Birth Defects and Prenatal Diagnosis

• Birth defect, congenital malformation, and congenital anomaly are

synonymous terms used to describe structural, behavioral, ftinc-
tional, and metabolic disorders present at birth. Terms used to
describe the study of these disorders are teratology (Gr. teratos;
monster) and dysmorphology.
The causes of
birth defects fall
into three
categories
Risk of Birth Defects Being Induced
Types of Abnormalities
• Malformations occur during formation of structures,
• Disruptions result in morphological alterations of already formed
structures and are caused by destructive processes.
• Deformations result from mechanical forces that mold a part of the
fetus over a prolonged period.
Environmental Factors
• Abnormal positioning of
the lower limbs and
clubfeet as examples of
deformations. These
defects are probably
caused by oligohy-
dramnios (too littie
amniotic fluid].
Principles of Teratology
• Susceptibility to teratogenesis depends on the genotype of the
conceptus and the manner in which this genetic composi- tion
interacts with the environment.
• Susceptibility to teratogens varies with the developmental stage at
the time of exposure.
• Manifestations of abnormal development depend on dose and
duration of exposure to a teratogen.
• Teratogens act in specific ways (mecha- nisms) on developing cells
and tissues to initiate abnormal embryogenesis (patho- genesis).
• Manifestations of abnormal development are death, malformation,
growth retardation, and functional disorders.
Examples of Phocomelia
Infectious Agents
• Rubella
• Cytomegalovirus
• Herpes símplex virus
• varicella virus
• Toxoplasmosis
Other Viral Infections and Hyperthermia
• Measles,
• mumps
• Hepatitis
• Poliomyelitis
• Echovirus
• coxsackie virus
• Influenza
• Fevers or possibly by external sources, such as hot tubs and saunas, is
teratogenic. Characteristically, neurulation is affected by elevated
temperatures, and neural tube defects, such as anencephaly and
spina bifida, are produced.
Radiation
• lonizing radiation kills rapidly proliferating cells, so it is a potent
teratogen, producing virtually any type of birth defect depending
upon the dose and stage of development of the conceptus at the time
of exposure.
Pharmaceutical Drugs and Chemical Agents
• The role of chemical agents and pharmaceutical drugs (medications) in the
production of ab- normalities in humans is difficult to assess for two reasons:
1. Most studies are retrospective, relying on the mother’s memory for a
history of exposure
2. Pregnant women take a large number of medications.

Examples : thalídomide, Isotretinoin, anticonvulsants diphenylhydantoin

(phenytoin), valproic acid, and trimethadíone, Antipsychotic and antianxiety
agents, Mycophenolate mofetil, anticoagulant, ACE inhibitors, ETC
Illicit Drugs, Alcohol, and Cigarettes
• One of the problems in today’s society is the eífect of maternal use of
social drugs, such as lysergic acid diethylamide (LSD), phencycli- dine
(PCP) or “ángel dust”, marijuana, co- caine, alcohol, and tobáceo on
embryonic and fetal development.
• Cocaine use has been linked to premature labor, intrauterine growth
retardation, and spontaneous abortion. Also, malformations of the
heart, genitourinary system, and brain.
• Alcohol may induce a broad spectrum of defects, ranging from
intelectual disability to structural abnormalities of the brain
(microcephaly, holoprosencephaly), face, and heart, the term fetal
alcohol spectrum dísorder (FASD) is used to refer to any alcohol
related defects.
• Cigarette smoking has been linked to an increased risk for orofacial
clefts (cleft lip and cleft palate). It also contributes to intrauterine
growth retardation and premature delivery.
- Hormones
• Androgenic Agents
• Endocrine Disrupters
• environmental estrogens
- Oral Contraceptives
- Cortisone
Maternal Disease
• Diabetes
• Phenylketonuria
• Nutrítionaf Deficiencies
• Obesity
• Hypoxia
• Heavy Metals
Male-Mediated Teratogenesis
• Paternal occupational and environmental exposures to mercury, lead,
solvents, alcohol, cigarette smoking, and other compounds to
spontaneous abortion, low birth weight, and birth defects.
• Advanced paternal age is a factor for an increased risk for some types
of structural birth defects, Down syndrome, and new autosomal
dominant mutations.
FETAL THERAPY
• Fetal Transfusion
• Fetal Medical Treatment
• Fetal Surgery
• Stem Cell Transplantatíon and Gene Therapy
PRENATAL DIAGNOSIS
• ultrasound,
• maternal serum screening,
• amniocentesis, and
• Chorionic villus sampling (CVS).
Introduction
• Rapid advances in the technologic basis of two imaging methods—
ultrasonography and magnetic resonance imaging (MRI)—have
resulted in highly accurate visualization of the fetal anatomy
• Sonography has been used routinely for accurate dating of pregnancy,
confirmation of pregnancy location and number of gestations,
prenatal diagnosis of congenital malformations, and assessment of
fetal well-being (American College of Obstetricians and Gynecologists,
2008).
Current Role
• The four main roles of prenatal ultrasonography in contemporary
obstetric practice are
1. to confirm fetal gestational age and number;
2. to search for fetal malformation;
3. to confirm fetal well-being; and
4. to aid in the performance of invasive diagnostic and
therapeutic fetal procedures.
3D
• Three-dimensional (3D) ultrasound allows for multiplanar imaging enabling
the examiner to move back and forth between different planes due to the
capability of viewing the fetus in three rather than two spatial planes
• Images can be reconstructed and the examiner can move the fetus into
ideal 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 speeds
result in more scanned slices and are used for nonmoving organs. Fast
speeds are preferable for moving structures.
4D
• The “four-dimensional” (4D) real-time imaging technique requires
ultrafast acquisition. 4D ultrasound displays a continuously updated
and newly acquired volume in any rendering modality. This creates
the impression of amoving structure (Timor-Tritsch and Platt, 2002).
• Nonetheless, this technology is rapidly advancing and has been
shown to be helpful. It appears to be useful as an adjunct to 2D
ultrasound in fetal echocardiography and in the diagnosis and further
evaluation of certain fetal anomalies such as cleft lip and palate and
skeletal anomalies
2D
• Fifty-four fetuses without abnormalities and 45 fetuseswith 82
abnormalities diagnosed by 2D ultrasoundwere evaluated. Agreement
between 3D/4D and 2D ultrasound occurred in 90.4% of cases. Six
anomalies were missed by 3D/4D when compared to 2D ultrasound.
There were also two discordant diagnoses. There was one
abnormality suspected by 3D/4D ultrasound, which was not
confirmed by 2D ultrasound.
• The sensitivity and specificity of 3D/4D ultrasound and 2D ultrasound
was 92.2% and 76.4% and 96.1% and 72.7%, respectively.
MRI
• 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.
• MRI provides excellent tissue discrimination in defining congenital
CNS abnormalities such as calvarial defects, differentiating
hemangioma or lymphangioma from encephalocele or meningocele,
and demonstrating partial or complete agenesis of the corpus
callosum. The finding of an abnormality of the corpus callosum is
often not isolated and frequently indicates the presence of other
cerebral abnormalities
• MRI can demonstrate not only the vascular anatomy, but also the
condition of the brain, which is of concern because these lesions can
be associated with encephalomalacia and macrocrania The presence
of encephalomalacia in cases of vein of Galen aneurysm indicates a
poor prognosis
MRI of the Fetal Neck
• Fetal MRI may be particularly useful in evaluating fetal neck masses.
Distinguishing between lymphangioma and a cervical teratoma may be
difficult based on ultrasound images alone.
• MRI can help with the assessment of the fetal airway so that proper
precautions are taken at delivery. MRI of cervical fetal masses allows for
more global imaging of the mass than with ultrasound because of the
larger field of view.
• In each case, as compared with ultrasound examination, fetal MRI provided
better detail about the size an position of the mass and its relationship to
the airway. MRI provides the best anatomic definition of the normal fetal
cranial structures and their relationship to the mass
MRI of the Fetal Chest
• The most common thoracic abnormalities identified on prenatal
ultrasound examination include congenital diaphragmatic hernia
(CDH), congenital cystic adenomatoid malformation (CCAM) of the
lung, bronchopulmonary sequestration (BPS), and fetal hydrothorax.
MRI of the Fetal Abdomen and Pelvis
• In fetuses with oligohydramnios, ultrasound evaluation can be extremely
difficult, whereas fetal MRI is unaffected by a lack of amniotic fluid. It is
often difficult to distinguish proximal from distal small-bowel obstruction
on prenatal ultrasound examination. There are different MRI signal
characteristics that are helpful in these cases, distinguishing proximal from
distal small bowel.
• The imaging of the fetal urinary tract with ultrasound examination is
excellent and rarely improved on by MRI. Exceptions to this include cases
of obstructive uropathy complicated by oligohydramnios, polycystic
kidneys, and renal tumors. This is also true of sacrococcygeal teratomas,
which arise from Hensen’s node at the tip of the coccyx. Sacrococcygeal
teratomas are most commonly exophytic, but can also extend into the
pelvis or abdomen with compression of bladder and intestines.
MRI in aMultiple Gestation
• 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.
• FetalMRIis not indicated as a primary imaging method in any fetal
anomaly or condition. As discussed above, however, there are
instances in which the information provided by fetal MRI
complements that obtained by prenatal ultrasound examination.
First Trimester Screening for Aneuploidy
When performing nuchal translucency sonography, it is absolutely
essential to ensure optimal technique, which can be attained by
focusing on the following criteria (Abuhamad, 2005):
• Fetus should be imaged in the midsagittal plane, ideally with the fetal
spine down.
• The image should be adequately magnified so that only the fetal
head, neck, and upper thorax fill the viewable area.
• Fetal neck should be neutral, with care being taken to avoid measurements
in the hyperflexed or hyperextended positions.
• The skin at the fetal back should be clearly differentiated from the
underlying amniotic membrane, either by visualizing separate echogenic
lines or by noting that the skin line moves with the fetus.
• Measurement calipers should be placed on the inner borders of the
echolucent space, and should be perpendicular to the long axis of the
fetus.
• Ultrasound and transducer settings should be optimized to ensure clarity
of the image and of the borders of the nuchal space in particular. This may
require transvaginal sonography in certain situations.
ENLARGED NUCHAL TRANSLUCENCY AND
CYSTIC HYGROMA IN THE FIRST
TRIMESTER
• It is now clear that a subset of fetuses with very large nuchal translucency
measurements can be effectively identified in the first trimester that have
an extremely high risk of fetal aneuploidy or other adverse pregnancy
outcomes. This finding has been described as septated cystic hygroma, and
is present when the nuchal translucency space is enlarged extending along
the entire length of the fetus, and in which septations are clearly visible.
• Septated cystic hygroma is seen in more than 1 in 300 first trimester
pregnancies. In a recent prospective study of routine first trimester
sonographic screening, septated cystic hygromawas shown to have a 50%
chance of being associated with fetal aneuploidy, with most cases being
Down syndrome, as well as cases of Turner syndrome and trisomy 18.
NASAL BONE SONOGRAPHY IN THE
FIRST TRIMESTER
• There appears to be a clear association between the absence of the
fetal nasal bones on first trimester ultrasound examination and Down
syndrome.
• Adequate imaging of the fetal nasal bones can be technically
challenging in the first trimester, and careful attention to correct
technique should therefore be paid to ensure consistency in
technique. The nasal bones should be visualized on ultrasound along
the midsagittal plane with a perfect fetal profile. The fetal spine
should be down, with slight neck flexion. Two echogenic lines at the
fetal nose profile should be visualized; the superficial echogenic line is
the nasal skin, and the deeper echogenic line represents the nasal
bones.
FIRST TRIMESTER DUCTUS VENOSUS
SONOGRAPHY
• In a series of early studies evaluating this association, between 59%
and 93% of aneuploid fetuses had abnormal first trimester ductus
venosus flow velocities.
• Abnormal ductus venosus flow velocities were also found in as few as
3% or as many as 21% of normal fetuses. It may therefore be possible
that fetal ductus venosus flow velocity waveform analysis may be
useful to modify a patient’s final risk for aneuploidy following
completion of the nuchal translucency measurement.
FIRST TRIMESTER TRICUSPID
REGURGITATION EVALUATION
• An association has been suggested between fetal aneuploidy and
abnormal tricuspid regurgitation noted during first trimester
sonography.
• To perform this assessment, the fetus should be oriented so that the
chest wall is anterior and the fetal heart should be insonated parallel
to the ventricular septum. A pulsed Doppler gate of approximately 3
mm size is then placed across the tricuspid valve, with care to ensure
that the angle to the direction of flow is as close to zero as possible.
• Significant tricuspid regurgitation is considered to be present if a
regurgitant jet of at least 60 cm/s is noted extending to more than
half of systole.
NUCHAL TRANSLUCENCY SCREENING
IN MULTIPLE GESTATIONS
Nuchal translucency measurements are broadly similar between singleton and twin
pregnancies, implying that the Down syndrome detection rates should be similar. The false-
positive rate of nuchal translucency screening might be higher in monochorionic twins
because some complications unique to monochorionic gestations, such as twinto-twin
transfusion syndrome, might present with increased nuchal translucency measurement

Options for first trimester screening for Down syndrome therefore include providing either a
fetus-specific risk based on nuchal translucency alone, or providing an overall overall
pregnancy risk based on combined serum and sonographic markers
Second Trimester Screening for Aneuploidy
• Options for second trimester screening include serum screening using
the Quad test (alphafetoprotein, human chorionic gonadotropin,
unconjugated estriol, and inhibin-A), sonographic screening using the
so-called Genetic Sonogram, and combinations of serum and
sonographic screening.
The sonographic approach to establishing the presence or absence of
each of the commonly utilized minor markers is summarized below:

1. Nuchal fold
2. Echogenic bowel
3. Humerus and femur length
4. Echogenic intracardiac focus
5. Pyelectasis
6. Nasal bones
7. Choroid plexus cyst
COMBINED FIRST AND SECOND
TRIMESTER SCREENING
• Integrated Screening
• Stepwise Screening
• Contingent Screening
SECOND TRIMESTER SCREENING IN
MULTIPLE GESTATIONS
• Interpretation of maternal serum screening, however, can be difficult
because of the potential for discordancy between twins and the impact of
different placentas on the various analytes. On average, second trimester
levels of the commonly utilized biochemical markers are twice as high as in
singleton pregnancies.
• In dichorionic pregnancies, if one fetus is euploid and another is aneuploid,
the opposite direction in which biochemical markers from individual
placentas go may be masked by the overall maternal serum levels.
• Maternal serum markers may be interpretable however using the
“pseudorisk” approach. This involves dividing the observed multiple of the
median (MoM) values found in each twin pregnancy being evaluated, by
the median value found in normal singletons.