prenatel diagnosis

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					   TOPIC REVIEW

PRENATAL DIAGNOSIS


        Wipada Laosooksathit , int 3
               OVERVIEW
• GENETIC COUSELING
• SCREENING TEST, NON INVASIVE TEST
  – ULTRASOUND
  – SERUM MARKER
  – OTHER
• DIAGNOSIS TEST, INVASIVE TEST
  –   AMNIOCENTESIS
  –   CHORIONIC VILLUS SAMPLING (CVS)
  –   PERCUTANEOUS UMBILICAL BLOOD SAMPLING (PUBS)
  –   OTHER
• SUMMARY & BENEFIT
• PRENATAL DIAGNOSIS IN FUTURE
GENETIC COUSELING
            Background


• 3-5% of babies have a major birth
  defect or mental retardation
• Congenital abnormalities account for
  20-25% of perinatal deaths
   Condition increase risk of
    chromosome anomaly
• Fetal aneuploidy
  – Maternal age ≥ 35 yr
  – Maternal age ≥ 31 yr with dizygotic twin
  – Previous fetal autosomal trisomy
  – Previous fetal 47,XXX or 47,XXY
  – Chromosomal translocation
  – Chromosomal inversion
  – History of triploidy
Condition increase risk of
 chromosome anomaly
 • Fetal aneuploidy
   – Repetitive first trimester abortion
   – Parental aneuploidy
   – Major structural defect
 • Isolated structural anomalies
   – previous child with a birth defect
 • Familial genetic disease
  Other recommended PND

• positive screening test
• concerns about having child with birth defect
  or genetic disease
• genetic diseases common for certain ethnic
• pregnant woman with type 1 DM , epilepsy
• exposed to viral infections , excessive
  medication , environmental hazards
• history of parental consanguinity
 Genetic risk calculation
• Mendelian risk (single gene defect) eg
  hemophilia
  – Autosomal dominant
  – Autosomal recessive
  – Sex-linked recessive
• Empirical risk eg neural tube defects ,
  heart defects
  RISK OF CHROMOSOMAL ABNORMALITIES IN LIVE-BORN INFANTS
                                                Total Risk for
Maternal              Risk for Down
Age (yr)                Syndrome                Chromosomal
                                               Abnormalities*
  20                    1/1,667                    1/526
  21                    1/1,667                    1/526
  22                    1/1,429                    1/500
  23                    1/1,429                    1/500
  24                    1/1,250                    1/476
  25                    1/1,250                    1/476
  26                    1/1,176                    1/476
  27                    1/1,111                    1/455
  28                    1/1,053                    1/435
  29                    1/1,000                    1/417
  30                     1/952                     1/384
  31                     1/909                     1/384
  32                     1/769                     1/323
  33                     1/625                     1/286
  34                     1/500                     1/238
  RISK OF CHROMOSOMAL ABNORMALITIES IN LIVE-BORN INFANTS
                                                Total Risk for
Maternal              Risk for Down
Age (yr)                Syndrome                Chromosomal
                                               Abnormalities*
  35                     1/385                     1/192
  36                     1/294                     1/156
  37                     1/227                     1/127
  38                     1/175                     1/102
  39                     1/137                      1/83
  40                     1/106                      1/66
  41                      1/82                      1/53
  42                      1/64                      1/42
  43                      1/50                      1/33
  44                      1/38                      1/26
  45                      1/30                      1/21
  46                      1/23                      1/16
  47                      1/18                      1/13
  48                      1/14                      1/10
  49                      1/11                      1/8
          Prenatal diagnosis

• Screening test - no risk of miscarriage but not
  provided definitive answer
  – required diagnostic test to confirm diagnosis
  – screen for chromosomal anomalies and neural
    tube defects
• Diagnostic tests - extremely accurate, but
  carry a risk of miscarriage
 SCREENING TEST
NON INVASIVE TEST
       Noninvasive techniques
• Fetal visualization
   –   Ultrasound
   –   Fetal echocardiography
   –   Magnetic resonance imaging (MRI)
   –   Radiography
• Serum marker
   – Measuring MSAFP
   – Measuring maternal unconjugated estriol
   – Measuring maternal serum beta-human
     chorionic gonadotropin (HCG)
   – Others
NON INVASIVE TEST
  ULTRASOUND
  ULTRASONOGRAPHY

• For major structural anomalies
  – In low risk   controversial
• For minor abnormalities
  – Clues that suggest chromosomal
    abnormalities
  – eg Nuchal translucency (NT), nuchal fold ,
    nasal bone
    ULTRASONOGRAPHY
• First Trimester Findings
  – Normal evaluation of fetal number
     •   location of the placenta
     •   evaluation of the fallopian tubes and ovaries
     •   location of the pregnancy (intrauterine or ectopic)
     •   measurement of the crown-rump length (CRL) or the
         gestational sac diameters
  – Nuchal translucency
  – Abnormal
GS
CRL
Nuchal translucency
             ULTRASOUND

• Second and Third Trimester Findings
  –   Head and intracranial anatomy
  –   Face
  –   Heart and chest
  –   Abdomen
  –   Kidneys
  –   Spine
  –   Extremities
  –   Placenta, amniotic fluid, uterus and other
      structures
         ULTRASOUND

• ultrasound findings associated with
  chromosome abnormalities eg Down
  syndrome
  – nuchal edema or translucency
  – hyperechoic bowel
  – Pyelectasis
  – choroid plexus cysts
  – short humerus and femur lengths
NON INVASIVE TEST
 SERUM MARKER
         SERUM MARKER

• Serum marker
  – Measuring MSAFP
  – Measuring maternal unconjugated estriol
  – Measuring maternal serum beta-human
    chorionic gonadotropin (HCG)
  – Others
     • Pregnancy associated plasma protein - A ( PAPP-A)
     • Inhibin A
Maternal serum alpha-fetoprotein

 •   Glycoprotein
 •   Yolk sac (early), liver and GI tract (late)
 •    Unknown function
 •   14-22 wk , highest sense 16-18wk
 •   2.0 or 2.5 MoM is upper limit of normal
Maternal serum alpha-fetoprotein
• Elevated level              • Low level
   – NTD                         – Chromosomal trisomy
   – Pilonidal cysts             – Gestational
   – Esophageal or intestinal      trophoblastic disease
     obstruction                 – Fetal death
   – Liver necrosis              – Insulin-dependent
   – Cystic hygroma                diabetes mellitus
   – Sacrococygeal teratoma
   – Open abdominal wall defects
   – Urinary obstruction
   – Renal anomalies
   – Congenital skin defect
   – etc.
Human chorionic gonadotropin

 • Glycoprotein
 • Syncytiotrophoblast
 • High level in Trisomy 21
 Unconjugated estriol (UE3)

                DHEAS

       16 alpha -hydroxy-DHEAS

                  Estriol
• level indicated well-being of the fetus
• low level in Trisomy 21
         Triple screening
• Expanded AFP test
  AFP plus
  Multiple-marker screening test
• Most common second-trimester screening
  protocol

• Maternal serum alpha-fetoprotein (MSAFP)
  Human chorionic gonadotropin (hCG)
  Unconjugated estriol (UE3)
         Triple screening
• Positive test indicates increased risk
• Negative test indicates no increased risk
  but not mean normal fetus
• screening for pregnant women under the age
  of 35 years
  (amniocentesis to those 35 years or older)
• multiple fetuses cannot be assessed
          Triple screening

• Accuracy depends on
  – pregnancy dating
  – patient information
  – screening parameters utilized by laboratory
• definitive diagnosis can be made only by
  chromosome analysis of fetal tissues
  obtained by CVS, amniocentesis or PUBS
           Other marker

- Pregnancy associated plasma protein - A
  ( PAPP-A)
- Inhibin A
 Condition       MSAFP       uE3       HCG       InhibinA   PAPP-A   USG


Neural tube
  defect
            Increased       Normal    Normal        -         -      √


Trisomy 21        Low        Low     Increased Increased     Low     √

 Trisomy
  18,13
                  Low        Low         -          -        Low     √

  Molar
pregnancy
                  Low        Low     Very High      -         -      √

  Multiple
 gestation
                Increased   Normal   Increased      -         -      √

Fetal death
 (stillbirth)
                Increased    Low       Low          -         -      √
DIAGNOSIS TEST
 INVASIVE TEST
         Invasive techniques
• Fetal visualization
   – Embryoscopy
   – Fetoscopy
• Fetal tissue sampling
   –   Amniocentesis
   –   Chorionic villus sampling (CVS)
   –   Percutaneous umbilical blood sampling (PUBS)
   –   Percutaneous skin biopsy
   –   Other organ biopsies, including muscle and liver
       biopsy
 INVASIVE TEST
AMNIOCENTESIS
       AMNIOCENTESIS

• Early amniocentesis
• Second-trimester amniocentesis
        Early amniocentesis
• 11-14 weeks
• 1 ml per week of gestation
• Advantage to CVS
  – accurate as obtained in the second trimester
  – familiar technique
  – assess amniotic fluid alpha-fetoprotein
  – chromosomal mosaicism confined to the placenta
    is reduced
  – reduction of maternal cell contamination
         Early amniocentesis
• Disadvantage
  – difficult to perform because amnion and chorion still
    separated
  – placenta is extensive that require transplacental
    approach
  – increased risk of fetal loss
  – increased rate of post-procedure amniotic fluid
    leakage
  – associated with increased incidence of talipes
    equinovarus
  – and culture failure rates of 1%
Second-trimester amniocentesis

•   14 - 20 wk
•   Aspirate initial 1-2 ml then 20 ml of fluid
•   Chromosome , DNA analysis, AFP
•   Complication
    – Transient vaginal spotting or Amniotic fluid leakage
      1-2%
    – Chorioamnionitis 0.1%
    – Injury to fetus - rare
    – Fetal loss 0.5%
    – Rh sensitization
Second-trimester amniocentesis
      INVASIVE TEST
CHORIONIC VILLUS SAMPLING
          (CVS)
 Chorionic villus sampling


• 10 – 13 wk
• Available earlier than amniocentesis
• Transcervical or transabdominal approach
  based on placental location
• Chromosome, DNA analysis
• neural tube defects and other structural
  malformations cannot be detected
CVS
CVS (transcervical)
CVS (transabdominal)
   Chorionic villus sampling

• Complication
   – Transcervical – fetal loss 3.7%
   – Transabdominal – fetal loss 1.5%
   – loss rate associated with more than one attempt
   – Oromandibular-limb hypogenesis – before 9 wk
• Absolute contraindications
   – transcervical approach - active cervical or
     vaginal infections
  Chorionic villus sampling


• Uninformative data due to
  – Inadequate sample
  – Placental mosaicism 1.2-2.5%
  – Maternal cell contamination
     INVASIVE TEST
PERCUTANEOUS UMBILICAL
 BLOOD SAMPLING (PUBS)
    PUBS , Cordocentesis

•   After 16 wk
•   Genetic analysis when CVS or
    amniocentesis results confusing
•   Location - umbilical vein near placental
    origin
    PUBS , Cordocentesis

• advantage
  – Rapid diagnosis (24 to 48 hr)
  – Direct karyotyping
  – Hematologic problem (diagnosis &
    treatment)
  – Immunologic test
  – PaO2,PCO2,pH level
    PUBS , Cordocentesis
• Complication – more common than other
   – Cord vessel bleeding 50%
   – Cord hematoma 17%
   – Fetal-maternal hemorrhage 66% , 17%
   – Fetal bradycardia 3-12%
   – Procedure-related fetal death 1.4%
• Complication depend on
   – operator experience (most critical factor)
   – posterior placentae
   – performed prior to 19 weeks
   PUBS , Cordocentesis

• still the method of choice for
  – diagnostic and therapeutic in
    erythroblastosis fetalis
  – fetal platelet count
        10 - 13 weeks                Chorionic villus sampling (CVS)

        10 - 14 weeks                      Early amniocentesis

      15 weeks - term
  Optimum* 15 weeks - 20 1/2             Standard amniocentesis
           weeks
       15 - 21 weeks
                                         Multiple marker screening
 Optimum** 16 weeks - 18 1/2            (MSAFP + additional markers)
             weeks

      18 weeks - term                      Targeted ultrasound
 Optimum* 17 1/2 - 24 weeks


       18 weeks- term                    Fetal echocardiography
    Optimum* 18 - 24 weeks

                                       Percutaneous umbilical blood
      18 weeks - term                            sampling
                                                  (PUBS)
 *Optimum times for procedures are dependent on maternal habitus.
**Optimum times for serum tests are based on best times for neural tube
                         defect detection.
   OTHER INVASIVE TEST


• Percutaneous skin biopsy
• Other organ biopsies, including liver
  and muscle biopsy
SUMMARY & BENEFIT
                    SUMMARY
• Recording the history
   – the best time to offer carrier testing is also prior to
     conception
   – risk assessment
   – Pedigree analysis can sometimes help to identify the mode
     of inheritance
• Confirming the diagnosis in the affected
  individual
• Determining whether prenatal diagnosis is
  possible
        10 - 13 weeks                Chorionic villus sampling (CVS)

        10 - 14 weeks                      Early amniocentesis

      15 weeks - term
  Optimum* 15 weeks - 20 1/2             Standard amniocentesis
           weeks
       15 - 21 weeks
                                         Multiple marker screening
 Optimum** 16 weeks - 18 1/2            (MSAFP + additional markers)
             weeks

      18 weeks - term                      Targeted ultrasound
 Optimum* 17 1/2 - 24 weeks


       18 weeks- term                    Fetal echocardiography
    Optimum* 18 - 24 weeks

                                       Percutaneous umbilical blood
      18 weeks - term                            sampling
                                                  (PUBS)
 *Optimum times for procedures are dependent on maternal habitus.
**Optimum times for serum tests are based on best times for neural tube
                         defect detection.
                   benefit
• Determine outcome of pregnancy
• Decide whether to continue the pregnancy
• Indicate possible complication arise at birth
  process
• Management of remaining weeks of
  pregnancy
• Prepare for the birth of a child with
  abnormality
• Improve outcome of pregnancy using fetal
  treatment
     PRENATAL DIAGNOSIS
         IN FUTURE

• less invasive and less risky diagnostic
  procedures
  – Preimplantation genetic diagnosis (PGD)
  – Fetal cell from maternal serum
                 PGD

• screen embryos from IVF with ICSI for genetic
  disease
• Avoid termination of pregnancy
• embryos are cultured to Day 3 (8-10 blastomeres)
• remove one or two blastomeres (not differentiate)
• Determine embryo not affected by genetic disease
• Day 5, healthy embryos are transferred back
• HCG beta is examined next 2 weeks to determine
  pregnancy
• PGD is not 100% accurate due to embryo mosaicism
 fetal cells from the mother's blood

• not yet clinically available
• Cells collected 18 weeks onward
• Difficult to isolate a quantity of cells sufficient
  for analysis
• Cell persist in maternal circulation ,difficult to
  determine that cell come from current preg or
  past one
• sensitivity is 40-50%

				
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Description: genetic counseling;screening test;non invasive test--ultrasound,serummaker;diagnostic test;invasive test-amniocentesis,chorionic villus sampling(CVS),percutaneous blood sampling (PUBS),prenatal dignosis in future