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Pregnancy DiagnosisPregnancy Diagnosis
Prenatal Diagnosis Prenatal Diagnosis
Obstetrics and Gynecology Hospital of Fudan UniversityXing Chen, MD.Email: [email protected]
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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