Trisomy 18 Workup

Updated: Aug 13, 2020
  • Author: Mithilesh Kumar Lal, MD, MBBS, MRCP, FRCPCH, MRCPCH(UK); Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Approach Considerations

First-trimester, noninvasive screening based on maternal age, serum markers, and sonographic “soft markers” has demonstrated a high sensitivity for the diagnosis of trisomy 18, [4, 5, 6] and it is now being applied routinely. [1]

Low levels of human chorionic gonadotrophin (hCG) and low unconjugated estriol (uE3) in maternal serum during mid trimester are useful predictors for an increased risk for trisomy 18.

A first-trimester biochemical screening for trisomy 18 is possible, because a retrospective study revealed reduced levels of pregnancy-associated plasma protein A (PAPP-A) and free beta–human chorionic gonadotropin (β-hCG) at 8-13 weeks' gestation

The multiples of the mean (MoM) in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG.

Screening for trisomy 18 using a combination of maternal age, PAPP-A, and beta-hCG has a detection rate of 76.6% with a false-positive rate of 0.5%.

Additional studies are required to confirm these findings.


Laboratory Studies

Prenatal diagnosis

Amniocentesis is routinely recommended at 14-16 weeks' gestation when trisomy 18 is suspected. It remains the criterion standard with which all other invasive diagnostic tests are compared. Amniocentesis testing for chromosome disorders is 99.5% accurate and is associated with a small risk of pregnancy loss (about 1 in 200-300).

Chorionic villus sampling (CVS) is performed at 10-13 weeks' gestation. An earlier CVS test is thought to be associated with a small risk (1 in 300-1000) of fetal transverse limb deficiency, a small chance of maternal cell contamination, and a 0.5-1% risk of fetal loss after the procedure. The accuracy (96-98%) is less than that of mid trimester amniocentesis because of confined placental mosaicism and maternal cell contamination.

Percutaneous umbilical blood sampling (PUBS) is of limited use, except in cases detected late in pregnancy. The preimplantation diagnosis is not of any realistic relevance for current care.

False positive prenatal diagnosis of trisomy 18 using fluorescence in situ hybridization (FISH) has been reported due to rare familial variants involving the failure of hybridization of α-satellite DNA or hybridization to false target chromosomes. [19] This underscores the necessity to adhere to the American College of Medical Genetics guidelines for interpretation of FISH results.

The American College of Obstetricians and Gynecologists (ACOG) recommends that patients categorized by screening as high risk for fetal aneuploidy be offered invasive testing such as amniocentesis or chorionic villus sampling. Although these invasive procedures are highly accurate, they are expensive and entail a risk of miscarriage. [20, 21]

ACOG also recommends that pregnant women be offered noninvasive screening for fetal chromosomal abnormalities. [22] The realization that fetal nucleic acids are present in maternal blood [23] spawned efforts to analyze cell-free DNA (cfDNA) for fetal conditions. Chromosome-selective sequencing of cfDNA can distinguish 98% of trisomy 18 in the first trimester (and all cases of trisomy 21) from euploid pregnancies. [24]

Postnatal diagnosis

See the list below:

  • Hematologic studies in patients with trisomy 18 during the first week of life

    • Thrombocytopenia: This is the most common hematological abnormality detected, occurring in 83% of those with trisomy 18; some patients need platelet transfusions. [25]

    • Neutropenia: This is the second most commonly detected abnormality. Neutrophil concentrations exceeding the reference range for age were reported in 42% of patients with trisomy 18. [25]

    • Abnormal erythrocyte values: This is the third most common hematological abnormality detected. Only 43% of patients with trisomy 18 had normal erythrocyte values; [25] anemia was detected in 40%, and polycythemia was detected in 17%.

  • Conventional cytogenetic and fluorescence in situ hybridization (FISH) studies

    • FISH for rapid diagnosis (most laboratories, ≤24 hours) is more sensitive for mosaicism in the neonatal period (if unknown prenatally), followed by karyotyping, which is necessary even if FISH confirms the diagnosis for the rare translocation; karyotyping is also necessary if the diagnosis is made prenatally to confirm the type of trisomy 18.

    • The genetic studies are what is important for diagnosis and to help the family with difficult decisions in these fragile infants; rapid confirmation of diagnosis is crucial.

    • Full trisomy 18 (about 95% of cases)

    • Trisomy 18 mosaicism (about 5% of cases)

    • Translocation type trisomy 18 syndrome (very rare)


Imaging Studies

Prenatal ultrasonography

Most fetuses with trisomy 18 have detectable structural abnormalities. [26]

Ultrasonographic abnormalities include microcephaly and Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia).

Choroid plexus cysts may be present.

Visceral anomalies are common and include GI anomalies (eg, omphalocele, esophageal atresia), congenital heart defects (eg, septal defect with polyvalvular disease), and renal anomalies (eg, polycystic enlarged horseshoe kidneys, ectopic kidneys).

Fetuses typically have overlapping digits, with the second and fifth fingers overlapping the third and fourth fingers, respectively. Overall posturing of the wrists suggests contractures, clubfeet, and rocker-bottom feet.

The frequencies of congenital anomalies detectable with prenatal ultrasonography are as follows:

  • Persistent abnormal position of fetal fingers - 89%

  • Choroid plexus cysts - 43%

  • Abnormally shaped fetal head (strawberry or lemon) - 43%

  • Two-vessel umbilical cord - 40%

  • Cardiac defects - 37%

  • Intrauterine growth retardation - 29%

  • Omphalocele - 20%

  • Neural tube defects - 9%

  • Cystic hygroma or lymphangiectasia - 14%

  • Oligohydramnios/polyhydramnios - 12%

  • Renal defects - 9%

First trimester ultrasonographic findings in fetuses with trisomy 18 are as follows [27] :

  • Nuchal translucency (> 95th percentile) - 91%

  • Nuchal translucency (> 99th percentile) - 77%

  • Absent/hypoplastic nasal bone - 53%

  • Generalized subcutaneous edema - 49%

  • Omphalocele - 21%

  • Abnormal posturing of hands - 6%

  • Megacystis - 4%

  • Cardiac defect - 4%

  • Pleural effusions - 4%

  • Echogenic yolk sac - 4%

  • None - 2%

Three-dimensional and four-dimensional ultrasonography

These offer diagnostic advantages for many anomalies associated with trisomy 18, especially for anomalies of the extremities and face. These studies can be a powerful adjunct to two-dimensional ultrasonography in the prenatal anatomic evaluation of fetuses with trisomy 18. [28]

Fetal echocardiography

Abnormal cardiac findings are detectable using echocardiography in most patients with trisomy 18. A wide spectrum of heart defects is observed. In a study from Lin et al, the anomalies identified included ventricular septal defect (94%), patent ductus arteriosus (77%), atrial septal defect (68%), and complex congenital heart defects (32%). [29]

Heart malformations can be reliably diagnosed, even in the first trimester at the time of nuchal translucency measurement. These require follow-up beyond the first trimester. Most cardiologists would want to obtain fetal echocardiography after 18 weeks' gestation to confirm a cardiac malformation, especially to determine the specific type.


Other Tests

See the list below:

  • A barium swallow is indicated for gastrointestinal (GI) anomalies.

  • In Lin et al's study, using brain ultrasonography, the most common brain lesion revealed was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%), and choroid plexus cysts (19%). [29] Ultrasonography is also indicated for genitourinary anomalies.

  • Skeletal radiography is used to discern phocomelia, absent radius, tight flexion of the fingers with the second over the third and the fifth over the fourth, talipes equinovarus, short sternum, hemivertebrae, fused vertebrae, short neck, scoliosis, rib anomaly, and dislocated hip.