First-trimester combined screening is effective for the detection of unbalanced chromosomal translocations at 11 to 12 weeks of gestation

Abstract

The first trimester combined screening, which analyzes fetal nuchal translucency and levels of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein A (PAPP-A) in maternal serum, is routinely used to detect abnormal pregnancies associated with Down syndrome and other trisomy aneuploidies. Based on the hypothesis that major chromosomal translocations could lead to similar biochemical and developmental outcomes during early embryo development, we compared these markers among pregnancies with normal, balanced, or unbalanced fetal karyotypes. Among the parents, 71 (73%) carry balanced reciprocal translocation and 26 (27%) have Robertsonian translocation. Of the 97 pregnancies tested, 39 (40%), 37 (37%), and 22 (23%) fetuses had normal karyotype, balanced chromosomal translocations, and unbalanced chromosomal translocations, respectively. Importantly, we found that pregnancies with an unbalanced translocation had significantly higher free β-hCG multiple of the median (MoM) and larger nuchal translucency thickness than those with normal karyotype or balanced translocations. Analysis showed that the area under a receiver operating characteristic curve (AUC) is 0.716, 0.820, and 0.936 for free β-hCG MoM, PAPP-A MoM, and fetal nuchal translucency, respectively. When these 3 independent factors were combined, the AUC reached 0.976. In addition, logistic regression showed that the most optimal model for predicting an unbalanced chromosomal translocation is a combination of PAPP-A and nuchal translucency with an AUC of 0.980. Therefore, the first trimester combined screening is not only effective in the screening of Down syndrome and other trisomy abnormalities but also has high sensitivity for the detection of unbalanced chromosomal translocations in fetuses.

Keywords: PAPP-A.; chromosomal translocation; first trimester combined screening; nuchal translucency; β-hCG.

Figure 1.

Flowchart of the study design. NT indicates nuchal translucency.

Figure 2.

The sensitivity and 100-specificity of individual and combinations of biomarkers for the prediction of the pregnancies with unbalanced chromosomal translocations. Best cutoff values for free β-hCG: 0.992 MoM, PAPP-A: 0.605 MoM, and NT: 2.1 mm were determined based on the ROC curve analysis. The 45 line (deep-red color) indicates the theoretical plot of a test with no discrimination between unbalanced chromosomal translocations and control. First trimester combined screening (free β-hCG, PAPP-A, and NT), 1 in 874. β-hCG indicates β-human chorionic gonadotropin; MoM, multiple of the median; PAPP-A, pregnancy-associated plasma protein A; NT, nuchal translucency; ROC, receiver operating characteristic.