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Genetic Evaluation of Fetal Sonographic Abnormalities
Introduction
Structural malformations, many of which can be diagnosed antenatally, are present in approximately 2%–3% of live births. Fetuses with structural malformations are at increased risk for an underlying genetic disorder, even in the setting of a normal karyotype. The clinical prognosis is highly variable depending on the presence of a genetic syndrome, the specific type of anomaly that is present, as well as whether the anomaly is isolated or part of a spectrum of malformations involving other organ systems.
What Is the Role of Ultrasound in Identifying Fetal Anomalies?
Fetal assessment by ultrasound is a standard component of prenatal care. The American College of Obstetricians and Gynecologists (ACOG) recommends that all obstetric patients be offered ultrasound evaluation at least once during pregnancy. The average number of ultrasounds performed in the United States has increased from 1.5 per pregnancy in 1995 to between four and five scans in low-risk patients in 2011.
Screening for congenital anomalies by ultrasound is the primary indication for second-trimester anatomic imaging and has been demonstrated to improve the detection of major fetal anomalies before 24 weeks (RR 3.46 [95% CI: 1.67–7.14]). Factors that influence detection rates include the setting in which the ultrasound is performed (community based vs. tertiary care), the fetal gestational age at the time of the study, and technical imaging challenges such as obesity. Adherence to a systematic imaging protocol improves prenatal diagnosis of anomalies. In pregnancies where a malformation is identified and termination is chosen, there is over 98% confirmation of the primary diagnosis.
What Is the Difference Between a Standard and Detailed Anatomic Scan?
The American Institute of Ultrasound in Medicine (AIUM) and ACOG distinguish between standard second-trimester examinations and detailed examinations. A standard examination is utilized to evaluate fetal anatomy in a population at low risk for congenital anomalies. A more comprehensive or detailed obstetrical ultrasound examination is performed for women at increased risk for a congenital malformation based on medical history, results of laboratory evaluations, or concerns identified on a standard obstetrical ultrasound examination. Detailed fetal anatomic imaging is performed by a provider with additional training and expertise in obstetrical imaging and dysmorphology assessment. It is important to recognize that despite optimal imaging and diagnostic testing, there is a residual risk of an undetected abnormality. Additionally, false-positive findings may occur. These may be structural anomalies that are suspected but not confirmed after birth, “markers” of aneuploidy (see Chapter 10 ) or conditions such as ventriculoseptal defects or mild ventriculomegaly that may resolve during the course of pregnancy.
What Is the Impact of Gestational Age in Identifying Fetal Anomalies?
The Late First-Trimester Scan: 11 0 –13 Weeks
A late first-trimester ultrasound is performed primarily to measure the nuchal translucency (NT) as a component of first-trimester risk assessment for aneuploidy (see Chapter 8 ). Although a thickened nuchal translucency confers an increased risk of aneuploidy, it is also a marker for increased risk of structural anomalies and other genetic conditions. Imaging the fetus at this gestational age provides the first opportunity to perform an anatomic assessment of the fetus. Although this is not currently standard practice in the United States, it is feasible by dedicated sonographers and sonologists.
Estimates of detection rates for major anomalies between 11 weeks 0 days and 13 weeks 6 days vary from 18% to 84%, with most authors reporting a sensitivity of approximately 50% for major anomalies. The detection rate depends on the anatomic area that is being evaluated.
A systematic review of 78,002 fetuses that underwent ultrasound examination between 11–14 weeks found that the detection rate of nuchal defects was 92%, whereas only 34% of limb, face, and genitourinary tract anomalies were detected. In addition, there was a higher detection rate in fetuses evaluated between 13 and 14 weeks than those examined between 11 and 12 weeks. Detection rates are higher in those with multiple abnormalities compared with a single finding, and in high-risk populations (61%) compared with low-risk populations (32%). The adherence to an imaging protocol improves detection rates as does the use of transvaginal imaging. With experience and recognition of additional markers, detection rates may improve.
Some anomalies, such as anencephaly, alobar holoprosencephaly, body stalk anomalies, omphalocele, and major disruption of fetal contour, should almost always be detected during this gestational age window. Others, such as cardiac defects, spina bifida, and facial clefts, are more challenging to diagnose. Finally, some anomalies, such as those involving the corpus callosum and congenital lung malformations, are not detectable at this early gestational age, partly because of timing of embryologic development. As with all obstetrical imaging, the natural history of some diagnosed abnormalities may not be fully understood or may change with advancing gestation.
The early anatomic evaluation of the fetus allows patients to consider the implications of the condition detected and pursue expert consultation and diagnostic testing. Detection of structural anomalies between 11 and 14 weeks allows those patients who choose to terminate to do so at an earlier gestational age, when the procedure is safer. For those who continue their pregnancy, a follow-up ultrasound examination at 18–22 weeks is necessary to better elucidate the abnormality.
It is important that patients understand that a “normal” first-trimester ultrasound does not exclude all major or lethal anomalies and this imaging window does not replace the standard second-trimester anatomic assessment of the fetus.
Second-Trimester Anatomic Survey
The gold standard for prenatal anomaly screening by ultrasound in the United States is an ultrasound examination performed between 18 and 22 weeks of gestation. Anatomic imaging should be performed in accordance with a contemporary imaging protocol. This may be a standard scan performed in patients at “low risk” for congenital anomalies or a detailed scan in those who are at “increased risk.”
The majority of literature on routine screening for congenital anomalies in unselected populations was performed several decades ago with wide variations in reported detection rate of anomalies. The Eurofetus study, performed in 61 obstetric centers between 1990 and 1993 reported a prenatal detection of 61.4% of fetuses with an anomaly and 56.2% of all malformations. The detection of major anomalies was 73.7% compared with 45.7% of minor anomalies. Overall, 55% of major anomalies were detected before 24 weeks. The sensitivity of anomaly detection was 88.3% for the central nervous system and 84.8% for the genitourinary tract, as compared with 38.8% for the heart and great vessels.
In more contemporary literature evaluating first and second-trimester anatomic imaging, approximately 75%–95% of structural malformations may be suspected or detected. Detection rates will vary with the population studied, the follow-up available, the experience and skill of the imager, the imaging protocol utilized, and imaging conditions such as obesity, which may preclude an optimal anatomic evaluation.
Third-Trimester Scans
Routine ultrasound in the third trimester is not currently standard practice. However, there are certain anomalies that are not usually diagnosed until this advanced gestational age, such as microcephaly, lissencephaly, or achondroplasia ( Fig. 11.1A and B ). The contribution of a third-trimester scan was demonstrated in a prospective study of 8074 fetuses who had previously had a normal first and second-trimester ultrasound and were reexamined between 28 and 32 weeks. At the third-trimester ultrasound, an additional 15% of the total anomalies were diagnosed despite two prior normal ultrasounds. The anomalies diagnosed in the third trimester were primarily urogenital, cardiovascular, and central nervous system anomalies. Overall, 90% of anomalies in the cohort were detected prenatally, whereas 10% were not detected until after birth.
What Is the Importance of a Systematic Ultrasound Evaluation Using Pattern Recognition?
If a fetal anomaly is identified, it is incumbent on the sonologist to formulate a differential diagnosis. The sonologist must be a detective, using a deliberate stepwise approach of observation and deductive reasoning. With pattern recognition of genetic syndromes in mind, a structured systematic and thoughtful evaluation of other organ systems, looking for sentinel features, will allow the sonologist to narrow the differential diagnosis.
As an example, a required anatomic component of the standard fetal ultrasound includes evaluation of the upper lip. Facial clefts are relatively prevalent, occurring in about 15 per 10,000 live births in the United States. Contemporary reports suggest that approximately 69%–80% of cleft lip with or without cleft palate is diagnosed before 24 weeks’ gestation. In nearly two-thirds of fetuses in which a cleft lip is identified, there will be an associated cleft palate. Cleft palate without a disrupted lip is most often not diagnosed prenatally. In 77% of cases, a facial cleft is an isolated finding; however, in 16% of cases, they are associated with malformations in other organ systems and approximately 7% of cases occur as part of a recognized genetic syndrome.
Once a facial cleft is identified, it is critical to determine the extent of the clefting. How much of the lip does it involve? Does it extend to the nares or even up the face to the orbits? Does it involve the palate? Is it unilateral, bilateral, or central? The risk of associated anomalies increases with more severe degrees of clefting.
There are numerous chromosomal abnormalities and genetic syndromes associated with facial clefting, and an attempt to uncover sentinel features by detailed anatomic evaluation will narrow the differential diagnosis of a potentially nonisolated condition. If the fetus has a central or median cleft, an examination of the central nervous system and cardiac anatomy should be performed. Additionally, the hands should be evaluated for postaxial polydactyly, which would lead to a suspicion of trisomy 13, or if a facial cleft is associated with choroid plexus cysts and clenched hands, trisomy 18 would be suspected ( Fig. 11.2 ). If the median cleft is associated with polysyndactyly or a bifid hallux, one must consider oro-facial-digital syndrome as an etiology. If the cleft is associated with ectrodactyly of the hands (split or cleft hand), ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome would be the most likely diagnosis. Facial clefting may be associated with skeletal dysplasias, and an evaluation of the ribs, long bones, and hands may lead to a suggestion of Roberts syndrome or Majewski syndrome. If the anatomic evaluation reveals that the cleft does not follow an expected embryologic sequence and other asymmetric defects such as transverse limb defects are present, the sonologist should look for evidence of amniotic bands. In some rare cases, the cleft may extend up the face and involve the orbits (Tessier cleft). Even in cases of presumed isolated clefting, family history is important to potentially differentiate a sporadic event from the autosomal dominant Van der Woude syndrome. Once a facial cleft is identified and the differential diagnosis narrowed, genetic counseling and diagnostic testing is recommended.
What Is the Role of Pattern Recognition in Common Aneuploidy Syndromes?
Each of the common autosomal trisomies presents with a relatively distinct constellation of findings that allows a tentative prenatal diagnosis based on imaging. Detailed anatomic assessment with attention to pattern recognition including evaluation of the fetal hands helps narrow the suspected diagnosis. Other chromosomal anomalies that may be encountered, such as monosomy X and triploidy, also have distinct features that often can be recognized on prenatal sonographic evaluation. These conditions may be diagnosed by karyotype.
Trisomy 21 (Down Syndrome)
Trisomy 21 is the most common chromosomal abnormality resulting in a live birth, occurring in approximately 1 in 700 pregnancies. Prenatal sonography evaluating the nuchal translucency and/or second-trimester “markers” of aneuploidy in conjunction with standard analyte screening can identify at least 85%–90% of affected fetuses. Sonography alone is useful in identifying 50%–80% of affected fetuses based on “markers” and to a lesser extent structural anomalies. Please see Chapter 10 for further discussion of ultrasound markers of aneuploidy. Approximately 20%–30% of fetuses with trisomy 21 will have a structural malformation. The major structural anomalies identified in fetuses with trisomy 21 include cardiac anomalies such as atrioventricular canal defects, tetralogy of Fallot, and ventriculoseptal defects. Noncardiac abnormalities include mild ventriculomegaly, duodenal atresia, and esophageal atresia. Fetuses with trisomy 21 may also have abnormal fluid collections, such as a pericardial or pleural effusions, or nonimmune hydrops.
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