You certainly can't blame O'Brien for being uncomfortable. But you also have to think, Keiko was in an emotionally difficult place and needed some kind of emotional comfort even if it was just a hug. As a husband it's kind of his obligation to provide that comfort to the extent Keiko needed it.
It's true Keiko's brain chemistry was different but all her memories and her built up habits and behavioral reactions are still there. The difference in brain chemistry would have changed her feelings and reactions but philosophically speaking would not change who she was at her core.
I mean, it's a show about mankind putting principle before instinct. I'd like to think, in the long run, O'Brien would have adjusted to Keiko having the form of a much younger person.