The purpose of prenatal screening
and diagnosis is not just to detect fetal abnormalities but also to allay
anxiety and provide assistance to prepare for a child with a specific
disability. Prenatal screening cannot be used to rule out all possible fetal
abnormalities. It is limited to determining whether the fetus has (or probably
has) designated conditions indicated by late maternal age, family history, or
well-defined risk factors.
There are multiple methods that can
assist in diagnosing a fetus regarding genetic disorders, including ultrasonography,
maternal serum (blood) screening tests, amniocentesis, chorionic villus
sampling, and percutaneous umbilical fetal blood sampling (Fig. 7.14). Prenatal
diagnosis can also pro- vide the information needed for prescribing prenatal
treatment for the fetus. For example, if congenital adrenal hyperplasia is
diagnosed, the mother can be treated with adrenal cortical hormones to prevent
masculinization of a female fetus.
Ultrasonography
Ultrasonography is a noninvasive
diagnostic method that uses reflections of high-frequency sound waves to
visualize soft tissue structures. Since its introduction in 1958, it has been
used during pregnancy to determine the number of fetuses, fetal size and
position, amount of amniotic fluid, and placental location. It also is possible
to assess fetal movement, breathing movements, and heart pattern. There is also
good evidence that early ultrasonography (i.e., before 14 weeks)
accurately determines gestational age.
Improved resolution and real-time
units have enhanced the ability of ultrasound scanners to detect congenital anomalies.
Ultrasonography makes possible the in utero diagnosis of cardiac defects,
hydrocephalus, spina bifida, facial defects, congenital heart defects,
congenital diaphragmatic hernias, disorders of the gastrointestinal tract,
skeletal anomalies, and various other
defects. Three-dimensional (3D) sonography has become useful in better
assessing facial profiles and abdominal wall defects. A fetal echocardiogram
can be done as follow-up for
possible cardiac anomalies. Fetal MRI can be done to better assess skeletal, neurological, and other anomalies. Intrauterine diagnosis of congenital
abnormalities permits better monitoring, further workup and planning with
appropriate specialties, preterm delivery for early correction, selection of
cesarean section to reduce fetal injury, and, in some cases, intrauterine
therapy.
Maternal Serum Markers
Maternal blood testing began in the
early 1980s with the test for AFP. Since that time, a number of serum factors
have been studied as screening tests for fetal anomalies.
Current maternal testing favors
first trimester screening for all women between 11 and 13 weeks combining
nuchal translucency seen on sonogram with PAPP-A level, hCG level, and maternal
age to determine a risk for trisomy 21, 13, and 18. PAPP-A, which is secreted
by the placenta, has been shown to play an important role in promoting cell differentiation
and proliferation in various body systems. In complicated pregnancies, the
PAPP-A concentration increases with gestational age until term. Decreased
PAPP-A levels in the first trimester (between 10 and 13 weeks) have been shown
to be associated with Down syndrome. When used along with maternal age, free β-hCG, and ultrasonographic
measurement of nuchal
translucency, serum PAPP-A levels can report-edly
detect 85% to 95% of affected pregnancies with a false-positive rate of
approximately 5%.
A maternal serum AFP can then be
done alone in the second trimester to assess for NTDs, though for pregnant
women with access to good quality sonography centers, a level II ultrasound for
anatomical viewing of the spine can exclude greater than 99% of spinal defects.
For pregnant women presenting too
late for first trimester screening, the quad screen using AFP, hCG, inhibin A,
and unconjugated estriol is used to screen for trisomy and NTDs between 15 and
22 weeks of pregnancy. The use of ultrasonography to verify fetal age can
reduce the number of false- positive tests with this screening method.
AFP is a major fetal plasma protein
and has a structure similar to the albumin found in postnatal life. AFP is made
initially by the yolk sac, gastrointestinal tract, and liver. Fetal plasma
levels of AFP peak at approximately 10 to 13 weeks’ gestation and decrease
until the third trimester when the level
peaks again. Maternal and amniotic fluid levels of AFP are elevated
in pregnancies where
the fetus has
an NTD (i.e., anencephaly and open spina
bifida) or certain other mal-formations such as an anterior abdominal wall
defect in which the fetal integument is not intact. Although NTDs have been
associated with elevated levels of AFP, decreased levels have been associated
with Down syndrome.
A complex glycoprotein, hCG, is
produced exclusively by the outer layer of the trophoblast shortly after
implantation in the uterine wall. It increases rapidly in the first 8 weeks of
gestation, declines steadily until 20 weeks, and then plateaus. The single
maternal serum marker that yields the highest detection rate for Down syndrome
is an elevated level of hCG. Inhibin A, which is secreted by the corpus luteum
and fetoplacental unit, is also a maternal serum marker for fetal Down
syndrome.
Unconjugated estriol is produced by
the placenta from precursors provided by the fetal adrenal glands and liver. It
increases steadily throughout pregnancy to a higher level than that normally
produced by the liver. Unconjugated estriol levels are decreased in Down
syndrome and trisomy 18.
Amniocentesis
Amniocentesis is an invasive
diagnostic procedure that involves the withdrawal of a sample of amniotic fluid
from the pregnant uterus usually using a transabdominal approach (see Fig.
7.14). The procedure is useful in women with elevated risk on first trimester
screen or quad screen, abnormal fetal findings on sonogram, or in parents who
are carriers or with a strong family history of an inherited disease.
Ultrasonography is used to gain additional information and to guide the
placement of the amniocentesis needle. The amniotic fluid and cells that have
been shed by the fetus are studied. Amniocentesis can be performed on an
outpatient basis starting at 15 weeks. For chromosomal analysis, the fetal
cells are grown in culture and the result is available in 10 to 14 days. Beyond
prenatal diagnosis, amniocentesis can also be done throughout the pregnancy as
needed for testing. In cases of suspected chorioamnionitis, an amniocentesis
can be done to assess for infection of the amniotic fluid. Fetal lung maturity
can be assessed by amniocentesis by looking for the lecithin/sphingomyelin
(L/S) ratio and presence of phosphatidyl glycerol to help with delivery
planning in some cases.
Chorionic Villus Sampling
Chorionic villus sampling is an
invasive diagnostic procedure that obtains tissue that can be used for fetal
chromosome studies, DNA analysis, and biochemical studies. Sampling of the chorionic villi usually is done after 10
weeks of gestation. Performing the test before 10 weeks is not recommended
because of the danger of limb reduction defects in the fetus. The chorionic
villi are the site of exchange of nutrients between the maternal blood and the
embryo—the chorionic sac encloses the early amniotic sac and fetus, and the
villi are the primitive blood vessels that develop into the placenta. The
sampling procedure can be performed using either a transabdominal or
transcervical approach (see Fig. 7.14). The fetal tissue does not have to be
cultured, and fetal chromosome analysis can be made available in 24 hours. DNA
analysis and biochemical tests can be completed within 1 to 2 weeks.
Percutaneous Umbilical Cord
Blood Sampling
PUBS is an invasive diagnostic
procedure that involves the transcutaneous insertion of a needle through the
uterine wall and into the umbilical artery. It is performed under ultrasonographic
guidance and can be done any time after 16 weeks of gestation. It is used for
prenatal diagnosis of hemoglobinopathies, coagulation disorders, metabolic and
cytogenetic disorders, and immunodeficiencies. Fetal infections such as rubella
and toxoplasmosis can be detected through measurement of immunoglobulin M
antibodies or direct blood cultures. Results from cytogenetic studies usually
are available within 48 to 72 hours. Because the procedure carries a greater
risk of pregnancy loss compared to amniocentesis, it usually is reserved for
situations in which rapid cytogenetic analysis is needed or in which diagnostic
information cannot be obtained by other methods. In the process of doing PUBS
to assess fetal anemia, a blood transfusion can be administered to the fetus as
needed.
Cytogenetic and
Biochemical Analyses Amniocentesis and chorionic villus sampling
yield cells that can be used for cytogenetic and DNA analyses. Biochemical
analyses can be used to detect abnormal
levels of AFP and abnormal
biochemical products in the maternal blood and in specimens of amniotic fluid
and fetal blood.
Cytogenetic studies are used for
fetal karyotyping to determine the chromosomal makeup of the fetus. They are
done to detect abnormalities of chromosome number and structure. Karyotyping
also reveals the sex of the fetus. This may be useful when an inherited defect
is known to affect only one sex.
Analysis of DNA is done on cells
extracted from the amniotic fluid, chorionic villi, or fetal blood from
percutaneous umbilical sampling to detect genetic defects such as inborn errors
of metabolism. The defect may be established through direct demonstration of
the molecular defect or through methods that break the DNA into fragments that
can be studied to determine the presence of an abnormal gene. Direct
demonstration of the molecular defect is done by growing the amniotic fluid
cells in culture and measuring the enzymes that the cultured cells produce.
Many of the enzymes are expressed in the chorionic villi. This permits earlier
prenatal diagnosis because chorionic
villi. This permits earlier prenatal diagnosis because the cells do not need to be subjected to prior culture. DNA studies are
used to detect genetic defects that cause inborn errors of metabolism, such as
Tay-Sachs disease, glycogen storage diseases, and familial
hypercholesterolemia. Prenatal diagnoses are possible for more than 70 inborn
errors of metabolism.
The newest realm of fetal diagnosis
involves looking at fetal DNA in the maternal blood. Some private companies and
many research institutions are exploring the efficacy of looking at fetal DNA
for sex determination and other genetic testing. More research is needed before
this will be offered to all women.
