While no cause has been established for stillbirth in the majority of cases, the rate of fetal death rises exponentially as gestation progresses beyond 38 weeks and we have hypothesized that these fetal deaths are related to placental aging. The placenta is a link between mother and fetus, it supplies nutrients and oxygen to the fetus, it removes wastes from the fetus, and protects the fetus from attack by the mother’s immune system. In our pilot study, we have collected 10 placentas from women at 38 weeks of gestation (term) and 10 placentas collected at 41 weeks of gestation (post-dated). We compared the two groups for alterations in markers of aging including: telomere length measured by real-time PCR, oxidative DNA damage assessed by immunohistochemistry and both mTOR, and autophagic pathways using immunohistochemistry and western blot. Post-dated placentas showed signs of ageing including shortening of telomeres and DNA damage. Activity of mTORC1 was increased in post-dated placentas, whereas activity of mTORC2 decreased. Increases in LAMP2 and IGF2R, and the co-localisation of mTOR and LAMP2 in lysosomes indicated altered autophagic activity in post-dated placentas consistent with accumulation of abnormal protein. Our data confirmed biochemical signs of senescence in post-dated placentas. The known exponential increase in unexplained intrauterine death that occurs after 38 weeks of gestation may therefore be a consequence of aging of the placenta and its decreasing ability to supply the increasing needs of the growing fetus.
We now wish to extend this work to determine if we can detect markers of the placental aging in the blood of the pregnant women. The placenta sheds DNA, RNA and fragments of the syncytiotrophoblast into the maternal blood and diagnostic tests to detect Down’s syndrome are already in clinical use using free placental DNA in maternal blood samples. We propose a diagnostic test for risk of stillbirth using the markers of placental aging that we have already determined in the placenta itself. For the development of this test we will compare concentrations of key markers in the blood of women delivering at term (38 weeks) with those delivering post-dates (41 weeks) and with those delivering growth restricted babies (another risk factor for stillbirth)