產前

:進展Guo Luo,

M.D.,

Ph.D.Director,

Center

for

Perinatal

MedicineDanbury

Hospital,

Danbury,

CTAssociate

Professor,

University

of

Vermont

&

Yale

UniversitySchool

of

Medicines

ofGuo Luo,

M.D.,

Ph.D.

has

nointerest

to

declare

in

regards

to

this

topic.Director,

Maternal-fetal

Medicine,

AssociateProfessor,

Department

of

Obstetrics

&Gynecology,

University

of

Connecticut,School

of

Medicine.2目的回顧產前關于產前的歷史的影像學的關于非整倍體的篩查及的3產前影像學:超聲MRI鏡妊娠篩查:孕早期及孕中期篩查孕婦

游離DNA遺傳

:絨毛活檢羊膜腔穿刺術核型分析o人類

組5產前

的歷史超聲:1950年被引進20世紀90年代快速改進并廣泛使用羊膜腔穿刺術1877年首次開展（因為羊水過多)研究1966年首次應用于70年代后普遍使用絨毛活檢(CVS)–第一例1968–在1980年-1990年被廣為接受1990年至今，

篩查、人類

組

及分子

學快速發展產前主要結構異常次要結構異常7超聲軟標記8孕中期超聲標記非整倍體（似然比（LR）常見的非整倍體鼻骨發育不全(缺失或≤2.5

mm)51~60%

DS頸褶增厚>6

mm17~35%

DS股骨短(<第三百分位數)3DS肱骨短(<第三百分位數)8DS腎盂擴張1腸管強回聲6DS單臍動脈1第五指中指骨發育不全/缺失2DS脈絡叢囊腫7T

18心臟的強回聲灶2DS10血流動力學評價11MCA

DopplerMari

G,

et

al.

N

Eng

J

Med

2000;

342:9-1412Mari

G,

et

al.

N

Eng

J

Med

2000;

342:9-14MCA評估

貧血Oepkes

et

al.

NEJM,

2006.前瞻性多中心研究165例

因為孕婦紅細胞同種免疫有貧血風險.MCA-PSV

doppler:敏感性88%，特異性82%羊水delta-OD450:敏感性76%，特異性77%縱向發展14差異<平均孕齡第五百分位數或<平均孕齡2個標準差大多數孤立的短股骨是正常的或是性的在18到24周

為短股骨的，有13%在隨訪后為正常FGR非整倍體骨骼發育不良15種族變異16技術變化17技術變化8技術變化19腦發育的磁成像掃描20正常小腦發育不全葉外型肺癥2223非整倍體的篩選10

11

12

13

1415

16

17

18

19

2020…40

weeks1st

trimester

blood

draw2nd

trimester

blood

drawNuchal

TranslucencyTrimester

(11-14

weeks)Combined

test

(NT,PAPP-A,

-hCG)Second

Trimester

(15-20

weeks)Triple

test

(AFP,

uE3,

-hCG)

Quad

test

(AFP,

uE3,

-hCG,

InhA)Both

1st

and

2nd

trimesters

(10-14

+

15-20

weeks)Full

integrated

test

(NT,

PAPP-A,

-hCG

,

Quad)Serum

integrated

test

(PAPP-A,

-hCG

,

Quad)Sequential

integrated

test

(combination

of

both)Canick

J,

Palomaki

GE,

AA

resentation

2008.

Washington,

DC.ed

Ultrasound24CRL=

45

mm25Median:

中位數1.2mm2.1mm95th

percentile:CRL=

84

mmMedian:95th

percentile:1.9mm2.7mmThe

99th

percentile:

3.5

mm.96,127

pregnancies.

Lancet

351

(1998),

pp.

343–346頸項透明層NT(mm)異常核型DemiseAnomaly畸形Alive

&well<95%<1%<2%<2%97%95-99%4%<2%3%93%3.5-4.421%3%10%70%4.5-5.433%4%19%50%5.5-6.451%10%24%30%>

6.565%19%46%15%Souka

et

al.

AJOG

2005;192:1005-21.26Trimesters

Biochemical

Screen27孕早期篩查除了篩查非整倍體異常NT：結構畸形低PAPP-A(<第五百分位數):生長受限，先兆子癇核實孕周確定絨毛膜性檢測

重大畸形，Second

Trimesters

Biochemical

Screen29Malone

FD,

Canick

JA,

Ball

RH,

Nyberg

DA,

et

al..

N

Engl

J

Med.

2005

Nov10;353(19):2001-20

1.30雙向終生攜帶細胞可能

在某些有些是干細胞，在遇到壓力或是損傷時可

員微嵌合體是普遍的Lo

YM,

et

al.

AJHG

1999;

64:218-24Bianchi

DW,et

al.

AJMG

2000;

91:22-8O’Donoghue

K.

Lancet

2004;

364:179(male

stem

cell

inthe

bone

marrow

of

a

woman50

years

after

the

birth

of

her

only

son)細胞交換History

of

NIPT（無創產前檢查）105:16266-71Blood

drawat

9-20

weeksHigh-throughput

approachesSophisticated從ècfDNA中分離

cfDNA是不可行的中3-10%的cfDNA來自于è

更確切的說è中的cfDNA來自于胎盤cfDNA量很少(1

μg

in

20

mL)Lo

YM,

et

al.

AJHG

1998;

62:768-75Ariga

H,

et

al.

Transfusion

2001;

41:1524-30NIPT的步驟**

OO

ll

titi

tt

dd

hh

bb

bblili

hh

dd

((BBii

hhii

tt

ll

OObb

tt

tt

GG

ll

20122012

119119

889900

990011

ffVV

ii

tt

HH

lthlth?)?)Commercial

NIPT

in

US**

Three

prospective

studies

have

been

published

(Palomaki

GE,

et

al.Genet

Med

2011

for

Sequonom

CMM?;

Bianchi

DW,et

al.

Obstet

Gynecol

2012

for

Verinata

Health?;

Nicolaides

KH,

et

al.

Prenat

Diagn

2013

for

Natera?)Comparison

of

Techniques

for

Prenatal

Diagnosis

using

Cell-Free

DNACompanies

inUnited

States

*Technical

approachAccuracy

of

detection

**Failed(‘no

call’)SequencingBioinformaticsAneuploidySensitivitySpecificitySequonom

CMM?MPSSZ-score+T21T1898.6%100%99.8%99.7%3-8%GC

correctionT1391.7%99.0%45,X----47,XXY----Verinata

Health?MPSSZ-score+NCV+T21T18100%97.2%100%99.8%3-5%T1378.6%99.4%45,X93.8%99.8%47,XXY----Ariosa

Diagnostics?ed(chromosomes21

and18)FDOARNTSERT21T18100%98%100%100%3%T13----45,X47,XXY--------1-7%Natera?ed(SNPs)esoperate

outside

ofSNPs

from

Hapmap+Parentalthe

U.SupportS.T21T18100%100%100%100%1-20%T13100%100%*

Two

additional

compani45,X47,XXY100%100%100%100%ACOG

Committee

Opinion

No.

545.

Obstet

Gynecol

2012;

120:1532-4NIPT適應癥NIPT檢測

非整倍體適用于高危的單胎妊娠，如：高齡孕婦篩查異常史非整倍體孕婦或有非整倍體超聲異常NIPT局限性cfDNA為胎盤來源（而非來自于

）所有NIPT方法分析的是總量cfDNA，而不是提取或搜集

cfDNAcfDNA已經是片段(~150-200

bp)半衰期短,排除前次妊娠的干擾測量的區別是定量的而不是定性的通常2%的cfDNA

來自于21號21三體

因為具有三條21號 ，從而增加了50%的循環遺傳物質，

NIPT正想檢測出這種差異。36NIPT

是