The placenta is a critical fetal exchange organ, with a complex branching tree-like structure. Its surface is covered by a single multinucleated cell, the syncytiotrophoblast, which bathes in maternal blood for most of pregnancy. Mechanosensing protein expression by the syncytiotrophoblast at term suggests that shear stress exerted by maternal blood flow may modulate placental development and function. However, it is not known how the mechanosensitive capacity of the syncytiotrophoblast, or the shear stress it experiences, change across gestation. Here, we show that the syncytiotrophoblast expresses both mechanosensitive ion channels (Piezo 1, Polycystin 2, TRPV6) and motor proteins associated with primary cilia (Dynein 1, IFT88, Kinesin 2), with higher staining for all these proteins seen in late first trimester placentae than at term. MicroCT imaging of placental tissue was then used to inform computational models of blood flow at the placentone scale (using a porous media model), and at the villous scale (using explicit flow simulations). These two models are then linked to produce a combined model that allows the variation of shear stress across both these scales simultaneously. This combined model predicts that the range of shear stress on the syncytiotrophoblast is higher in the first-trimester than at term (0.8 dyne/cm2median stress compared to 0.04 dyne/cm2) when considering both these scales. Together, this suggests that the nature of blood flow through the intervillous space, and the resulting shear stress on the syncytiotrophoblast have important influences on placental morphogenesis and function from early in pregnancy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10439-022-03129-2.