I have a file here that is twice that size and do not experience this issue.
I'd try running a recover on a copy of the file to see if any issue exist. (You may need to let the recover run over night). Then test the recovered copy, even if no trouble is found to see if the problem persists in the recovered copy.
Also check to see if this can happen on just any layout in your file or just one or two layouts. It's possible to have corrupted layout that is not detectable as a problem by recover. Thus, if the problem seems specific to a particular layout or two, you may be able to repair your file by recreating the damaged layouts.