From the Guidelines
The most appropriate diagnostic test to confirm the suspected genetic disorder in this 12-week pregnant woman with decreased pregnancy-associated plasma protein (PAPP-A) and increased beta-human chorionic gonadotropin (β-hCG) levels is chorionic villus sampling (CVS) for chromosomal analysis, as it can detect the presence of aneuploidy and provide a definitive diagnosis. The first trimester screening results showing decreased PAPP-A and increased β-hCG are characteristic markers suggestive of aneuploidy, such as trisomy 21 (Down syndrome) 1. At 12 weeks' gestation, CVS is the preferred diagnostic test to obtain placental tissue for chromosomal analysis, as it can be performed earlier than amniocentesis (which is typically done after 15 weeks) 2.
Key Considerations
- CVS can detect the presence of aneuploidy, including trisomy 21, and provide a definitive diagnosis 1.
- Chromosomal analysis on CVS or amniocentesis demonstrating nonmosaic trisomy or sex chromosome aneuploidy consistent with the noninvasive prenatal screening (NIPS) result is considered confirmation of a positive NIPS and therefore of an affected fetus 1.
- A full study on CVS or amniocentesis demonstrating a normal karyotype would not typically warrant additional metaphase cell counts or other analyses, but a mosaic result on CVS should not be considered confirmatory and may require follow-up amniocentesis 1.
Diagnostic Approach
- The American College of Medical Genetics and Genomics (ACMG) recommends follow-up prenatal diagnostic testing for all patients with positive NIPS results, which can be accomplished by either CVS or amniocentesis 1.
- Chromosomal microarray (CMA) testing on either CVS or amniotic fluid may be used as confirmatory diagnostic testing in cases with positive NIPS results, or as reflex testing in cases with initial normal results from chromosome analysis 1.
- The choice of diagnostic test should be based on the suspected anomaly and the patient's individual circumstances, with consideration of the risks and benefits of each test 2.
From the Research
Diagnostic Test Results for Genetic Disorders
To confirm a suspected genetic disorder in a 12-week pregnant woman with decreased pregnancy-associated plasma protein (PAPP-A) and increased beta-human chorionic gonadotropin (β-hCG) levels, the following diagnostic test results are relevant:
- Nuchal Translucency (NT) Measurement: A study published in 2005 3 found that first-trimester NT measurement has high sensitivity and specificity for Down syndrome screening.
- Maternal Serum Markers: Research from 1998 4 showed that screening of maternal serum for fetal Down's syndrome in the first trimester is feasible, with a detection rate of 63% for hCG and 60% for its free beta subunit.
- Cell-Free DNA Screening: A 2018 study 5 highlighted the benefits and limitations of cell-free DNA screening for aneuploidy, including a detection rate of 99.2% for Down syndrome, but also noted limitations such as not every woman receiving an interpretable result and the limited number of targeted aneuploidies.
Recommended Diagnostic Tests
Based on the evidence, the following diagnostic tests are recommended:
- Combined First-Trimester Test: This test combines NT measurement, maternal serum markers (free β-hCG and PAPP-A), and maternal age to assess the risk of Down syndrome and other chromosomal abnormalities 5.
- Invasive Prenatal Diagnosis: If the screening test results indicate a high risk of genetic disorder, invasive prenatal diagnosis such as chorionic villus sampling (CVS) or amniocentesis may be offered to confirm the diagnosis 3, 6, 7.