Trophoblast Invasion in Pregnancies Complicated by Trisomy 21: A Spectrum of Abnormalities
(PowerPoint Slides - 1.02MB PDF Format)

Drs. Michael McMaster, Alexi Wright, and Susan Fisher
University of California, San Francisco, California

Chromosome abnormalities are common causes of congenital malformations and spontaneous abortions. Nearly half of all miscarriages have abnormal karyotypes and occur during the first few weeks of life. Given the timing, it is likely that implantation and placentation are intimately involved in selection against chromosomally abnormal embryos. While the presence of aneuploid cells in the placenta is associated with poor pregnancy outcome, it is unclear exactly how aneuploidy affects placentation.

This work examines the differentiation pathway that leads to cytotrophoblast (CTB) invasion of the uterine interstitium and vasculature in placentas from pregnancies complicated by trisomy 21. We hypothesized that aneuploidy would alter CTBs' ability to properly invade the uterine wall, perhaps contributing to the 30 percent spontaneous abortion rate seen in these conceptuses. Because most trisomy 21 pregnancies survive, however, we expected that many CTBs would differentiate normally. We also hypothesized that trisomy 21 CTBs would show a range of phenotypes, mirroring the diversity seen in the clinical disease.

The results of the study suggest that the genotype of the placenta has a profound impact on the formation of anchoring villi as well as CTB interstitial and endovascular invasion. At a morphological level, we observed extensive fibrinoid deposition along the CTB shell that was associated with apoptosis of CTBs differentiating along the invasive pathway. One of the most surprising results was the wide range of phenotypic abnormalities we observed in placentas with a 47,21 karyotype. Samples with less apoptosis had relatively normal staining patterns for cell- surface markers expressed by CTBs in the early stages of differentiation and decreased staining for late-stage markers, suggesting that a subset of invasive CTBs differentiated normally, while others were eliminated. Other 47,21 samples we examined contained extensive CTB apoptosis and showed decreased staining for antigens at every stage of differentiation in situ and an inability to differentiate in culture.

We speculate that the morphological, phenotypic, and functional differences among CTBs from different trisomy 21 placentas may explain why a significant number of these pregnancies end in spontaneous abortion, while others survive to term. Finally, our findings suggest that a similar interplay between genetic and environmental factors may contribute to the range of phenotypes observed among individuals with Down syndrome.