Ultrasound Markers for Aneuploidy in the Second Trimester


Soft ultrasound markers were initially described as a screening method for trisomy 21 to improve the detection rate over that based on age-related risk alone. Soft markers are not structural abnormalities; rather, they are minor ultrasound findings identified in the midtrimester that may be a variant of normal but are noteworthy because they have been associated with an increased risk of fetal aneuploidy. Commonly identified soft markers addressed in this chapter include echogenic intracardiac focus (EIF), choroid plexus cyst (CPC), single umbilical artery (SUA), echogenic bowel, urinary tract dilation (UTD) (previously known as pyelectasis or pelviectasis), short humerus and/or femur, and thickened nuchal fold.

Contemporaneous with the advancement in aneuploidy detection using soft markers was the development of improved screening methods to predict aneuploidy risk, including first-trimester screening with maternal serum analytes and nuchal translucency measurement. In 2011, the introduction of cell-free DNA (cfDNA) techniques greatly improved the ability to screen for common aneuploidies. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend that cfDNA screening be offered to patients with a higher risk for common aneuploidies, although any patient who desires aneuploidy screening may elect to pursue cfDNA screening.

Given the high sensitivity of maternal serum screening algorithms and cfDNA for trisomy 21, 18, and 13, the role of ultrasound-based screening for aneuploidy is in evolution. The purpose of this chapter is to focus on the evaluation and management of isolated ultrasound soft markers diagnosed in the second trimester.

What Is the Initial Approach After a Soft Marker Is Identified?

Once a soft marker is identified, a detailed ultrasound examination is recommended to ensure the finding is isolated (i.e., there is only a single soft marker that does not co-occur with any structural abnormality or other soft marker), as the presence of multiple soft markers increases the risk of aneuploidy. In the case of multiple soft markers or a structural abnormality, the approach to evaluation should be individualized. If an isolated soft marker is confirmed, subsequent evaluation and counseling depends on the nature of the soft marker and associations with nonaneuploid conditions.

The presence or absence of specific soft markers has been used to modify the probability of trisomy 21, and secondarily that of trisomy 18, using positive and negative likelihood ratios (LRs). This approach requires an accurate assessment of (1) the a priori, or pretest, risk (age-related risk at the time of delivery or age-related risk in the midtrimester) of the aneuploidy of interest; (2) the posttest risk based on a screening test, if performed; (3) validated and reproducible sonographic definitions for the identification of each soft marker; and (4) accurate estimates of sensitivity and specificity to generate the positive and negative LRs of an isolated soft marker for a particular aneuploidy. Once the risk estimates and LRs are determined, then a final risk estimate incorporating the presence or absence of an ultrasound soft marker for the aneuploidy of interest can be calculated.

In general, positive LRs from approximately 1.5–5 confer a small increase in the likelihood of the outcome, LRs between 5 and 10 confer a moderate increase in the likelihood of the outcome, and LRs greater than 10 confer a significant increase in the likelihood of the outcome. The absence of structural anomalies or additional soft markers likely decreases this risk, although formulas to assess the interaction of these risks are not readily available. Regardless of the screening strategy used, there is no one threshold value of posttest probability above which additional aneuploidy evaluation is routinely recommended, as risk estimates represent a continuum.

The approach to calculating posttest probability was particularly useful when patients desired aneuploidy screening and soft markers helped shape the “genetic sonogram” as another tool to further refine risk prediction. As data on soft markers have accumulated, variability in positive and negative LR estimates has been noted because of differences in patient populations studied, variability in the definition of a specific finding, and subjectivity in the detection rate as well as other causes.

When reviewed in aggregate, the current data suggest that the positive likelihood ratios for the common soft markers, with the exception of a thickened nuchal fold, are all exceedingly low (ranging from less than 1 to 6, in general). This low range suggests that if a positive likelihood ratio were to be incorporated into a patient’s individual risk for aneuploidy, based on the available results from cfDNA or serum/integrated screening, there would not be a meaningful change in the estimate of absolute aneuploidy risk and thus would not warrant additional counseling or testing based solely on the identification of the isolated soft marker. National recommendations from the Royal College of Obstetrics & Gynecology in the United Kingdom and from the Society of Obstetricians and Gynaecologists of Canada (SOGC) Genetics Committee and the Canadian College of Medical Geneticists (CCMG) suggest not adjusting a patient’s a priori risk for trisomy 21 with the presence of any one soft marker, with the exception of a thickened nuchal fold.

Moreover, if a woman has undergone diagnostic testing and the results indicate a normal karyotype, identification of a soft marker for the purposes of aneuploidy screening is insignificant and should be reported as such.

What Is the Significance of an Echogenic Intracardiac Focus?

An EIF is defined as a small (<6 mm) echogenic area in either cardiac ventricle that is as bright as surrounding bone and visualized in at least two separate planes ( Fig. 10.1 ). EIFs may appear in either cardiac ventricle, although left-sided EIFs are more common, and are thought to represent microcalcifications of papillary muscles. The pathogenesis of this finding is unclear.

FIG. 10.1

Echogenic intracardiac focus.

Courtesy of Bryann Bromley, MD.

EIFs are identified in 3%–5% of karyotypically normal fetuses, and significant ethnic variation exists. In the largest analysis of 7480 ethnically diverse women having amniocentesis, the prevalence of EIF was 8.3% among Middle-Eastern women, 6.9% among Asian-American women, 6.7% among African-American women, 3.4% among Hispanic women, and 3.3% among Caucasian women, with lower prevalence among Asian-Indian and Native-American women. Smaller studies have demonstrated a higher prevalence of EIF among women of Asian descent, with estimates up to 30%.

EIFs do not represent a structural or functional cardiac abnormality, and they have not been associated with cardiac malformations in the fetus or newborn. Fetal echocardiography and additional ultrasound imaging solely to serially follow an EIF are not recommended, and no postnatal follow-up is indicated. When isolated, an EIF should be considered a variant of normal.

Since the first descriptions of EIFs as a soft marker for trisomy 21, a subsequent large body of literature has demonstrated varying positive likelihood ratios for trisomy 21, depending on the population studied and whether the EIF was isolated or in combination with other soft markers. Overall, however, the association between the presence of an EIF and trisomy 21 is weak. In the presence of an isolated EIF, the risk of trisomy 21 is not meaningfully altered, and therefore, an isolated EIF can be considered a variant of normal and additional aneuploidy evaluation is not indicated in women previously screened for aneuploidy. In the absence of any prior aneuploidy screening, the positive likelihood ratio for an EIF ranges between 1.4 and 1.8, with lower confidence bounds extending to or beyond 1, suggesting little to no increased risk.

What Is the Significance of a Choroid Plexus Cyst?

A CPC is a small fluid-filled structure within the choroid of the lateral ventricles of the fetal brain ( Fig. 10.2 ). Sonographically, CPCs appear as echolucent cysts within the echogenic choroid. CPCs may be single or multiple, unilateral or bilateral, and most often are less than 1 cm in diameter. CPCs are identified in approximately 1%–2% of fetuses in the second trimester and are commonly isolated findings in euploid fetuses. CPCs are present in 30%–50% of fetuses with trisomy 18 but in such cases are typically seen alongside multiple structural anomalies, including structural heart defects, clenched hands, talipes deformity of the feet, growth restriction, and polyhydramnios.

FIG. 10.2

Choroid plexus cyst.

Courtesy of Bryann Bromley, MD.

A CPC is not considered a structural or functional brain abnormality, and nearly all resolve by 28 weeks. Patients may be counseled that neurodevelopmental outcomes in euploid children born after a prenatal diagnosis of choroid plexus cysts have not shown differences in neurocognitive ability, motor function, or behavior. Consequently, no additional ultrasound imaging is recommended solely to serially follow an isolated CPC, and no postnatal follow-up is indicated. When isolated, in a population previously screened for aneuploidy, CPCs should be considered a variant of normal, and no additional aneuploidy testing is indicated. In a population that has not been screened for aneuploidy, positive LRs for trisomy 18 ranged from 0.9-5.6, with the vast majority suggesting little risk. Based on the literature, the best estimate for the LR is less than 2. The presence of a choroid plexus cyst does not alter the risk of trisomy 21.

What Is the Significance of a Single Umbilical Artery?

The normal umbilical cord contains two arteries and one vein; single umbilical artery (SUA) is the result of atrophy or agenesis of one of the arteries. An SUA can be detected on cross section of the umbilical cord during a routine second-trimester ultrasound exam or using color-flow Doppler to examine the umbilical arteries in the pelvis at an even earlier gestational age ( Fig. 10.3 ).

FIG. 10.3

Single umbilical artery.

Courtesy of Bryann Bromley, MD.

The incidence of SUA is 0.25%–1% of all singleton pregnancies and up to 4.6% of twin gestations. An isolated SUA should be distinguished from an SUA that is present with other abnormalities. Co-occuring structural abnormalities most commonly involve the cardiovascular and renal systems. With an SUA and a structural abnormality, the frequency of associated aneuploidy ranges from 4% to 50%. A thorough assessment of cardiac anatomy should be performed by a practitioner experienced in the detection of fetal cardiac anomalies, and if adequately visualized and normal, fetal echocardiogram is not routinely recommended. For patients with an isolated SUA, there is no increased risk of aneuploidy.

Isolated SUA has been associated in some studies with an increased risk of fetal growth restriction (FGR), although other studies suggest that an isolated SUA does not place the fetus at increased risk for FGR. In a cohort of fetuses with isolated SUA, the observed incidence of growth restriction was not higher than that expected. Similarly, in a cohort of fetuses with isolated SUA compared with those without isolated SUA, rates of SGA at birth did not differ between groups. Moreover, a metaanalysis did not demonstrate a statistically significant difference in mean birthweight or a statistically significant increase in proportion of SGA births among fetuses with isolated SUA. However, a cohort study with a larger control group of fetuses with a three-vessel cord did demonstrate an increased risk of FGR, polyhydramnios, oligohydramnios, placental abruption, cord prolapse, and perinatal mortality among those with isolated SUA, after controlling for other confounders. This study was not included in the metaanalysis above. Given conflicting evidence, third-trimester ultrasound for evaluation of growth can be considered; antenatal testing is recommended only if fetal growth restriction or other indications develop.

At the time of delivery, pediatricians should be notified of the prenatal findings. Postnatal exam of infants with a prenatal diagnosis of isolated SUA revealed structural anomalies in up to 7% of fetuses in one study.

What Is the Significance of Echogenic Bowel?

Echogenic bowel is diagnosed when the fetal bowel displays echogenicity equal to or greater than that of surrounding fetal bone, typically the iliac wing ( Fig. 10.4 ). Transducer frequency can influence the diagnosis because higher frequency transducers tend to exaggerate the finding. Therefore, a lower frequency transducer (5 MHz or less) with harmonic imaging turned off and set at lower gain should be used to confirm the diagnosis.

FIG. 10.4

Echogenic bowel.

Echogenic bowel is observed in up to 1.8% of second-trimester ultrasound exams. This finding is often isolated, but an increased incidence of structural anomalies, particularly renal and cardiac anomalies, has been demonstrated in fetuses with echogenic bowel. Although isolated echogenic bowel can be a transient or idiopathic finding in approximately 0.5% of all fetuses, it can also be associated with a wide range of pathologic conditions such as cystic fibrosis, congenital viral infection, primary gastrointestinal pathology, intraamniotic bleeding, and growth restriction. The estimated incidence of each possible etiology varies because of small sample size studies and the subjectivity in the diagnosis.

Echogenic bowel has also been associated with trisomy 21 and less commonly with other karyotypic abnormalities. Echogenic bowel is present as an isolated finding in 4%–25% of fetuses with aneuploidy. Hypoperistalsis due to mechanical or functional bowel obstruction with subsequent dehydration of meconium is the proposed mechanism causing this finding in fetuses with abnormal karyotype. Among fetuses with isolated echogenic bowel, the positive LR for trisomy 21 depends on the population studied but ranges between 6 and 8.

Studies have also demonstrated the development of echogenic bowel following invasive procedures such as intrauterine fetal transfusions, secondary to fetal swallowing of blood from the amniotic cavity. It has been demonstrated that this finding may persist for 2–4 weeks following intrauterine transfusion.

Cystic fibrosis is associated with echogenic bowel, as abnormal pancreatic enzyme secretion leads to thickened meconium, and subsequent meconium ileus is observed in some newborns with cystic fibrosis. The risk for cystic fibrosis ranges from 0% to 13%. The finding of dilated loops of bowel in addition to echogenic bowel may increase this risk to as high as 17%. For all fetuses with isolated echogenic bowel, evaluation for cystic fibrosis is recommended. Parental cystic fibrosis carrier screening is the first step and should be determined if not previously assessed in the current or prior pregnancy. If both parents are found to be carriers, genetic counseling should be undertaken to discuss the risks and benefits of invasive testing for fetal genotyping. Racial and ethnic limitations of current cystic fibrosis screening panels should be taken into consideration when interpreting test results.

Congenital infection also has been associated with isolated echogenic bowel. Different mechanisms underlie the findings of echogenicity: (1) direct damage to the fetal intestinal wall with subsequent paralytic ileus; (2) intestinal perforation resulting in meconium peritonitis and focal calcification at the perforation sites; or (3) ascites secondary to hydrops leading to echogenicity on ultrasound. Cytomegalovirus (CMV) is the most commonly observed infection, but toxoplasmosis, rubella, herpes, varicella, and parvovirus also have been reported. Although the majority of studies report a 2%–4% incidence of congenital infection in fetuses with echogenic bowel, rates up to 10% have been reported. In a series of 650 cases with maternal primary CMV infection, seven fetuses with CMV infection had isolated echogenic bowel as the sole ultrasound finding.

For all fetuses with echogenic bowel, evaluation for CMV infection is recommended. Although symptomatic maternal infection is uncommon, a history should be taken to evaluate for possible timing of symptoms of CMV. CMV IgG and IgM titers should be considered, with IgG avidity testing as applicable. If results are suggestive of primary infection, then amniocentesis should be considered, with other counseling and evaluation as appropriate. Without a history of exposure or other clinical risk factors, the chance of positive results for other congenital infections, such as varicella, herpes, parvovirus, or toxoplasmosis, is very low. Therefore, routine testing for these other infections may not be useful; however, the utility of testing should be determined based on the clinical scenario, differential diagnosis, and potential exposures.

Primary gastrointestinal pathology such as bowel obstruction, atresia, meconium peritonitis, and perforation also may cause an echogenic appearance of the fetal bowel, usually in association with other findings. In cases of obstruction and atresia, decreased meconium fluid content is the proposed cause for the increase in echogenicity. The presence of meconium outside the intestinal lumen is likely responsible for the echogenic appearance in cases of bowel perforation.

Lastly, isolated echogenic bowel is associated with increased likelihood of growth restriction. The pathophysiology of this finding is presumably due to areas of ischemia resulting from redistribution of blood flow away from the gut. Third-trimester ultrasound for the evaluation of growth and appearance of bowel among fetuses with isolated echogenic bowel is therefore recommended.

Although isolated echogenic bowel is associated with a sevenfold increased odds of intrauterine fetal demise, with a mean gestational age in the second trimester, the majority of fetuses with isolated echogenic bowel have normal outcomes. The utility of antenatal fetal testing in this scenario is of unproven benefit. Partial or complete resolution of isolated echogenic bowel is reassuring, and normal fetal outcomes are likely. Normal fetal outcomes have been demonstrated in fetuses with persistence of echogenic bowel as well; thus, persistent echogenicity should not be viewed as a marker for adverse outcome. At the time of delivery, pediatricians should be made aware of the antenatal finding of echogenic bowel and prenatal workup performed, so that appropriate neonatal evaluation may be pursued.

What Is the Significance of Urinary Tract Dilation?

UTD was previously described with variable terminology, including pyelectasis, pelviectasis, and hydronephrosis. In 2014, a consensus statement defined norms for antenatal UTD based on anterior-posterior renal pelvis diameter (APRPD), with less than 4 mm being normal between 16 and 27 weeks’ gestation and less than 7 mm being normal between 28 weeks’ gestation and delivery ( Fig. 10.5 ). To fully assess and classify UTD, additional ultrasound features to be evaluated include presence of calyceal dilation, parenchymal thickness and appearance, ureteral dilation, bladder abnormalities, and amniotic fluid volume. The complete evaluation of the urinary tract results in classification of A1 (low risk) versus A2-3 (increased risk) UTD, which guides antenatal management as well as postnatal follow-up ( Table 10.1 ).

Jan 5, 2020 | Posted by in PEDIATRICS | Comments Off on Ultrasound Markers for Aneuploidy in the Second Trimester

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