If you are stuck on a special layout, you are likely to be disappointed if you start changing size on a real device or on one of the PC versions, like the Sony Reader Library. You need to check it out.
PDF may be the way to go if you must have a fixed layout. But it has its own problems. You may be able to work around these by limiting the amount of text per page and size of images so the page can be increased in size without everything going sideways.