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Tufts OpenCourseware
Author: Diana Bianchi, M.D.
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Prenatal Diagnosis


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition, C.V. Mosby Publishing, 2005.



The student should:

  1. Recognize major reasons for referral for prenatal diagnosis;
  2. Know approximate risks associated with different referral indications;
  3. Understand the various techniques used in prenatal diagnosis;
  4. Know the advantages and disadvantages of the these techniques;
  5. Know the basic steps involved in prenatal genetic counseling;
  6. Understanding some of the options available for treating the fetus in utero.

What are the Objectives of Prenatal Diagnosis?

  • To provide information to the prospective parents regarding fetal diagnosis
  • To counsel and support prospective parents for their reproductive decisions.
  • To potentially offer fetal therapy, and ideally, prevent some of the medical complications noted postnatally in infants.

What is Fetal Therapy?

  • Change the time, mode (cesarean section versus vaginal) or place (community hospital or academic medical center) of delivery.
  • Medical treatment of the mother to get the medication across the placenta and; hence, treat the fetus.
    • Examples:
      • Digitalis (digoxin) for fetal congestive heart failure,
      • B12 for methylmalonic acidemia,
      • Corticosteroids for congenital adrenal hyperplasia (prevent masculinization of a female fetus),
      • Cholesterol (in plasma) for Smith-Lemli-Opitz syndrome.
  • Surgical treatment of the fetus.

General Trends in Prenatal Diagnosis

  • Individual diagnosis to population-based screening.
  • Less invasive techniques (screening vs. diagnosis).
  • Earlier testing (first trimester vs. second trimester).

Current Techniques of Prenatal Diagnosis

Noninvasive: Sonography (fetal ultrasonograhic examination), fetal magnetic resonance imaging (MRI), maternal serum screening, fetal nucleic acids (DNA and RNA) in maternal blood and plasma

Invasive: Amniocentesis, chorionic villus sampling (CVS), cordocentesis, fetal biopsy, preimplantation genetic diagnosis

Noninvasive Prenatal Diagnosis

Ultrasonographic Examination

Two-dimensional or three-dimensional imaging of fetal anatomy via high-frequency sound waves. The relative density of different tissues is displayed as varying shades of gray. Fetal motion and cardiac function can be evaluated using real time imaging. Can be performed at any gestational age. No known risk to fetus or mother. Not 100% diagnostic. Heart anomalies especially difficult to diagnose.

  1. Abnormalities commonly detected:
    1. Multiple gestation (twins or triplets), growth restriction, abnormally low (oligohydramnios) or excess (polyhydramnios) amniotic fluid, brain structural anomalies, abdominal wall defects, neural tube defects (spina bifida), kidney and bladder abnormalities.
  2. New screening test: Increased nuchal translucency (NT) measurement.
    1. The fluid-filled space at the back of the fetal neck is easily visualized during the first trimester. This space can be measured. An increased measurement (compared to normal standards at a specific gestational age) has been shown to be associated with an increased risk of fetal Down syndrome and/or congenital heart disease.
  3. Three-dimensional imaging especially good for craniofacial malformations.

Fetal Magnetic Resonance Imaging (MRI)

Ultrafast MRI techniques allow imaging of the fetus while the fetus is moving. This technique is only used when ultrasound examination suggests a brain, thoracic or abdominal abnormality. The technique provides better resolution than ultrasound examination.

Maternal Serum Screening

Maternal serum screening involves measurement of proteins produced by the fetus or placenta. The results of an individual sample are reported as relative values compared to population standards (MoMs, multiples of the median). To interpret results, an accurate gestational age, maternal diabetes, maternal weight, maternal race, and smoking status must be known.

  1. Current testing in the U.S. is offered to all pregnant women and is performed in the second trimester (15-17 weeks). It consists of a "triple or quadruple panel" alpha-fetoprotein (AFP), unconjugated estriol (UE3), and the beta subunit of human chorionic gonadotropin (hCG). A fourth marker, inhibin, is being measured in some clinical screening programs.
  2. The current sensitivity of detection of fetal trisomy 21 is 80-85%. However, to achieve this level of sensitivity, 5% of cases are called "screen positive", although a normal fetus is present. Following an abnormal maternal serum screening test, the pregnant woman meets with a genetic counselor and is offered amniocentesis. Approximately 39 amniocenteses are performed on normal fetuses to detect one fetus with trisomy 21. This results in the loss of some normal fetuses due to the risks associated with amniocentesis (see below).
  3. A current area of investigation is the markers that are useful in the first trimester - pregnancy associated plasma protein - A (PAPP-A) and the free beta subunit of hCG.

Maternal Serum Screening

Fetal Cells and DNA in Maternal Blood and Plasma

Because of the concerns regarding the consequences of the high false positive rate associated with maternal serum screening, alternative approaches are being explored.

  1. Fetal nucleated erythrocytes can be physically isolated from maternal blood and used as a template for FISH analysis using chromosome-specific probes.
  2. Surprisingly high amounts of fetal DNA circulate freely within maternal blood. This DNA likely originates from placental cells that undergo apoptosis. The amount of fetal DNA in the mother increases as the gestation progresses.
  3. Fetal DNA in the mother's blood is being used for non-invasive diagnosis of gender and fetal blood type, such as Rhesus D positivity.

Invasive Prenatal Diagnosis

  1. Maternal age >35 years at time of delivery
  2. Fetal structural abnormality seen on ultrasound examination
  3. Abnormal maternal serum screen result
  4. Family history of prior chromosome abnormality or Mendelian disorder
  5. Extreme anxiety

Amniocentesis (The "Gold Standard")

Over thirty years of clinical experience exist with this technique. Transabdominal aspiration of amniotic fluid (about 30 cc) under ultrasound guidance. Usually performed at 15-17 weeks of gestation. Cells in amniotic fluid originate in fetal mouth and bladder. Cells are cultured for chromosome analysis; results take 7-10 days. Cells can be used for biochemical (enzyme) analysis or DNA analysis. This amniotic fluid is assayed for alphafetoprotein as a screen for open neural tube and abdominal wall defects. There is a 1 in 200 (0.5%) chance of miscarriage following amniocentesis. "Early" amniocentesis (10-14 1/2 weeks) is associated with causing club foot in the fetus.

Chorionic Villus Sampling (CVS)

This is a newer technique, available only since 1983. It is performed using a transcervical or transabdominal ultrasound guided catheter or needle to aspirate chorionic villi. The technique is usually performed at 11 weeks of gestation. Results of chromosome analysis are available in 2-7 days. Villi are preferable to amniotic fluid cells for prenatal diagnosis of certain conditions, such as osteogenesis imperfecta. There is a 1 in 100 risk of miscarriage associated with CVS. Advantages of CVS Over Amniocentesis
  1. Performed in 1st trimester.
  2. Restores privacy to reproductive decisions.
  3. Tissue obtained is preferable for DNA analysis.
  4. Cells are mitotically active; karyotyping is rapid.
  5. Detects mosaic trisomy, thereby identifying fetuses at risk for uniparental disomy (UPD). Disadvantages of CVS
  1. Elevated chance of miscarriage (0.5 versus 1%).
  2. Slightly elevated risk of maternal infection.
  3. Possibly causes limb malformations.
  4. Confined placental mosaicism detection in 1% of cases.
  5. Amniotic fluid alpha-fetoprotein not assayed.

Cordocentesis (PUBS, Percutaneous Umbilical Blood Sampling)

This technique consists of percutaneous ultrasound-guided needle aspiration of 1-3 ml of fetal blood from the umbilical cord at the placental insertion site. Cannot be performed at less than 18 weeks gestation. Used to diagnose congenital infection, thrombocytopenia, 3rd trimester chromosome abnormalities, or anemia. The risk of miscarriage or preterm labor is 1-5%.

Fetal Biopsy

As more genes are cloned, fetal genetic conditions are increasingly being diagnosed on any nucleated cell. Occasionally, however, there is no DNA diagnosis available, so a needle is placed into the uterus to acquire small pieces of fetal tissue.

Examples include:

  • muscle biopsy to stain for the presence of dystrophin in a male fetus at risk for Duchenne muscular dystrophy or
  • skin biopsy in a fetus at risk for inherited skin disorders such as epidermolysis bullosa.

Preimplantation Genetic Diagnosis (PGD)

Major advantage is that termination of pregnancy is avoided. In vitro fertilization is required (costly, and medical risks to woman). An individual cell is removed from the pre-implantation embryo and used for FISH or PCR analysis. Requires advance knowledge of the familial molecular abnormality in single gene disorders and specialized laboratories that can analyze single cells.

Major Indications:

  • Known single gene mutation in family; DNA mutation is identified; only embryos without mutation are transferred.
  • One parent carries a balanced chromosome translocation; PGD is used to increase chance of a successful pregnancy.
  • Gender determination and transfer of only female embryos in known X-linked condition.
  • In women of advanced age (>38), PGD is used to screen embryos for common aneuploidy such as trisomies 13, 18, 21. Transfer of embryos that do not have these aneuploidies.

The Future

  • Primary prevention of birth defects. (You should all be taking multivitamins that include 0.4-mg of folic per day. It is the single most important step you can take to prevent birth defects!).
  • Advances in molecular cytogenetics ¡§the molecular karyotype¡Â¨ Using CGH arrays
  • Further study of the psychological effects of prenatal screening and diagnosis on prospective parents.
  • Open fetal surgery (randomized trial of fetal surgery for neural tube defect repair is ongoing).
  • Stem cell and gene therapy for the fetus. Reference

O'Brien B, Bianchi DW. Fetal therapy for single gene disorders. Clinical obstetrics and Gynecology. 2005;48:1-12