Clinical Genetics IV: The
Practice of Prenatal Diagnosis
December 3(Monday), 2001
Required Reading: Principles
of Medical Genetics
TD, Collins FS, Ginsburg D
Williams and Wilkins
BE FAMILIAR WITH GENERAL ISSUES SURROUNDING PRENATAL DIAGNOSIS
- Know that all couples face a nearly
3% risk that their child will be born with a medical problem or
birth defect that will require intervention.
- Understand that prenatal tests are used
specifically and selectively. There is no 100% guarantee of a healthy
baby even if when prenatal tests are done (such as cytogenetic analysis
and ultrasounds) and are completely normal.
- The use of non-directive genetic counseling
in prenatal diagnoses, selective terminations, and assisted reproductive
technologies is extremely important.
- Understand that ethnocultural, moral,
and/or religious backgrounds that may strongly influence an individuals
or couples choice surrounding prenatal diagnosis, selective
termination of a pregnancy, and the use of reproductive technologies.
Appreciate the difficult decisions that individuals, couples and
families must face when encountering situations where pregnancy
termination is being considered or presented as an option.
- Examine your own moral/religious/cultural
beliefs regarding challenging and complex issues surrounding prenatal
diagnosis and available options. Make an effort to understand the
potential biases you may bring to a genetic counseling session where
these issues are discussed. Find ways to address your feelings and
concerns regarding these issues prior to meeting with your patients
to avoid introducing personal biases.
- Understand the grief process associated
with unanticipated pregnancy loss due to genetic causes or due to
pregnancy termination that couples might face.
Be aware of the important role a physician or other health care
worker can play in helping individuals/couples/families cope with
that grief. Specifically, understand the importance of providing
individuals with education information about their fetus and the
disorder, address why this may have happened without implying blame,
provide for "remembrances" of their fetus (photographs,
clips of hair, a chance to hold their fetus), access to support
groups/counseling, and general information about recurrence risk.
An autopsy and further genetic studies may be needed to understand
the cause of fetal demise and the parents should understand the
need for these studies and plans for follow-up counseling should
be made. It is important to raise the issue of burial of the fetus
and/or memorial services as some individuals/couples desire and
benefit from these services. It is usually not helpful to
suggest that couples make immediate decisions about having future
pregnancies at the acute time of the loss. For instance, the time
of a pregnancy loss or termination would not be the ideal time to
recommend various sterilization procedures to avoid having future
pregnancies or, at the other extreme, to suggest they forget
about this loss and try to have another baby as soon as possible.
It is usually most helpful to see individuals/couples back after
the loss/termination to discuss future family planning issues, more
details about recurrence risks, and reproductive options.
- Know that some couples undergo preconception
genetic counseling and evaluation prior to becoming pregnant
in order to determine their risks and prepare for future prenatal
testing if desired. Understand this concept and the utility of such
- Understand the variable effects of
prenatal diagnosis that results in pregnancy termination on gene
frequency and disease frequency.
In general, selective terminations of fetuses with later adult-onset
autosomal diseases that have a low mutation rate and high reproductive
fitness could have a significant effect on gene frequency whereas
selective termination of fetuses with autosomal recessive disorders
which are lethal in childhood would only effect the gene frequency
if carriers would also decide to have less children, reducing the
chance of having other carriers.
KNOW THE APPLICATIONS
AND LIMITATIONS OF PRENATAL DIAGNOSTIC TECHNIQUES
- Be able to generally describe the
major kinds of prenatal diagnostic techniques. Know the indications,
applications, benefits and limitations of the different types
of prenatal diagnostic techniques.
- Be able to describe the general differences
between the commonly applied techniques of amniocentesis
and chorionic villus sampling (CVS).
- Know that CVS can be done earlier in
the pregnancy (generally 9-12 weeks gestation) than amniocentesis
(generally 16-20 weeks gestation) and the risk of fetal loss during
CVS is relatively low, 1% or less. Risks from amniocentesis are
even lower about .5% or slightly less. Thus since the risks are
not dramatically different, many women prefer CVS since that can
be done earlier providing results that may help them decide whether
or not to terminate a pregnancy.
- The risks of fetal loss associated with
percutaneous umbilical blood sampling (PUBS) or fetal
blood sampling are higher than amniocentesis or CVS. The risks
are relatively low if done later in the pregnancy (when the umbilical
vessel is bigger) but this is at a time when pregnancy termination
is no longer a potential option. For this reason, some individuals
might accept the higher rate of loss (approximately 2%) associated
with this technique during the early-mid second trimester in order
to obtain a relatively rapid diagnosis.
- Cytogenetic studies on amniocytes and
trophoblasts generally take 10-14 days, as they must be cultured
before cytogenetic analysis can be done. DNA tests from CVS samples
often do not require culturing and can be done often within 3-5
days if it is a PCR based test. Fetal blood cell cytogenetic analysis
and DNA analyses can be done in 3-5 days.
- PUBS may be the best way to detect a
disorder for which other biochemical, molecular, or cytogenetic
studies are not yet available. Although there has been some progress
in detecting fetal cells in maternal blood specimens, this is not
yet state-of-the-art for most prenatal tests.
- Understand the potential utility and
limitations of fetal ultrasounds in evaluating a fetus for
structural birth defects.
- Know the difference between screening
tests and more definite genetic tests.
- Understand that
is routinely done during most pregnancies and elevated measurements
of maternal alpha fetal protein may indicate a neural tube abnormality
and therefore requires further evaluation. Know that other factors
such as wrong gestational dates, fetal death, and multiple gestations
may cause erroneous elevations of serum AFPs. A lower than normal
AFP screen can be associated with chromosomal trisomies such as
Down syndrome but this is not very specific or sensitive. Use of
AFP screening along with screening of other metabolites including
unconjugated estriol and human chorionic gonadotropin increases
the sensitivity of the screen and is reported to pick up approximately
60% of infants with Down syndrome. Because serum AFP screening alone
and/or the "triple screen" is not even close to 100% specific
or 100% sensitive it is imperative that these tests be recognized
as only screening tests and that more definitive studies (e.g. detailed
ultrasounds for elevated AFP levels and chromosome analyses if trisomy
is being considered) must be done in order to establish or
disprove a suspected diagnosis.
- Understand that the cytogenetic, biochemical,
and molecular techniques used in prenatal diagnosis are generally
similar to standard techniques but have different specimen requirements
and, oftentimes, different urgency associated with the testing.
Pregnancy terminations are legal only up to 24 weeks gestation in
most states. Additionally, many couples note that termination is
emotionally harder at later dates.
- Understand the importance of good prenatal
care avoidance of known teratogens AND the use of vitamin
supplementation to reduce birth defects. Specifically, known about
the importance of taking FOLIC ACID to reduce neural tube defects
as well as other birth defects. All women of child bearing age should
who are at "risk" of becoming pregnant should have an
adequate intake of folic acid PRIOR to and during pregnancy.
BE AWARE OF EXISTING AND
EMERGING ASSISTED REPRODUCTIVE TECHNOLOGIES
- Understand that a variety of assisted
reproductive technologies are available for couples to consider
including (but not limited to): artificial insemination (donor sperm),
sex selection based on sperm sorting followed by assisted reproductive
techniques to achieve pregnancy, donor ovum with or without surrogate
parenting, in-vitro fertilization, and even preimplantation diagnosis.
- Know that preimplantation diagnosis
means that fertilization takes place in vitro and DNA tests are
performed on single cells of very early embryos (4-16 cell stage).
If the cell does not have the mutation being tested for, the embryo
it was derived from is allowed to implant in a uterus prepared for
- Know that in-vitro fertilization techniques
can result in multiple fetuses and that selective termination of
some fetuses is sometimes done to increase the chances of having
healthy babies born near term.
- Know that new technologies that have
reproductive potential are being developed.
Know what the issues are surrounding somatic cell mammalian cloning
by nuclear transfer. Understand that this technique of taking the
nucleus from an adult somatic cell and implanting it into an enucleated
egg that is allowed to implant in an appropriate uterine environment
has resulted in the birth of rodent and sheep clones. Know that
worldwide discussions are taking place regarding potential applications
of similar methods of human cloning.