So I've installed Skyrim via the installer provided within PlayOnMac, however I don't believe this issue is specific to Skyrim, nor to PlayOnMac, though if I find a good solution I'll pass it on in case it can be provided to others.
The basic issue is that no matter what I seem to set, it still appears to be possible for the mouse to register as outside the game window, causing clicks (in the case of Skyrim these are the attack buttons) to fail to register until the cursor is moved back "inside".
It seems that the Skyrim setup does include screen limiting by default, as it works fine a lot of the time, however its almost as if the pixels on the very edge of the screen still somehow count as outside the playable area, as this is where the mouse cursor appears when the game stops responding to it. However I can't be completely sure this is the case as I would think the cursor would be stuck at the screen edges a lot of the time anyway (since the game only cares about direction not position).
Is there anything else I can try to prevent the native (not Skyrim's) mouse cursor suddenly appearing and messing with control of a game?