험을줄이고, 가족에대해서는염색체이상태아에대한마음의준비를할시간적여유를주고조기에임신종결을고려할수있도록여러가지산전선별검사가연구되고있다. 본논문에서는염색체이상을가진태아를조기에발견하기위해현재임상적으로시 행되고있는모체혈청검사및초음파검사소견의종류에대해알아보고, 가장효율적인선별검사방법은무엇인지알아보고자한다. 나아가현재의다중표지자검사방법을대체할수있는더욱정확도가높은비침습적선별검사로알려진 cfdna를이용한선별검사에대해서도다루어보고자한다. 본론 1. 임신제1삼분기선별검사 (First-Trimester Screening) 1) 초음파검사산전태아초음파검사는비침습적검사로서임신중태아에부작용이없다는장점을가지고있어산부인과영역에서널리쓰이고있다. 태아염색체이상이있을시구조적인기형이동반되는경우가많아초음파검사를통해홀배수체와같은염색체이상을예측할수있다

3 태아의염색체이상을발견하기위한산전선별검사 (1) 목덜미투명대 (Nuchal translucency) 태아목덜미투명대는초음파에서태아의목뒤연조직과피부조직경계사이에체액이차있는무에코성피하공간을말한다. 이는임신제 1삼분기모든태아에서나타나는초음파소견으로, 림프관형성부전이나심장기형에의한심부전, 다운증후군등의경우증가된소견을보인다. 특히, 목덜미투명대두께가증가할수록태아홀배수체의위험이증가하여태아홀배수체진단에있어매우우수한선별검사도구로사용된다. (Table 1)(Fig 1, 2) 1992년 Nicolaides 등 4 은최초로이두께가 3.0 mm 이상으로증가하는경우태아홀배수체위험이높다고하였다. 그러나임신주수에따라서, 그리고태아머리-엉덩길이 (crown-rump length, CRL) 증가에따라서목덜미투명대두께도증가한다. 따라서이후여러연구결과비정상목덜미투명대증가기준을 3.0 mm와같은고정된수치를사용하기보다는해당머리-엉덩길이의 95백분위수를기준으로하는것을권고하고있다. 5,6 검사자의숙련도및가이드라인에따라진단률이달라질수는있으나여러연구에서대개목덜미투명대검사단독시행시다운증후군진단율이 76.8% (4.2% 의위양성률 ) 정도라밝히고있다. 7 이러한목덜미투명대증가는또한태아의주요선천성심기형, 대혈관기형, 태아기형, 이형성, 유전적증후군등과도연관되어있어태아홀배수체뿐아니라다양한선천성태아이상을예측하는데중요한초음파표지자가될수있다. (2) 코뼈 (Nasal bone) 유무다운증후군특징적인소견중의하나로 nasal bone hypoplasia를들수있다. 태아코뼈는임신전기간동안초음파상에보이게되는데몇몇연구에의하면임신 11-14주사이에초음파상코뼈가보이지않는것이 trisomy 21 및다른염색체이상과강한연관성을가진다고한다 (Table 2) 정상적으로는초음파에서 3개의선이보여야한다. Figure 1을보면이마에가까운쪽의두개의강한에코성선은윗쪽이피부이고아랫쪽이코뼈를나타낸다. 그리고세번째선은피부라인을따라바로아래쪽으로에코성으로보이는데이것은코끝을의미한다. Figure 2의trisomy 21 태아의초음파에서는피부를나타내는에코성선아래쪽으로코뼈를의미하는에코성선이소실되어있음을볼수있다. 여러연구결과를통합하여보면 Trisomy 21 태아의 69% 에서코뼈가보이지않았고정상염색체태아의 1.4% 에서코뼈가보이지않았다. 7 (3) 부수적인초음파소견이외에도 Trisomy 21 태아는도플러초음파에서 ductus venosus에비정상적인혈류속도를보일수있고 maxillary hypoplasia 를보이는경우도있다. Trisomy 18 에서는조기태아성장지연, 서맥, 배꼽탈장, 단일배꼽동맥등을보일수있고, Trisomy 13에서는태아빈맥, 조기태아성장지연, megacystis, holoprosencephaly 또는배꼽탈장등을흔히보인다고한다

4 2) 모체혈청검사 (1) 임신관련혈장단백질 A (pregnancyassociated plasma protein A, PAPP-A) PAPP-A는임신중에분비되는단백질의한종류로서태아홀배수체가있는경우임신제 1삼분기에감소한다는사실이밝혀지면서다운증후군등의선별검사에유용하게사용되고있다. (2) free β-hcg 태반의태아쪽에서만들어지는호르몬으로상승시다운증후군위험이높아지게된다. hcg는 α, βsubunit으로이루어져있으며순환혈액속에는 α, β가결합된 active form hcg와 free α-hcg, freeβ -hcg가존재하고있다. 다운증후군에서모체혈청 PAPP-A는중앙값이대략 0.5 MoM (Multiple of the Median) 으로약 50% 정도감소되어있고 free β-hcg는약 2 MoM으로두배상승되어있다. 7 임신제1삼분기선별검사로위의두표지자를같이측정할경우진단률은 60~74% 이고이때의위양성률은 5% 이다. 12,13 3) 복합선별검사 (The First Trimester Combined Test) 태아목덜미투명대두께는임신제1삼분기모체혈청표지자인 PAPP-A, β-hcg 농도와상관관계없이독립적으로태아홀배수체와관련이있으므로임신제1삼분기에혈청검사 (PAPP-A, β-hcg) 와목덜미투명대검사를병행하는복합선별검사를시행 하면선별검사의정확도를높일수있다. Rosen T 등 14 의메타분석결과를보면복합선별검사는발견율 86% (84~88 95% CI), 위양성률 5.1% 로다운증후군을발견할수있다고보고하였고 SURUSS 연구에서는다운증후군발견율이약 86% ( 위양성률 5%), FASTER trial에서는복합선별검사시임신 11주, 12주, 13주에서다운증후군발견율이각각 87%, 85%, 82% ( 위양성률 5%) 로나타났다. 12,13 이는제 1삼분기에목덜미투명대두께만시행한경우나 Dual test (PAPP-A + free β-hcg) 만시행한경우에대략70% 대의발견율을보인것에비해더높은정확도를보여준다. 2. 임신제2삼분기선별검사 (Second-Trimester Screening) 1) 초음파검사초음파적소견은주기형 (major structural anomalies) 과소기형 (minor anomalies) 으로분류할수있는데주기형이발견된경우염색체이상의고위험으로보고염색체검사를시행하는것이일반적으로받아들여지고있으나소기형이단독발견되었을경우에는추가검사의필요성을신중하게검토하여야한다. 정상태아에서도관찰될수있으나임신주수가경과하면서소실되기도하는기형을특히 "soft markers" 라고한다. 15 이러한표지자가발견된경우태아홀배수체위험이높아지나진단적이지는않고각각의홀배수체와의연관정도는다양하게나타날수있어염색체이상가능성을고려하여추가적인검사를결정하는것이중요하다

5 태아의염색체이상을발견하기위한산전선별검사 (1) 홀배수체와관련된주기형 (Major anomalies) Table 3에서 13, 18, 21 trisomy, 터너증후군에서주로발견되는구조적주기형소견을정리하였다. (2) Soft markers 제2삼분기에흔한 soft markers는목덜미두꺼워짐, 고에코성의장, 짧아진사지, 신우확장증, 심장내에코발생부위, 맥락막총낭종등이있다. 1 목덜미두꺼워짐 (Nuchal Fold Thickness) Nuchal fold란태아목뒤쪽의피부두께를의미한다.(fig.3 B) Cavum septum pellucidum과 thalami 레벨의태아머리횡단면을측정하는데뒤쪽으로는소뇌가포함되도록한다. 후두뼈바깥경계와피부바깥쪽경계사이의거리를측정한다. 두꺼워진정도에대한정의는센터마다다를수있으나일반적으로임신18~24주에 6 mm 이상일때, 16~18주에 5 mm 이상이라면유의미하게증가하였다고본다. 16 목덜미두꺼워짐은임신제1삼분기에시행하는목덜미뒤쪽의액체공간을측정하는목덜미투명대 (Nuchal translucency) 와혼동하지않도록한다. 메타분석에의하면목덜미두께증가시다운증후군위험도가대략 17배정도증가한다. (CI 8-35) 2 고에코성의장 (Echogenic Bowel) 고에코성장은주변의뼈와비슷하거나그 이상의고에코성을보이는태아장영역을의미한다.(Fig.3 E) 고에코성장이보이면 trisomy 13, 18, 21 그리고성염색체이상의위험이높아진다. 또한장폐색, 선천성감염, 드물게는낭성섬유증에서이차적인태변장마비와도관련이있는것으로알려져있다 짧아진사지 (Shortened humerus, Shortened femur) 짧아진사지는해당임신에서 2.5 백분율이하이거나 biparietal diameter (BPD) 에서예측하는것보다 0.9 이하인경우로정의한다. 18 특히 trisomy 21에서발견되는특징이다. 4 신우확장증 (Renal pyelectasis) 정상태아에서는 renal pelvis 내에구형의저에코성공간크기가 5 mm 미만으로나타나지만이보다커지는경우신우확장증이있다고본다. 19 (Fig.3 D) 신우확장증소견이단독으로존재하고다른위험요소가없다면다운증후군확률은낮으며침습적인진단검사를시행해야할중요도는떨어진다. Renal pelvis가 10 mm보다증가한다면선천적인수신증 (conngenital hydronephrosis) 과동등하게고려할수있으며적절한추가적인검사가시행되어야한다 맥락막총낭종 (Choroid plexus cyst) 맥락막총낭종은임신14~24주에보이는양성낭종으로, 측뇌실내맥락막에서보인다. (Fig.3 A) 그크기나낭종갯수는임상적인

6 중증도와관련성이없으며제2삼분기동안 1% 정도의유병률을갖는다. 21 Trisomy 18 태아의 50% 에서맥락막총낭종이보이나다른동반기형없이맥락막총낭종만단독으로존재하는경우는 10% 에불과하다 심장내에코발생부위 (Echogenic intracardiac focus, EICF) 심장내에코발생부위는태아심장의한쪽또는양쪽심실의유두근 (papillary muscle) 영역에보이는국소적인에코성부위로정의할수있다. 22 (Fig.3 C) 발생빈도는좌심실이나양심실이높으나태아홀배수체위험도가높은것은오히려발생빈도가낮은우심실, 양심실및에코발생부위가여러개인경우이다. 2) 모체혈청선별검사 (1) 삼중검사 (Triple test) Triple test는임신중기에임신부나이와더불어혈청afp, total hcg 및 ue3를측정하여분석하는방법이다. 여러다중표지자의정확도를비교한대규모전향적연구가영국 (Serum, Urine and Ultrasound Screebubg Study; SURUSS) 과미국 (First and Second Trimester Evaluation of Risk for Fetal Aneuploidy; FASTER) 에서있었다. FASTER trial에의하면다운증후군임신시 AFP는중앙값 0.74 MoM, hcg 1.79 MoM, unconjugated estriol (ue3) 0.70 MoM 특징을보인다. 12 위양성률 5% 에서 Triple test는다운증후군발견율이 74% (SURUSS), 70% (FASTER) 에이 른다. 12,13 Triple test는 18 삼염색체선별검사에도또한이용될수있다. 18 삼염색체에서는모든혈청표지자농도가감소하는특징을지닌다. (2) 사중검사 (Quadruple test) 1992년 Van Lith 등이처음 inhibin A와 trisomy 21 사이의연관관계를보고한이후로후속연구들을통해 Triple test에 dimeric inhibin alpha (inhibin A) 검사를추가하여 quad test를시행하게되었다. 23 FASTER trial에따르면다운증후군에서 inhibin A는약 MoM값을나타낸다고알려져있다. 12 위양성률 5% 에서 Quad test는다운증후군발견율이 81% (SURUSS, FASTER) 에이른다. 12,13 3. 임신제1삼분기와 2삼분기검사병합 (Combined First- and Second- Trimester Screening) 1) 통합검사 (Integrated screening) Integrated screening은 Serum integrated test 및Full integrated test로나뉠수있다. Full integrated test는임신제1삼분기에 PAPP-A 및목덜미투명대검사를시행하고제2삼분기에 quadruple test (AFP + total hcg + ue3 + inhibin A) 를순차적으로시행한다음, 검사결과는제2삼분기검사까지모두끝난후알려주게된다. Serum integrated test는 full integrated test에서목덜미투명대검사만제외한검사방법이다

7 태아의염색체이상을발견하기위한산전선별검사 2) 순차적선별검사 (Stepwise sequential screening) 임신제1삼분기에 PAPP-A, 목덜미투명대검사를시행하고선별검사결과가양성이라면바로침습적인염색체검사 (chorionic villus sampling) 를시행하거나, 위험도를재평가하기위해서제2삼분기 triple test 나quadruple test를기다리게된다. 즉, integrated screening과다른점은 1삼분기검사가끝난후환자에게검사결과를알려주고침습적진단검사를진행할것인지를결정하게된다는점이다. 3) 분할선별검사 (Contingency screening) Contingency screening 역시임신제1삼분기에 PAPP-A, nuchal translucency 검사를시행한다. 하지만 stepwise sequential screening과다른점은제1삼분기검진결과를 1차절단선 (cut-off) 및 2차절단선 (second cut-off) 을기준으로 3 그룹으로나눈다. Cut-off를넘어서는고위험군은침습적인진단검사를시행하고 second cutoff아래의저위험군이라면더이상추가적인검사는시행하지않는다. 두기준값사이의중간위험군은임신제2삼분기모체혈청검사를권고하게된다. 24 기준으로 67~81% 의발견률을보이고있는데반해 1삼분기와 2삼분기검사를통합한 integrated test는위양성률 5% 정도에서발견율 96% 까지보여가장효과적인검진방법이라할수있다. 7, Chromosome-selective sequencing of cell-free DNA (cfdna) 현재염색체이상을진단하는 gold standard 는결국융모막융모생검및양수천자와같은침습적인검사를통해태아세포의핵형을분석하는것이다. 하지만이러한검사는잠재적으로유산, 출혈, 감염과같은합병증의위험성이있다. 따라서모체혈청검사및초음파와같은비침습적인검사를선별검사에이용하고있으나, 다양한표지자를이용한여러조합의검사가있어임상적으로적용할수있는하나의알고리듬이존재하지않는다. 이러한한계를보완할수있는대체선별검사로서모체혈청내에존재하는 21번염색체와 18번염색체 fetal cell-free DNA (cfdna) 양을분석하여태아홀배수체를진단하고자하는비침습적인산전검사 (Non -Invasive Prenatal Testing, NIPT) 를개발하려는연구가진행되고있다. Table 4에산전검사로가능한여러검사조합을다운증후군발견율및위양성률에따라정리하였다. 연구결과를비교해보면임신 1삼분기 combined test (hcg + PAPP -A + NT) 가위양성률 3~5% 로 85% 전후의다운증후군발견률을보이고, 임신 2삼분기의 Quadruple test가위양성률 3~5% 3개국 4002명의임신 10~22주사이임신부를대상으로한전향적코호트연구인 Non-Invasive Chromosomal Evaluation (NICE) 연구결과에따르면 cfdna를이용한선별검사에서 Trisomy 21에대해민감도 100% (95% CI, %), 위양성률 0.03% (95% CI, %) 를보였으

8 며, Trisomy 18에대해서는민감도 97.4% (95% CI, %), 위양성률 0.07% (95% CI, %) 을보였다. 40 따라서임신10주정도의이른시기에한번의혈액검사를통해 trisomy 21을 99% 이상발견할수있어불필요한융모막융모검사나양수천자와같은침습적인검사로인한잠재적인위험을감소시키는장점이있다고한다. 하지만현재의초음파검사및모체혈청검사등의선별검사와어떻게조합시킬것인가의문제가있고오히려현재의혼란을더가중시켜진단검사를받아야할임신부의의사결정을지연시켜진단이늦어질수있다. 또한아무리좋은선별검사라하더라도침습적인진단검사보다더정확도가높지는않으며, 침습적인검사는완전한핵형분석이가능하므로흔한홀배수체뿐만아니라잠재적인유전적이상에대한정보까지제공해줄수있는장점이있다. 따라서현재의선별검사를대체할수있는임상적으로적용가능한검사가되기위해서는좀더많은논의와연구가필요할것으로보인다. 결론 태아홀배수체선별검사는임신제 1삼분기, 제 2삼분기에시행할수있는초음파와여러모체혈청표지자검사조합에따라다양한방법으로시행할수있다. 제1삼분기검사로는 Double test에 NT를결합한통합검사의발견율이높으며, 제2삼분기검사로는 Triple test가일반적으로이용되어왔으나최근에는 inhibin A를추가한 Quad test가더많이이용되고있다. 제1삼분기와 2삼분기선별검사를모두시행하는 Integrated test는발견률이높고위양성률이낮아현재로서는가장용이하게효율적으로이용할수있는방법이기는하나제1 삼분기에검사한후 3-4주후에한번더채혈을하고그결과를기다려야하는불편함이있다. 따라서모든임신부에게공통된방식으로선별검사를시행하기보다각검사의특징과발견율, 위양성률을숙지한후임산부의연령과초음파소견, 환자의순응도에맞춰개별적으로검사방법을선택적용할필요가있다. 현재의산전선별검사는태아이상을조기에진단할확률을높이고침습적인진단검사횟수를줄일수있는장점이있으나선별검사의종류가다양하고하나의알고리듬이존재하지않아임산부에게혼란을줄수있으며선별검사를하더라도침습적인진단없이모든홀배수체태아를진단할수는없다는한계가있다. 따라서더높은정확도로태아홀배수체를진단할수있는비침습적인산전검사 (Non-Invasive Prenatal testing, NIPT) 를개발하기위한노력이앞으로도계속되어야할것이다. 참고문헌 1. 홍창의. 소아과학. 제8판. 서울. 대한교과서 ( 주 ), 2004; Park SY, Kim JW, Kim YM, et al. Frequencies of fetal chromosomal abnormalities at prenatal diagnosis: 10 years experiencies in a single

9 태아의염색체이상을발견하기위한산전선별검사 institution. J Korean Med Sci 2001; 16: Mujezinovic F, Alfirevic Z. Procedurerelated complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007;110: Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimesterof pregnancy. Br Med J 1992;304: Chung JH, Yang JH, Song MJ, et al. The distribution of fetal nuchal translucency thickness in normal Korean fetuses. J Korean Med Sci 2004;19: Kim MH, Park SH, Cho HJ, et al. Threshold of nuchal translucency for the detection of chromosomal aberration: comparison of different cut-offs. J Korean Med Sci 2006;21: Nicolaids KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191: Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at weeks of gestation: an observational study. Lancet 2001;358 : Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH. Absent nasal bone at weeks of gestation and chromosomal defects. Ultrasound Obstet Gynecol 2003;22: Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at weeks scan. Ultrasound Obstet Gynecol 2004; 23: Snijders RJM, Sebire NJ, Nayar R, Souka A, Nicolaides KH. Increased nuchal translucency in trisomy 13 fetuses at weeks of gestation. Am J Med Genet 1999;86: Fergal D, Jacob A, Robert H, et al. First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-Trimester or Second-Trimester Screening, or Both, for Down s Syndrome. N Engl J Med 2005;353: Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down s syndrome: the results of the Serum Urine and Ultrasound Screening Study (SURUSS). J Med Screen 2003;10: Rosen T, D Alton ME. Down syndrome screening in the first and second trimesters: what do the data show? Semin Perinatol 2005;29:

10 15. Van den Hof MC, Wilson RD; Diagnostic Imaging Committee, Society of Obstetricians and Gynaecologists of Canada; Genetics Committee, Society of Obstetricians and Gynaecologists of Canada. Fetal soft markers in obstetric ultrasound. J Obstet Gynaecol Can 2005;27: Gray DL, Crane JP. Optimal nuchal skin - fold thresholds based on gestational age for prenatal detection of Down syndrome. Am J Obstet Gynecol 1994;171: Muller F, Dommergues M, Aubry MC, et al. Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome. Am J Obstet Gynecol 1995;173: Benacerraf B, Gelman R, Frigoletto F. Sonographic identification of second -trimester fetuses with Down s syndrome. N Engl J Med 1987;317 : Adams MM, Erickson JD, Layde PM, Oakley GP. Down's syndrome. Recent trends in the United States. JAMA 1981;246: Arger PH, Coleman BG, Mintz MC, et al. Routine fetal genitourinary tract screening. Radiology 1985;156: Yoder PR, Sabbagha RE, Gross SJ, Zelop CM. The second-trimester fetus with isolated choroid plexus cysts: a meta-analysis of risk of trisomies 18 and 21. Obstet Gynecol 1999;93: Shipp TD, Benacerraf BR. Second trimester ultrasound screening for chromosomal abnormalities. Prenat Diagn : Van Lith JMM, Pratt JJ, Beekhuis JR, Mantingh A. Second trimester maternal serum immunoreactive inhibin as a marker for fetal Down s syndrome. Prenat Diagn : Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester: model predicted performance using metaanalysis parameters. Semin Perinatol 2005;29: ACOG Committee on Practice Bulletins. ACOG practice bulletin: screening for fetal chromosomal abnormalities. Obstet Gynecol.2007;109: Rhoads GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med. 1989; 320: Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2003; (3):CD Tabor A, Philip J, Madsen M, Bang

11 태아의염색체이상을발견하기위한산전선별검사 J, Obel EB, Nørgaard-Pedersen B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet. 1986;1: Comstock C, Malone FD, Ball RH, et al. for the FASTER Research Consortium. Is there a nuchal translucency millimeter measurement above which there is no added benefit from first trimester screening? Am J Obstet Gynecol. 2006;195: Saltvedt S, Almstrom H, Kublickas M, et al. Screening for Down syndrome based on maternal age or fetal nuchal translucency: a randomized controlled trial in 39,572 pregnancies. Ultrasound Obstet Gynecol. 2005;25: Dugoff L, Hobbins JC, Malone FD, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concen-trations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol. 2004;191: Benacerraf BR. The role of the second trimester genetic sonogram in screening for fetal Down syndrome. Semin Perinatol. 2005;29: Saltvedt S, Almstrom H, Kublickas M, Valentin L, Grunewalk C. Detection of malformations in chromosomally normal fetuses by routine ultrasound at 12 or 18 weeks of gestation a randomized controlled trial in 39,572 pregnancies. BJOG. 2006;113: Crane JP, LeFevre ML, Winborn RC, et al. A randomized trial of prenatal ultrasonographic screening: impact on the detection, management, and outcome of anomalous fetuses. The RADIUS Study Group. Am J Obstet Gynecol. 1994;171: 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 Engl J Med. 1999;341: Bishop AJ, Marteau TM, Armstrong D, et al. Women and health care professionals preferences for Down s Syndrome screening tests: a conjoint analysis study. BJOG. 2004;111: Ledbetter DH, Zachary JM, Simpson JL. Cytogenetic results from the U.S. Collaborative Study on CVS. Prenat Diagn. 1992;12: Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet. 1998;352:

39. Milunsky A, Milunsky J. Genetic counseling: preconception, prenatal, and perinatal. In: Milunsky A, ed. Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment. 4th ed.

12 39. Milunsky A, Milunsky J. Genetic counseling: preconception, prenatal, and perinatal. In: Milunsky A, ed. Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment. 4th ed. Baltimore, Md.: Johns Hopkins University Press;1998: Norton ME, Brar H, Weiss J,et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;207:137. e1-8. Fig. 1 Ultrasound image of a chromosomally normal fetus at 12weeks with normal nuchal translucency thickness and an observable nasal bone

13 태아의염색체이상을발견하기위한산전선별검사 Fig. 2 Ultrasound image of a 12-week trisomy 21 fetus with increased nuchal translucency thickness (short arrow) and an absent nasal bone. (long arrow)

Fig.3 Fetal Ultrasonographic Markers for Risk of Down syndrome A, Fetal brain with a choroid plexus cyst. B, Fetal neck demonstrating thickening of the nuchal region.

14 Fig.3 Fetal Ultrasonographic Markers for Risk of Down syndrome A, Fetal brain with a choroid plexus cyst. B, Fetal neck demonstrating thickening of the nuchal region. C,Bright focus in the fetal heart (echogenic intracardiac focus). D, Dilatation of the renal collecting systems (renal pyelectasis). E, Increased brightness in the fetal bowel (echogenic bowel).humeral and femoral shortening are defined by comparing measurements to a normal distribution and are not illustrated

15 태아의염색체이상을발견하기위한산전선별검사 Table 1. A multicenter study that was co-ordinated by the Fetal Medicine Foundation Fetal karyotype N NT > 95 th percentile Risk 1 in 300 Normal (4.4%) 7907 (8.3%) Trisomy (71.2%) 268 (82.2%) Trisomy (74.8%) 97 (81.5%) Trisomy (71.7%) 37 (80.4%) Turner syndrome (87.0%) 48 (88.9%) Triploidy (59.4%) 20 (62.5%) Other* (64.1%) 51 (79.7%) Total (5.0%) 8428 (8.8%) Data are given as the number of pregnancies with NT thickness > 95 th percentile and an estimated risk for trisomy 21 that was based on maternal age, fetal NT, and CRL of 1 in 300. * Deletions, partial trisomies, unbalanced translocations, sex chromosome aneuploidies. Data from Kypros H et al. Am J Obstet Gynecol 2004; 191:

16 Table 2. Incidence of absent nasal bone at 11 to 13+6 weeks of gestation in chromosomally abnormal fetuses Chromosomal abnormality Absent nasal bone (n/n) Trisomy /333 (68.8%) Trisomy 18 68/124 (54.8%) Trisomy 13 13/38 (34.2%) Triploidy 0/19 (0) Turner s syndrome 5/46 (10.9%) XXY, XXX. XYY 1/20 (5.0%) Other 8/48 (16.7%) Data from Cicero S et al. Ultrasound Obstet Gynecol 2004;23:

17 태아의염색체이상을발견하기위한산전선별검사 Table 3. Aneuploidy risk of major structural fetal malformation Structural defect Aneuploidy risk Most common aneuploidy (Trisomy) Cystic hygroma 60~75% 45X (80%),21,18,13,XXY Hydrops 30~80% 13,21,18,45X Hydrocephalus 3~8% 13,18,triploidy Hydranencephaly Minimal Holoprosencephaly 40~60% 13,18,18p- Cardiac defect 5~30% 21,18,13,22,8,9 Diaphragmatic hernia 20~25% 13,18,21,45X Omphalocele 30~40% 13,18 Gastroschisis Minimal Duodenal atresia 20~30% 21 Bladder outlet obstruction 20~25% 13,18 Facial cleft 1% 13,18, deletions Limp reduction 8% 18 Clubfoot 20~30% 13,18,4p-,18q- Single umbilical artery Minimal Data from Shipp TD, et al. Am J Obstet Gynecol 1998;178: and Nyberg DA and Crane JP. Chromosome abnormalities. In:Nyberg DA, et al. Diagnostic ultrasound of fetal anomalies: text and atlas. Chicago (IL): Year Book Medical; p

18 Table 4. Available Options for Antenatal Testing First trimester Test Timing(weeks) Detection rate of Down syndrome(%) Chorionic villus sampling 10 to to 2 False-positive rate(%) Nuchal translucency 10-4/7 to 13-6/7 70 to ro 5 hcg and PAPP-A 10 to to 58 5 hcg, PAPP-A, and NT 11 to to 89 Second trimester Less than 3 to 5 Amniocentesis 16 to to 0.6 Triple screen (hcg, maternal serum AFP, ue3) Quadruple screen (hcg, inhibin A, maternal serum AFP, ue3) 15 to to to to 81 (up to 90 with ultrasonography) Ultrasonography 18 to to First and second trimester Full integrated screening (PAPP-A with NT) Serum integrated screening (PAPP-A without NT) Stepwise sequential screening (PAPP-A with NT) Contingency screening (PAPP-A with NT) 11 to 14 and 15 to to 14 and 15 to to 14 and 15 to to 14 and 15 to to to Less than 3 to 5 Less than 3 to 5 Less than 3 to 5 AFP=alpha-fetoprotein; hcg=human chorionic gonadotropin; PAPP-A=pregnancyassociated lasma protein A. Information from references 7, 25 through

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<3031C1BEBCB32DC1A4C0C72E687770> Korean Journal of Obstetrics and Gynecology Vol. 53 No. 12 December 2010 다운증후군의산전선별검사 경희대학교의과대학산부인과학교실 정 의 Prenatal screening for Down syndrome Eui Jung, M.D. Department of Obstetrics and Gynecology, Kyung