Prenatal diagnosis has revolutionized prenatal care and provides genetic, anatomic, and physiologic information about the fetus(es) that can be used to make informed decisions regarding pregnancy and delivery, thus improving maternal and fetal outcomes. Advances in the fields of maternal-fetal medicine, radiology, and genetics have greatly improved prenatal diagnosis.
is an Assistant Clinical Professor, Department of Obstetrics
& Gynecology, Columbia University Medical Center, New York,
is Professor and Chair, Department of Obstetrics and Gynaecology,
Royal College of Surgeons in Ireland, Rotunda Hospital, Dublin,
Prenatal diagnosis has revolutionized prenatal care from the
perspective of both the patient and the physician. For the patient,
prenatal diagnosis provides genetic, anatomic, and physiologic
information about the fetus or fetuses that can be used to make
informed and individualized decisions regarding the pregnancy. For
the physician, prenatal diagnosis provides vital information that
can be utilized for better antepartum management. Information
regarding specific anatomic anomalies affords the physician the
opportunity to offer the patient sophisticated prenatal procedures,
such as fetal surgery or selective fetal reduction in multiple
gestations. Likewise, prenatal knowledge about genetic,
physiologic, and/or anatomic abnormalities enables the physician to
tailor or manage the timing and mode of delivery for optimal
maternal and fetal outcomes. Prenatal diagnosis also allows the
neonatal and pediatric specialists to be adequately prepared for a
potentially ill neonate at delivery.
Recent progress in the fields of maternal fetal medicine,
radiology, and genetics has resulted in great advances in prenatal
diagnosis. The following article will review the recent major
advances in this rapidly progressing field.
Advances in the detection of fetal aneuploidy
In recent years, there have been significant advances in
antenatal screening for fetal aneuploidy. Fetal aneuploidy is
defined as an abnormal number of chromosomes instead of the usual
diploid complement of 46 chromosomes. One single additional
chromosome is termed
and is an important cause of congenital malformations as well as of
congenital mental retardation. Down syndrome (trisomy 21), Edwards
syndrome (trisomy 18), and Patau syndrome (trisomy 13) are the most
common trisomies. Trisomies 18 and 13 are lethal and affect
approximately 1 in 3000 and 1 in 5000 live births, respectively.
The majority of infants with trisomy 18 die by 1 year of age, while
the majority of infants with trisomy 13 die by 3 months of age.
Trisomy 21 is compatible with life and affects approximately 1 in
800 to 1 in 900 live births. It is associated with congenital heart
defects, most commonly the atrio-ventricular canal defect.
Initially, prenatal screening for Down syndrome constituted
offering amniocentesis to women of advanced maternal age (age ≥35
at estimated date of delivery) and to women with a previously
affected pregnancy. In the mid 1980s, it was noted that women in
the second trimester with decreased levels of maternal serum alpha
fetoprotein (AFP) were at increased risk for their pregnancy to be
complicated by Down syndrome. As a result, noninvasive
second-trimester Down syndrome screening for the general obstetric
population became feasible, and a multiple-marker serum panel was
established for this purpose.
Since >90% of all structural and chromosomal abnormalities
derive from pregnancies without risk factors, it is reasonable that
universal screening be provided.
Second-trimester maternal serum screening currently includes a
combination of 4 markers and is known as the "quad test." These
markers include AFP, human chorionic gonadotropin (hCG),
unconjugated estriol (uE3), and inhibin A.
For screening purposes, sonographic dating should be used instead
of menstrual dating, as it optimizes the performance of the test.
While screening references are available between 15 and 21 weeks'
gestation, the optimal time to perform this test is between 15 and
16 weeks' gestation. In addition, laboratories adjust for factors
that may affect values, such as maternal weight, race, multiple
gestation, and history of diabetes. It is important to note that
with regard to twins, the sensitivity for Down syndrome using the
quad test is only 47%, with a 5% false-positive rate.
Maternal serum screening in multiples has been limited because of
the potential for discordance between fetuses and because of the
impact of the various placentas on analytes.
In patients with a pregnancy affected by Down syndrome, the AFP
and uE3 levels are lower, while the hCG and inhibin A levels are
higher, than in unaffected pregnancies. In pregnancies affected by
trisomy 18, the AFP, uE3, and hCG levels are all low. The quad test
can detect approximately 75% cases of Down syndrome, with a 5%
Meanwhile, the quad test detects 85% to 95% of cases in women ≥35
years of age at estimated date of delivery, with a 25%
The disadvantages of this screening method include its relatively
late performance in the second trimester, resulting in definitive
diagnosis by amniocentesis being provided even later in gestation.
In addition, many cases of Down syndrome will not be detected with
this test, and the 5% screen-positive rate indicates that many
amniocenteses will be performed for every 1 case of Down syndrome
Due to the limitations of the quad test, great efforts have been
put forth to devise more efficient screening protocols. Because of
its ability to provide results early in pregnancy, first-trimester
screening is becoming increasingly more important. First-trimester
screening provides the opportunity for early risk assessment and
early diagnosis of fetal aneuploidy via chorionic villus sampling
(CVS). Early diagnosis allows for pregnancy termination earlier in
gestation, if the patient so desires, affording the patient greater
privacy. In addition, earlier pregnancy termination is associated
with decreased maternal morbidity.
First-trimester ultrasound is one of greatest contributors to
the recent advances in prenatal diagnosis and is rapidly becoming
the cornerstone of screening for fetal aneuploidy. Techniques used
to evaluate risk for Down syndrome during the first trimester
include nuchal translucency (NT) sonography, assay of
first-trimester maternal serum markers, nasal bone sonography, and
Doppler sonography of the ductus venosus.
The normal space between the spine and the overlying skin at the
back of the fetal neck during the first trimester is referred to as
the NT (Figure 1). A large NT has been associated with an increased
risk for aneuploidy, genetic disorders, anatomic abnormalities, and
poor pregnancy outcomes.
When obtained between 10 weeks 3 days and 13 weeks 6 days'
gestation, measurement of the NT has been shown to be a powerful
sonographic marker for trisomy 21.
It is unlikely that one pathophysiologic mechanism leads to an
enlarged NT. Possible etiologies include heart failure secondary to
structural malformations, abnormalities in the extracellular
matrix, and abnormal lymphatic development.
Nuchal translucency sonography is technically challenging and
can be obtained both transabdominally and transvaginally. The fetus
should be in a perfect midsagittal view. Careful attention should
be paid to distinguish the nuchal skin from the amnion. The fetus
should have a neutral neck, and the image should be magnified
significantly. Calipers need to be placed at the inner borders of
the NT space. Inter-and intraobserver variations in NT measurements
have been noted. Therefore, both continued education and ongoing
quality assurance are essential when NT measurements are used as a
The ability to measure NT depends on the sonographer, the proper
magnification of the fetus, the correct placement of the calipers,
the ultrasound equipment, the fetal position, and the maternal body
In a portion of cases, obtaining an adequate NT may not be
possible. When measuring the NT is difficult, the patient may
return for a repeat examination in 1 week, provided that the
gestational age is <14 weeks when the patient returns. Once the
NT measurement is acquired, a special software program is used to
convert the millimeter measurement into a multiple of the median
(MoM) value. The MoM value takes into account gestational age
variation in NT size, while allowing for the integration of
maternal age and serum results.
In multiple pregnancy, NT appears to be a promising modality for
screening for aneuploidy. As suggested previously, maternal serum
screening in multiples has been limited because of the potential
for discordance between fetuses and because of the impact of the
various placentas on analytes. The NT distribution does not seem to
differ significantly in singletons compared with twins. Thus, the
Down syndrome detection rate in multiples should be similar to that
of singletons. Further research is still needed, but this screening
modality appears to be an improvement over maternal serum
Some centers are already using NT measurements for screening for
aneuploidy in patients with multiples, and NT measurements have
been used for fetus selection in patients undergoing multifetal
When a cystic hygroma is present, the NT is markedly enlarged
and extends along the entire length of the fetus, with septations
clearly visible within the space (Figure 2). It is important to
remember that a cystic hygroma must be differentiated from a large
NT. A cystic hygroma occurs in approximately 1 in 300
first-trimester ultrasounds. The finding of a cystic hygroma has
been associated with a high risk for aneuploidy. The majority of
cases are trisomy 21, but cystic hygroma has been associated with
Turner syndrome, trisomy 18, trisomy 13, and triploidy. While many
cases of cystic hygroma will have a normal karyotype, a large
proportion of these cases will be complicated by a fetal
malformation, such as a cardiac defect or a skeletal anomaly.
Patients with a cystic hygroma on first-trimester ultrasound should
be referred to genetic counseling, as only a small proportion of
all cases of first-trimester cystic hygroma are associated with a
normal live-born infant.
First-trimester maternal serum screening
First-trimester maternal serum screening utilizes maternal serum
levels of pregnancy-associated plasma protein A (PAPP-A) and free
beta hCG between 10 and 14 weeks' gestation. In pregnancies
affected by Down syndrome, PAPP-A is lower compared with unaffected
pregnancies at 10 to 14 weeks' gestation. Meanwhile, maternal serum
levels of free beta hCG are higher in pregnancies affected by
trisomy 21 than in unaffected pregnancies. These 2 markers,
combined with maternal age, can detect up to 60% of cases of Down
syndrome, with a 5% false-positive rate.
Combined sonographic and serum screening
The most efficient method of first-trimester screening for
aneuploidy involves combining maternal age, NT, and the serum
markers PAPP-A and free beta hCG. Between 10 and 14 weeks'
gestation, this screening method may detect up to 82% of cases of
trisomy 21, with a 5% false-positive rate.
Timing is important, as studies have shown that the accuracy of
this screening protocol deteriorates over time. With this method,
trisomy 21 detection rates are 87% at 11 weeks and 82% at 13 weeks,
both at a 5% false-positive rate.
Nasal bone sonography is another first-trimester ultrasound
technique that has been proposed for screening for aneuploidy.
Similar to NT, this technique may be difficult to master and
elusive to obtain. Nasal bone sonography is performed between 10
and 14 weeks' gestation. A perfect midsagittal image is required,
and the fetal spine should be down with slight neck flexion. When
the fetal profile is facing upwards, it may be possible to
distinguish 2 echogenic lines at the fetal nose profile. The
superficial echogenic line is the skin, and the deeper line is the
nose bone. Failure to visualize the fetal nasal bone may be an
independent risk factor for fetal aneuploidy. The studies
suggesting that the absence of the fetal nasal bone may be used as
a marker for trisomy 21 are limited by the fact that they are
derived from high-risk populations. More recent research has
suggested that nasal bone evaluation may not be useful for general
Ductus venosus Doppler sonography
Doppler of the ductus venosus is another technique that has been
proposed for the first-trimester screening of fetal aneuploidy. The
ductus venosus usually demonstrates a triphasic flow pattern, with
forward flow reaching peaks during ventricular systole and early
ventricular diastole. Absent or reversed flow at the time of atrial
contraction is considered abnormal and has been suggested as a
marker for aneuploidy.
Doppler of the ductus venosus at this point is not used in the
general population for screening for aneuploidy. It is technically
challenging during the first tri-mester.
At 10 to 14 weeks' gestation, the ductus venosus vessel may be as
small as 2 mm while the Doppler gate size may be
0.5 to 2 mm in size. As a result, obtaining accurate flow
velocity waveforms from such a tiny vessel may be difficult without
contamination of the waveforms from the neighboring vessels. In
addition, it is uncertain whether the NT measurement and ductus
venosus flow are independent findings. If they are not independent,
it becomes statistically complex to use one test to alter risk
assessment derived from another test. At this time, screening for
aneuploidy using Doppler of the ductus venosus should be considered
While the advances in first-trimester screening are exciting,
there will always be a role for second-trimester screening. Many
patients may not present in time for first-trimester screening.
Likewise, many patients may not have access to providers skilled at
NT sonography or skilled at CVS. A portion of patients may prefer
amniocentesis to CVS. In addition to second-trimester maternal
serum screening (which was discussed previously), other
second-trimester screening methods include ultrasound detection of
anatomic abnormalities as well as ultrasound detection of minor
markers for aneuploidy.
At the time of second-trimester anatomic ultrasound, any major
fetal structural anomaly (such as a cardiac defect, omphalocele,
diaphragmatic hernia, duodenal or esophageal atresia, renal
abnormalities, clubbed or rocker-bottom feet, holoprosencephaly,
meningomyelocele, and/or proboscis) should prompt immediate
consultation with a genetic specialist, as these findings have been
associated with trisomy. Invasive prenatal diagnosis should be
offered for any major congenital anomaly. The optimal time to
perform an anatomic survey is at approximately 18 weeks' gestation,
as evaluation of the fetal anatomy is maximized at this time.
Likewise, amniocentesis results can be obtained in a timely manner,
and termination of pregnancy is still an option if the patient
In addition to major structural anomalies, second-trimester
ultrasound can detect minor markers for aneuploidy.
These findings are not fetal malformations. Rather, they are
specific ultrasound findings that have been associated with an
increased risk for fetal aneuploidy in certain high-risk
populations, such as those of advanced maternal age or those with
abnormal serum screening results. The role of these markers in the
low-risk population remains uncertain. These markers include nuchal
thickening, mild ventriculomegaly, a short humerus or femur,
echogenic bowel, enlarged cisterna magna, renal pyelectasis,
echogenic intracardiac focus, hypoplastic nasal bones, a single
umbilical artery, choroid plexus cysts, and overlapping fingers.
Detection of these minor markers should prompt consultation with a
genetic or maternal fetal medicine specialist who is experienced at
counseling patients regarding the risks associated with these
markers. Use of likelihood ratios may be useful for integrating
these markers into a precise risk assessment. A detailed discussion
of these markers is beyond the scope of this review.
Combined first- and second-trimester screening for
Another option for screening for aneuploidy that is gaining
popularity is combining first- and second-trimester screening.
Combined first-trimester NT and serum screening has shown similar
results as second-trimester serum screening with the quad test with
regard to screening for aneuploidy.
Combining first- and second-trimester screening maximizes the
performance of both of these screening modalities.
At this point in time, patients receiving care at centers offering
first-trimester screening and CVS may choose between 2 types of
first- and second-trimester combined screening: Integrated
screening and step-wise screening.
Integrated screening is a 2-step approach in which results are
withheld until both the first- and second-trimester screening tests
have been obtained, at which time a single risk assessment is
provided. Patients who opt for integrated screening have NT
performed between 10 and 14 weeks' gestation. A measurement of
PAPP-A is also obtained during this time period. Between 15 and 16
weeks' gestation, the quad test is performed, and all results are
integrated together. The trisomy 21 detection rate with this method
of screening is 94%, with a 5% false-positive rate.
This test is very attractive to many patients, as it maximizes the
Down syndrome detection rate while minimizing the false-positive
If NT is unavailable, "serum-integrated" testing that includes
obtaining PAPP-A in the first trimester followed by the quad test
in the second trimester may be performed.
In step-wise screening, patients undergo first-trimester testing
and are given the results at that time. The second-trimester
screening then utilizes the first-trimester results as the new a
priori risk. The advantage of this screening method is that
patients may opt for CVS in the first trimester if their screening
results indicate that their pregnancy is at increased risk for
aneuploidy. Otherwise, they can wait until the second-trimester
screening is completed and receive results that afford a better
Down syndrome detection rate.
Advances in the diagnosis of fetal congenital
Fast magnetic resonance imaging
While ultrasound remains the imaging modality of choice for the
fetus because of its widespread availability and reasonable cost,
it has several limitations. These include small field-of-view,
limited soft-tissue acoustic contrast, poor image quality in
pregnancies complicated by oligohydramnios, beam attenuation by
adipose tissue, and limited visualization of the posterior fossa
after 33 weeks' gestation because of bone cal-cification.
Magnetic resonance imaging (MRI) is now being used in conjunction
with ultrasound to provide additional information for prenatal
diagnosis. The advantages of MRI include the use of multiple planes
for reconstruction and a large field-of-view, making the
visualization of complicated anomalies easier.
Use of MRI was first described in pregnancy in 1983.
Its initial application was for maternal and placental
abnormalities. Fetal MRI was initially limited because of fetal
motion artifact. In the 1990s, fetal MRI became practical because
of the development of single-shot rapid acquisition sequence with
refocused echoes. This high-quality T2-weighted sequence has a
slice acquisition time of <1 second and essentially "freezes"
As a result, excellent fetal imaging can now be obtained without
maternal or fetal sedation (Figure 3).
Provided that there is no maternal contraindication, most
studies suggest that MRI is safe in pregnancy, as it allows the
acquisition of excellent soft-tissue contrast without using
However, several animal studies have suggested the possibility of
teratogenetic effects in early pregnancy.
While these studies may not be applicable to humans, they indicate
that MRI should be used with caution in the first trimester. The
risk of acoustic damage to the fetus is thought to be negligible.
Patients can be informed that according to the Safety Committee of
the Society for Magnetic Resonance Imaging, MRI is reasonable when
other nonionizing forms of radiation are inadequate, or when the
study would provide information that would otherwise require
exposure to ionizing radiation. While there is no evidence that MRI
can harm the fetus,
it is important to note that the United States Food and Drug
Administration asserts that the safety of fetal MRI "has not been
established," and that most of the centers using this imaging
technique in pregnancy limit its use to after the first trimester
and require informed consent prior to the procedure.
The main indication for fetal MRI is further evaluation of
inconclusive ultrasound findings. It is also useful for evaluation
prior to fetal surgery.
Fetal MRI has proven to be extremely helpful for the examination of
many suspected fetal anomalies. Definitive indications for fetal
MRI have not been established, and recommendations are based on
case reports, small case series, and expert opinion.
Ultrasound of the fetal brain can be limited because many anomalies
have a non-specific appearance. Likewise, technical factors can
limit the appearance of the brain, such as bone ossi-fication.
In addition, severe parenchymal abnormalities often cannot be
visualized with ultrasound.
Fetal MRI has been particularly helpful with the diagnosis and
management of suspected fetal central nervous system (CNS)
abnormalities and is suggested if a CNS abnormality is suspected on
Fetal MRI can aid in the diagnosis of ventriculomegaly, agenesis of
the corpus callosum, posterior fossa abnormalities, cortical gyral
malformations, hemorrhage, holoprosencephaly, arachnoid cysts,
neural tube defects, and vascular malformations.
In fact, MRI has changed the diagnosis and aided in the management
of many cases of suspected CNS abnormalities on ultrasound.
MRI can help better clarify the diagnosis and help patients make
decisions such as whether or not to continue with the pregnancy.
Levine et al
compared 242 ultrasound studies and 242 MRI studies of the CNS in
214 fetuses with suspected CNS abnormalities or who were at high
risk for CNS abnormalities. At confirmatory ultrasound, 69 fetuses
had normal CNS imaging. Approximately 80% of fetuses in the study
(171 of 242) had postnatal follow-up. MRI provided additional
information in 50% (72 of 145) of cases and actually revealed a new
major finding in 32% (46 of 145) of fetuses with abnormal
ultrasound findings. In patients with previable fetuses, this
information was utilized to help patients decide whether to
continue or terminate the pregnancy. In patients with viable
fetuses, this information was used to help determine the mode and
the location of delivery (community hospital versus tertiary care
In monochorionic twin pregnancies complicated by intrauterine
fetal demise (IUFD), fetal MRI can be used to diagnose multicystic
encephalomalacia, a devastating neurologic disorder that may occur
in up to 20% of monochorionic twins complicated by single IUFD.
Fetal MRI is usually performed 2 weeks following demise of a fetus.
A normal MRI following single IUFD in a monochorionic twin
pregnancy is thought to be reassuring. In addition, fetal MRI has
been used in other complicated monochorionic twins at risk for a
possible neurologic ischemic episode, such as cases complicated by
the twin-twin transfusion syndrome and cases that have undergone
invasive prenatal procedures, such as selective reduction using
cord ablative techniques.
The imaging modality may also be helpful in the diagnosis of
With regard to the fetal neck, MRI can help distinguish between
lymphangioma and cervical teratoma.
As neck masses can compromise fetal breathing at birth, MRI can
help with the assessment of the fetal airway so that the proper
precautions are taken at delivery.
Fetal MRI has also been helpful for the diagnosis of fetal
thoracic abnormalities such as congenital diaphragmatic hernia
(CDH), congenital cystic adenomatoid malformation of the lung, and
broncho-pulmonary sequestration. Fetal MRI helps with the
evaluation of the liver position in fetuses with CDH.
It may also be helpful with the assessment of fetal lung volumes in
these patients. In addition, complex genitourinary anomalies such
as cloacal exstrophy may be better imaged on MRI due to the larger
From the maternal aspect of care, if abnormal placentation is
suspected, MRI may help assess the degree of invasion and help
distinguish between placenta accreta, increta, and percreta.
MRI can be used to help distinguish the placenta from the
myometrium. Levine et al
evaluated 19 patients at risk for placenta accreta with ultrasound
and MRI. Five cases of accreta were diagnosed with vaginal
ultrasound and Doppler studies. In 1 patient with a posterior
placenta and history of myomectomy, MRI aided in the diagnosis of
placenta accreta, as the ultrasound imaging had not been
diagnostic. Other investigators have used MRI to assess placental
Accurate prenatal diagnosis of abnormal placentation is important
because it reduces fetal and maternal morbidity by enabling
specialized preoperative and postoperative care.
Fetal MRI is not currently recommended as a primary imaging
method for any fetal anomaly or condition. The information obtained
from MRI can be used in conjunction with the information obtained
from ultrasound. Fetal sonographic examination is important for
selecting appropriate fetuses whose management could benefit from
MRI. Fetal MRI is suggested for cases in which ultrasound cannot
make a definitive diagnosis and when a large field-of-view is
required. In addition, it may provide additional specific
information necessary for fetal intervention, including fetal
surgery. It is important to remember that that the field of fetal
MRI continues to rapidly evolve as technology advances and as new
applications are determined.
Similar to MRI, three-dimensional (3D) ultrasound allows for
multiplanar imaging and allows the examiner to move back and forth
between different planes because of the capability of viewing the
fetus in 3 rather than 2 spatial planes (Figure 4). Images can be
reconstructed, and the examiner can move the fetus into desired
positions that are often not possible with conventional ultrasound.
In addition, 3D scanning enhances imaging capabilities by
permitting surface rendering of a structure. Acquisition of
data-points through the entire volume of interest is required to
produce 3D ultrasound pictures. Acquisition quality depends on
acquisition speed. Slow acquisition speed results in more scanned
slices and is used for nonmoving organs. Fast speeds are preferable
for moving structures. The "four-dimension-al" (4D) real-time
imaging technique requires ultrafast acquisition. Four-dimensional
ultrasound displays a continuously updated and newly acquired
volume in any rendering modality. This creates the impression of a
Previously, it was thought that 3D ultrasound provided only
aesthetic images without contributing to prenatal diagnosis. There
are no accepted indications for 3D ultrasound in an obstetric
patient at this point. Few outcome studies have confirmed whether
or not this technology changes practices or clinical outcomes.
Nonetheless, this technology is rapidly advancing and has been
shown to be helpful in a research setting. It seems to be useful as
an adjunct to 2D ultrasound in certain clinical situations such as
fetal echocardiography and in the diagnosis and further evaluation
of certain fetal anomalies such as cleft lip and palate and
Preimplantation genetic diagnosis:
In the field of reproduction endocrinology, preimplantation genetic
diagnosis (PGD) is one of the most exciting new advances. It is a
form of prenatal diagnosis for cytogenetic and Mendelian disorders.
This technique allows for genetic testing prior to embryo transfer
in patients undergoing assisted reproductive technology (ART). One
or two cells are biopsied from embryos at the 6- to 8-cell stage
and are analyzed for chromosomal abnormalities or for single-gene
disorders. Alternatively, polar bodies can be biopsied from oocytes
for genetic testing as well. Preimplantation genetic diagnosis has
been used for couples at risk for having pregnancies affected by
single-gene or X-linked disorders. It has also been used for
couples with an age-related risk for aneuploidy and for couples who
carry balanced chromosomal rearrangements.
In addition, it is thought that patients who have experienced many
failed in-vitro fertilization (IVF) cycles or who have experienced
recurrent early pregnancy loss may benefit from PGD. Only embryos
free of the genetic abnormalities under evaluation are replaced at
the time of embryo transfer. The main drawback to this procedure is
that patients must undergo IVF in order to have PGD even if they do
not have any fertility issues. In-vitro fertilization has inherent
risks such as ovarian hyperstimulation and multiple gestations.
Besides being invasive, the technique is expensive. Furthermore,
PGD is still investigational, as there is insufficient information
to determine its impact on pregnancy and pediatric outcomes. At
this point, PGD is reserved for patients at high risk for genetic
Fetal cells and DNA in maternal circulation:
Noninvasive prenatal genetic diagnosis is an important area of
research, as it would be preferable to invasive methods such as
amniocentesis and CVS, which carry a small but definitive risk for
fetal loss. Isolating fetal cells or free fetal DNA from maternal
plasma is currently an exciting and promising area of research.
However, these techniques are extremely challenging. Many different
protocols have been developed using one or more techniques, such as
fluorescence-activated and magnetic-activated cell sorting, to
recover fetal cells after separation from whole blood.
Practical applications for the clinician have not yet been
One of the main limiting factors seems to be the rarity of such
cells in the maternal circulation. Enrichment techniques are needed
to help increase the yield.
Estimates of the number of fetal cells in the maternal circulation
vary depending on the gestational age and the technique used to
obtain the cells.
Current potential applications for analysis of fetal cells and
of cell-free fetal DNA in maternal circulation include noninvasive
detection of certain paternally inherited genetic traits and
noninvasive detection of fetal Rhesus (Rh) D genotype in
Rh(D)-sensitized patients. Noninvasive fetal genotyping would be
useful for the management of Rh(D)-sensitized patients whose
partners are heterozygous for the Rh(D) gene because no further
diagnostic or therapeutic procedures would be necessary if the
fetus was confirmed Rh(D)-negative.
In X-linked genetic disorders in which half of the fetuses will be
female and unaffected, fetal DNA determination of the fetal sex
could reduce the number of invasive procedures required for the
diagnosis of X-linked genetic disorders by 50%.
Additional clinical applications of fetal cells and fetal DNA in
maternal circulation may include screening for aneuploidy,
pre-eclampsia, or preterm labor.
These applications currently rely on the detection of Y-chromosomal
sequences and are limited to male fetuses.
The above noninvasive diagnostic methods are not yet in clinical
use but offer extremely exciting options for the future.
Noninvasive diagnosis of fetal anemia by Doppler
Previously, the diagnosis of fetal anemia required percutaneous
umbilical blood sampling (PUBS), an invasive procedure with an
inherent risk for fetal loss. Doppler measurements of the middle
cerebral artery peak systolic velocity can now be used to
noninvasively diagnose anemia in fetuses without hydrops who are at
risk for anemia secondary to conditions such as Rh(D) sensitization
and parvovirus B19 infection (Figure 5).
This noninvasive method of detecting fetal anemia de-creases the
number of invasive PUBS procedures needed in these high-risk
patients. The value of the middle cerebral artery peak systolic
velocity is expressed as multiples of the median. Middle cerebral
artery peak systolic velocity >1.50 multiples of the median is
considered suggestive of anemia and is considered an indication for
PUBS (Table 1).
While there have been exciting advances in the field of prenatal
diagnosis within the past few years, the future holds the promise
of great breakthroughs. Advances in the areas of genomics,
proteomics, and stem-cell research are anticipated. It is expected
that imaging mo- dalities will continue to improve, and it is hoped
that techniques used in the fields of noninvasive prenatal
diagnosis and in preimplantation genetic diagnosis will continue to
advance. Accurate prenatal diagnosis of fetal abnormalities
improves patient care by optimizing patient counseling and allowing
for informed patient and physician decision making.