Pregnancy DiagnosisPregnancy Diagnosis

Prenatal Diagnosis Prenatal Diagnosis

Obstetrics and Gynecology Hospital of Fudan UniversityXing Chen, MD.Email: xing_chen@21cn.com

Pregnancy DiagnosisPregnancy Diagnosis

For a woman with regular menstrual cycles, a history of one or more missed periods following a time of sexual activity without effective contraception strongly suggests early pregnancy

Signs and symptoms of early pregnancySigns and symptoms of early pregnancy

AmenorrheaAmenorrhea

Nausea with or without vomitingNausea with or without vomiting

Breast enlargement and tendernessBreast enlargement and tenderness

Increased frequency of urination without Increased frequency of urination without dysuriadysuria

FatigueFatigue

Physical Examination

softening and enlargement of the pregnant uteruscongestion and a bluish discoloration of the vagina (Chadwick sign)

softening of the cervix (Hegar sign)

Increased pigmentation of the skinappearance of circumlinear striae on the abdominal wall (striae gravidarum )

palpation of fetal parts

appreciation of fetal movement and fetal heart tones

Uterus Fundus HeightUterus Fundus Height

Pregnancy testhuman chorionic gonadotropin (hCG): α/β-subunitproduced in the syncytiotrophoblast

Urineapproximately 4 weeks following the first day of the last menstrual period

All urine pregnancy tests are best performed on early-morning urine specimens, which contain the highest concentration of hCG

Serumspecific and sensitive

by following serial quantitative hCG levels and comparing them to the expected rise derived from normative data for proven normal intrauterine pregnancies

In most normal pregnancies at hCG levels below 1,200 mIU/ml the hCG usually doubles every 48-72 HOURS and it normally increases by at least 60% every TWO DAYS

Ultrasound examination

Abdominal ultrasound allowing visualization of a normal pregnancy gestational sac 5 to 6 weeks after the beginning of the last normal menstrual period (corresponding to β-hCG concentrations of 5000 to 6000 mIU/mL)Transvaginal ultrasound often detects pregnancy at 3 to 4 weeks of gestation (corresponding to β-hCG concentrations of 1000 to 2000 mIU/mL)

Image of an early gestational Image of an early gestational sac containing a yolk sac sac containing a yolk sac and early embryo. The yolk and early embryo. The yolk sac is the circular sac is the circular hyperechoic structure hyperechoic structure adjacent to the embryo.adjacent to the embryo.

Image of an early gestational sac Image of an early gestational sac demonstrating the early embryo. demonstrating the early embryo. Calipers are placed at both ends of Calipers are placed at both ends of the embryo measuring the longest the embryo measuring the longest length from the "crown to the rump" length from the "crown to the rump" giving the crown-rump length. This giving the crown-rump length. This measurement is used for dating the measurement is used for dating the pregnancy. pregnancy.

Detection of fetal heart activity “fetal heart tones”

Acoustic fetoscopebeyond 18 to 20 weeks of gestational age

Electronic Doppler devicesapproximately 12 weeks of gestation

DiagnosisDiagnosis

Detection of human chorionic Detection of human chorionic gonadotropin (hCG) in blood or urinegonadotropin (hCG) in blood or urine

Identification of pregnancy by ultrasound Identification of pregnancy by ultrasound examinationexamination

Identification of fetal cardiac activity by Identification of fetal cardiac activity by Doppler ultrasoundDoppler ultrasound

Abnormal Pregnancy

Spontaneous abortion

Ectopic pregnancy

Trophoblastic disease

SUMMARYSUMMARY

The most common signs and symptoms of The most common signs and symptoms of pregnancy are amenorrhea, pregnancy are amenorrhea, nausea/vomiting, breast tenderness, urinary nausea/vomiting, breast tenderness, urinary frequency, and fatiguefrequency, and fatigue

The most sensitive method of detecting The most sensitive method of detecting hCG is a serum pregnancy testhCG is a serum pregnancy test

Almost all pregnant women will have a Almost all pregnant women will have a positive urine pregnancy test one week after positive urine pregnancy test one week after the first day of a missed menstrual periodthe first day of a missed menstrual period

SUMMARYSUMMARY

The diagnosis of early pregnancy is based primarily The diagnosis of early pregnancy is based primarily upon laboratory assessment of human chorionic upon laboratory assessment of human chorionic gonadotropin (hCG)gonadotropin (hCG)

Identification of pregnancy by ultrasound Identification of pregnancy by ultrasound examination or identification of fetal cardiac activity examination or identification of fetal cardiac activity by Doppler ultrasound are alternative methods, but by Doppler ultrasound are alternative methods, but sensitivity depends on the gestational agesensitivity depends on the gestational age

Transvaginal ultrasound examination can visualize Transvaginal ultrasound examination can visualize a gestational sac at 4.5 to 5 weeks of gestation a gestational sac at 4.5 to 5 weeks of gestation

Prenatal Diagnosis Prenatal Diagnosis

Detect genetic disorders and birth defects Detect genetic disorders and birth defects > 200 single gene disorders can be diagnosed> 200 single gene disorders can be diagnosedTesting done only when a family history or other riskTesting done only when a family history or other risk

Prenatal diagnosisPrenatal diagnosisis the science of identifying is the science of identifying

structural or functional structural or functional abnormalities-birth defects-in abnormalities-birth defects-in

the fetusthe fetus

Etiology of Birth DefectsEtiology of Birth Defects

MalformationMalformation

DeformationDeformation

DisruptionDisruption

OtherOther

MalformationMalformation

an intrinsic abnormality "programmed" in an intrinsic abnormality "programmed" in development, regardless of whether a development, regardless of whether a precise genetic etiology is knownprecise genetic etiology is known

spina bifidaspina bifida

DeformationDeformation

caused when a genetically normal fetus caused when a genetically normal fetus develops abnormally because of develops abnormally because of mechanical forces imposed by the uterine mechanical forces imposed by the uterine environmentenvironment

normal limb that develops contractures normal limb that develops contractures because of prolonged oligohydramniosbecause of prolonged oligohydramnios

DisruptionDisruption

which is a more severe change in form or which is a more severe change in form or function that occurs when genetically function that occurs when genetically normal tissue is modified as the result of a normal tissue is modified as the result of a specific insultspecific insult

an amnionic band causing a cephalocele an amnionic band causing a cephalocele or limb-reduction abnormalityor limb-reduction abnormality

OtherOther

Syndrome: Syndrome: trisomy 18trisomy 18

Sequence: Sequence: oligohydramnios leading to oligohydramnios leading to pulmonary hypoplasiapulmonary hypoplasia

AssociationAssociation: : VATERVATERvvertebral defectsertebral defects

anal anal aatresiatresia

ttracheoesophageal fistula with racheoesophageal fistula with eesophageal atresiasophageal atresia

rradial dysplasiaadial dysplasia

Techniques

Non-invasive

Minimally invasive

Invasive

Non-invasive techniques

Ultrasound

Magnetic Resonance Imaging (MRI)

UltrasoundUltrasound

Noninvasive, uses reflected sound waves Noninvasive, uses reflected sound waves converted to an imageconverted to an image

Transducer placed on abdomenTransducer placed on abdomen

See physical features of fetus, not See physical features of fetus, not chromosomeschromosomes

May ID some chromosomal abnormalities May ID some chromosomal abnormalities by physical featuresby physical features

Cleft lip and palate

Ventriculomegaly

Posterior urethral valve

Multicystic dysplastic kidney

3D/4D US3D/4D US

Minimally Invasive Techniques

Cell free fetal DNA (cffDNA)

Pre-implantation genetic diagnosis (PGD)

Fetal Cells in Maternal CirculationFetal Cells in Maternal Circulation

TypesTypes– Placental cellsPlacental cells– White blood cellsWhite blood cells– Immature red blood cells with nucleiImmature red blood cells with nuclei

Enter the bloodstream (~6 and 12 weeks)Enter the bloodstream (~6 and 12 weeks)

Fetal cells, only 1/100,000 in mother’s bloodFetal cells, only 1/100,000 in mother’s blood

Techniques need to be developed Techniques need to be developed

Preimplantation Genetic Diagnosis Preimplantation Genetic Diagnosis (PGD)(PGD)

Eggs collected, fertilized, allowed to developEggs collected, fertilized, allowed to develop

~Third day of fertilization, embryo has 6–8 ~Third day of fertilization, embryo has 6–8 cellscells

For PGD, one cell, a For PGD, one cell, a blastomereblastomere, , is removedis removed

DNA extracted and testedDNA extracted and tested

Embryo without genetic disorder are Embryo without genetic disorder are implanted into mother implanted into mother

Embryo - BlastomereEmbryo - Blastomere

Invasive Techniques

Chorionic villus sampling (CVS)

Amniocentesis

Percutaneous umbilical blood sampling (cordocentesis)

AmniocentesisAmniocentesis

Diagnose > 100 disorders, cells analyzed Diagnose > 100 disorders, cells analyzed for chromosomal and biochemical disordersfor chromosomal and biochemical disorders

Risk of infection and spontaneous abortionRisk of infection and spontaneous abortion

Normally only used when:Normally only used when:– Advanced maternal age Advanced maternal age – History of chromosomal disorder History of chromosomal disorder – Parent with chromosomal abnormalityParent with chromosomal abnormality– Mother carrier of X-linked disorderMother carrier of X-linked disorder

p. 46

Removal of about 20 ml of amniotic fluid containing suspended cells that were sloughed off from the fetus

Biochemical analysis of the amniotic fluid after the fetal cells are separated out

Centrifugation

Fetal cells are removed from the solution

Analysis of fetal cells to determine sex

Cells are grown in an incubator

Karyotype analysis

Chorionic Villus Sampling (CVS)Chorionic Villus Sampling (CVS)

Done for similar reasons as amniocentesisDone for similar reasons as amniocentesis

Performed earlier than amniocentesis Performed earlier than amniocentesis – 6–10 weeks vs. 16 weeks6–10 weeks vs. 16 weeks

Karyotypes available within a few hours or Karyotypes available within a few hours or daysdays

Increased risk of spontaneous abortion Increased risk of spontaneous abortion (0.5–2%)(0.5–2%)

Review of CVS ProceduresReview of CVS Procedures

Neural-Tube DefectsNeural-Tube Defects NTDs NTDs

Neural-Tube Defects (NTDs)Neural-Tube Defects (NTDs)

anencephalyanencephaly, , spina bifidaspina bifida, , cephalocelcephalocele, e, and other rare spinal fusion (and other rare spinal fusion (schisisschisis) ) abnormalitiesabnormalities

had higher levels of alpha-fetoprotein had higher levels of alpha-fetoprotein ((AFPAFP) in maternal serum and amnionic ) in maternal serum and amnionic fluidfluid

Maternal Serum AFP ScreeningMaternal Serum AFP Screening

influence factors: maternal weight, gestational age, diabetes, multifetal gestation

Alpha-fetoprotein (AFP)Alpha-fetoprotein (AFP)Glycoprotein of unknown Glycoprotein of unknown functionfunction

Used to screen for open Used to screen for open NTDs NTDs – 15-22 weeks gestation15-22 weeks gestation– Detection rate 80-85%Detection rate 80-85%

Used to screen for Used to screen for trisomy 21 trisomy 21 – 15-20 weeks gestation15-20 weeks gestation– Detection rate 20-25%Detection rate 20-25%

Evaluation of Maternal Serum AFP ElevationEvaluation of Maternal Serum AFP Elevation

genetic counselinggenetic counseling

diagnostic testdiagnostic test Specialized SonographySpecialized Sonography amniocentesisamniocentesis

Specialized SonographySpecialized Sonography

Transverse and sagittal images of the Transverse and sagittal images of the spine are increasingly used to characterize spine are increasingly used to characterize the size and location of spinal defectsthe size and location of spinal defects

anencephalyanencephaly

cephalocelecephalocelespina bifidaspina bifida

AmniocentesisAmniocentesis

amnionic fluid AFP levelamnionic fluid AFP level

assay for acetylcholinesteraseassay for acetylcholinesterase

AneuploidyAneuploidy

AneuploidyAneuploidy

Autosomal:Autosomal: – Trisomy 21 (Down syndrome)Trisomy 21 (Down syndrome)– Trisomy 18 (Edward syndrome)Trisomy 18 (Edward syndrome)– Trisomy 13 (Patau syndrome)Trisomy 13 (Patau syndrome)

Sex chromosome:Sex chromosome:– 47XXY (Klinefelter syndrome)47XXY (Klinefelter syndrome)– 45X (Turner syndrome)45X (Turner syndrome)

Trisomy 21Trisomy 21

1 in 600 livebirthsLearning disabilityCongenital heart defectsDuodenal atresiaMacroglossiaBrachycephalyEpicanthic foldsBrushfield spots

1 in 3,000 livebirthsNeurodevelopmental delayFlexion of the fingersColobomaHeart defects MicrocephalyHorseshoe kidney

Trisomy 18Trisomy 18

Down Syndrome, DS Down Syndrome, DS

Trisomy 18, 21Trisomy 18, 21

First/second trimester: Sonography and First/second trimester: Sonography and maternal serum markersmaternal serum markers

Second-Trimester ScreeningSecond-Trimester Screening

At 15 to 20 weeksAt 15 to 20 weeks

Triple test: Triple test: MSAFP (maternal serum alpha-fetoprotein )MSAFP (maternal serum alpha-fetoprotein ) hCG or freehCG or freeββ-hCG-hCG uE3 (unconjugated estriol )uE3 (unconjugated estriol )

Quadruple (Quad) test: Quadruple (Quad) test:

+ inh (dimeric inhibin alpha)+ inh (dimeric inhibin alpha)

Second Trimester Maternal Serum Second Trimester Maternal Serum Screening for AneuploidyScreening for Aneuploidy

Performed at 15-20 weeksPerformed at 15-20 weeksSingleton gestationSingleton gestationAdjusts age risk based on levels of Adjusts age risk based on levels of – AFPAFP– hCGhCG– Unconjugated estriol (uE3)Unconjugated estriol (uE3)– Inhibin-AInhibin-A

Detection rate in women Detection rate in women – <35: 60-75% for DS<35: 60-75% for DS– >35: 75% or more>35: 75% or more– >80% for trisomy 18>80% for trisomy 18

Positive screening rate 5%Positive screening rate 5%

“Triple” “Quad”

Unconjugated Estriol (uEUnconjugated Estriol (uE33))

Synthesized from DHEAS, converted to 16Synthesized from DHEAS, converted to 16OH-OH-DHEAS in fetal liver and then to uE3 by placentaDHEAS in fetal liver and then to uE3 by placentaLow levels associated with:Low levels associated with:– Trisomy 21Trisomy 21– Trisomy 18Trisomy 18– TriploidyTriploidy– Smith Lemli OpitzSmith Lemli Opitz– Steroid sulfatase deficiencySteroid sulfatase deficiency– Fetal demiseFetal demise– Congenital adrenal hypoplasiaCongenital adrenal hypoplasia

Inhibin-AInhibin-A

Polypeptide hormonePolypeptide hormone

Secreted by granulosa & Sertoli cellsSecreted by granulosa & Sertoli cells

In pregnancy secreted by fetoplacental In pregnancy secreted by fetoplacental unit, peaks at 8-10 weeks then declines unit, peaks at 8-10 weeks then declines until 20 and rises gradually until termuntil 20 and rises gradually until term

Maternal Serum Screening for Maternal Serum Screening for Trisomy 21 and 18Trisomy 21 and 18

Serum markerSerum marker Trisomy 21Trisomy 21 Trisomy 18Trisomy 18

AFPAFP

hCGhCG

uE3uE3

Inhibin-AInhibin-A N/AN/A

Maternal Serum ScreeningMaternal Serum Screening

AdvantagesAdvantages– Avoids an invasive Avoids an invasive

testtest– Avoid potential for Avoid potential for

fetal lossfetal loss– Identifies a fetus at Identifies a fetus at

riskrisk

DisadvantagesDisadvantages– AnxietyAnxiety– False reassuranceFalse reassurance

LimitationsLimitations– Provides a revised risk Provides a revised risk

assessment not a assessment not a diagnosisdiagnosis

– Sensitivity <100%Sensitivity <100%– Misses other Misses other

chromosome chromosome abnormalitiesabnormalities

First-Trimester ScreeningFirst-Trimester Screening

between 11 and 14 weeksbetween 11 and 14 weeks

maternal serum analyte screening: maternal serum analyte screening: hCG (or free hCG (or free ββ--hCG) hCG) pregnancy-associated plasma protein A (PAPP-A) pregnancy-associated plasma protein A (PAPP-A)

sonographic: nuchal translucency (NT)sonographic: nuchal translucency (NT)

combination of bothcombination of both

Pregnancy associated plasma protein APregnancy associated plasma protein A

Glycoprotein of unknown functionGlycoprotein of unknown function

Only reliable for detection of DS between Only reliable for detection of DS between 10-13 weeks10-13 weeks

Levels are 60% lower in DSLevels are 60% lower in DS

Highest detection rate of any marker (42%)Highest detection rate of any marker (42%)

First-trimester screeningFirst-trimester screening

Advantages:Advantages:– Sensitivity comparable to quad screenSensitivity comparable to quad screen– Performed earlierPerformed earlier– If positive option of CVSIf positive option of CVS– Option of earlier TAB if fetus affectedOption of earlier TAB if fetus affected– Increased privacyIncreased privacy

Disadvantages:Disadvantages:– Does not test for NTDsDoes not test for NTDs

Nuchal Translucency (NT)Nuchal Translucency (NT)

CVS vs AmniocentesisCVS vs AmniocentesisPerformed at 10-12 wksPerformed at 10-12 wks

Results available earlierResults available earlier

May lower anxietyMay lower anxiety

PrivacyPrivacy

If results abnormal option If results abnormal option of earlier TAB preferable of earlier TAB preferable to some couplesto some couples

Risk SAB <1%Risk SAB <1%

Performed at 15-17 wksPerformed at 15-17 wks

10-14 days for results10-14 days for results

SAB rate <1/300-600SAB rate <1/300-600

Test amniotic fluid AFP for Test amniotic fluid AFP for NTDNTD

Other markersOther markers

Nasal boneNasal bone

FMF angle (FMF angle (frontomaxillary facial anglefrontomaxillary facial angle))

Ductus venosusDuctus venosus

Tricuspid regurgitationTricuspid regurgitation

First Trimester US First Trimester US –– Nasal Bone Nasal Bone

Nasal bone present in a euploid fetus in the first trimester

Nasal bone absent in a fetus with T21in the first trimester

Second Trimester US Second Trimester US –– Nasal Bone Nasal Bone

3D US coronal view in the second trimester bilateral nasal bones present

Ductus VenosusDuctus Venosus

FMF AngleFMF Angle

Increased Increased beyond 85beyond 85 with T21with T21

Tricuspid RegurgitationTricuspid Regurgitation

First trimester screening for First trimester screening for trisomy 21 by ultrasound and age*trisomy 21 by ultrasound and age*

*SP = screen positive rate 5%

Test Performance

NT T21 70-80%

NT + nasal bone T21 85-90%

Abnormal Ductus Venosus waveform

T21 78% (at a SP rate of 1.7% in a high risk population)8

NT + nasal bone + abnormal DV

T21 >90% at a lower SP rate 2-3%

Sonographic findings in Trisomy 21Sonographic findings in Trisomy 21Cardiac defectCardiac defectDuodenal atresiaDuodenal atresiaThick nuchal foldThick nuchal foldRenal pyelectasisRenal pyelectasisEchogenic bowelEchogenic bowelEchogenic intracardiac focusEchogenic intracardiac focusSandal gapSandal gapCP cystCP cystShort mid-phalanx 5th fingerShort mid-phalanx 5th fingerShort femur/humerusShort femur/humerusFlat facies with maxillary hypoplasiaFlat facies with maxillary hypoplasiaMacroglossiaMacroglossia

Be aware…Be aware…

gestational age affects the accuracygestational age affects the accuracy

less sensitive in younger womenless sensitive in younger women

Be aware…Be aware…

strong association between increasing strong association between increasing nuchal translucency and fetal cardiac nuchal translucency and fetal cardiac anomaliesanomalies

nuchal translucency measurement is 3.5 nuchal translucency measurement is 3.5 mm or greater with a normal fetal mm or greater with a normal fetal karyotype, then targeted sonographic karyotype, then targeted sonographic examination, fetal echocardiography, or examination, fetal echocardiography, or both should be consideredboth should be considered

Sonographic Screening for AneuploidySonographic Screening for Aneuploidy

Major Structural DefectsMajor Structural Defects

"Soft Signs" "Soft Signs"

Diagnostic TechniquesDiagnostic Techniques

Second-Trimester AmniocentesisSecond-Trimester Amniocentesis between 15 and 20 weeksbetween 15 and 20 weeks

Early AmniocentesisEarly Amniocentesis between 11 and 14 weeksbetween 11 and 14 weeks

Chorionic Villus Sampling (CVS)Chorionic Villus Sampling (CVS) at 10 to 13 weeksat 10 to 13 weeks

Fetal Blood SamplingFetal Blood Sampling percutaneous umbilical blood sampling (PUBS) or percutaneous umbilical blood sampling (PUBS) or

cordocentesiscordocentesis

Fetal Tissue BiopsyFetal Tissue BiopsyPreimplantation Genetic DiagnosisPreimplantation Genetic DiagnosisFetal Cells in the Maternal CirculationFetal Cells in the Maternal Circulation

Fetal Therapy Fetal Therapy -to improve the intrauterine environment-to improve the intrauterine environment

blood product transfusionblood product transfusion

administration of medication administration of medication transplacentally or via the fetal circulationtransplacentally or via the fetal circulation

laser or radiofrequency ablation of laser or radiofrequency ablation of vascular anastomosesvascular anastomoses

amnioreductionamnioreduction

shunt placementshunt placement

fetal surgeryfetal surgery

Key Guidelines

All women contemplating any form of prenatal diagnosis should be adequately counselled about the risks, benefits and limitations of any test, and provided with non-directional written information

Screening test for Down's syndrome and ‘20 week’ scan for structural anomalies

Women at risk of having a baby with congenital heart disease should be offered an extra fetal echocardiogram at 21–24 weeks

The middle cerebral artery Doppler peak systolic velocity can be used as a non-invasive method for diagnosing of fetal anaemia

Key Guidelines

Serial ultrasound measurements are of undoubted use in monitoring fetal growth but all formulae currently used to estimate fetal weight are inherently flawed and may give errors up to ±14%

MRI is a useful adjunct to ultrasound in prenatal diagnosis especially in the diagnosis of intra-cranial, intra-thoracic and gastrointestinal anomalies

Key Guidelines

Cell free fetal DNA testing has become widely established for the management of Rhesus disease and certain sex linked genetic disorders. With further research it is poised to offer much greater benefits in the field of minimally invasive prenatal diagnosis

Pre-implantation genetic diagnosis provides the opportunity for parents to avoid the distress of invasive testing and possible termination. However, the ethical and legal debate is set to continue for many years

Key Guidelines

CVS should not be performed before 10 weeks of gestation as it has been associated with limb reduction abnormalities. It appears to be safer if it is performed transabdominally rather than transcervically

Amniocentesis should not be performed at less than 15 weeks of gestation as before this it is associated with greater risk of pregnancy loss and possible talipes in the fetus

Key Guidelines

In experienced hands CVS and amniocentesis both carry a similar procedure related risk of miscarriage of 0.5–1%

Percutaneous umbilical blood sampling is now limited to potentially lifesaving in utero transfusion procedures for severe fetal anaemia

Extension topicExtension topic

Ethical and human rights concernsEthical and human rights concerns

Screening is simpleScreening is simple

UltrasoundBlood

UltrasoundBlood Blood

BloodBlood

Blood

11-13w6d 16-20w

hCG, hCG, AFP, uE3, AFP, uE3,

InhibinInhibinQuadQuad 75-77%75-77%

Quad + Quad + PAPP-aPAPP-a

SIPSSIPS 82-84%82-84%

SIPS + SIPS + NTNT

IPSIPS 92-95%92-95%

NT+NB+PNT+NB+PAPP-APP-

a+hCGa+hCG

FTS with FTS with Nasal Nasal BoneBone

92-95%92-95%

17w

to

20w

13w

Sequential Screening for DSSequential Screening for DS

Offer 1st trimester screen(NT, PAPP-A, hCG)

DS risk >1 in 50

Offer counseling & CVS

DS risk <1 in 50

2nd trimester screen with Integrated Result(NT, PAPP-A,AFP, hCG, uE3, Inhibin)

DS risk >1 in 270

Offer counseling & amnio

Uses both 1st and 2nd Uses both 1st and 2nd trimester results to trimester results to adjust maternal age adjust maternal age risk for DS and takes risk for DS and takes advantage of higher advantage of higher detection ratedetection rate

Key wordsKey words

last menstrual period , LMP last menstrual period , LMP

three trimestersthree trimesters

Human chorionic gonadotropin, hCGHuman chorionic gonadotropin, hCG

Down SyndromeDown Syndrome

Neural-Tube DefectsNeural-Tube Defects

ReferenceReference

Obstetrics and Gynecology, 6th editionObstetrics and Gynecology, 6th edition

Williams Obstetrics, 23rd edition Williams Obstetrics, 23rd edition

Prenatal diagnosis: Types and techniques. Prenatal diagnosis: Types and techniques. Early Human Development. 2012 (88) :3–8Early Human Development. 2012 (88) :3–8

Clinical manifestations and diagnosis of early Clinical manifestations and diagnosis of early pregnancy. UpToDate21pregnancy. UpToDate21

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