What was the first Hollywood studio picture where the premarital aspect of sex wasn't presented as an issue?

Not necessarily showing a full sex scene. Just one where it was clear they'd had sex, but the fact of it being before marriage wasn't anything noteworthy?

I'm not sure, but there might be a difference between characters who don't find it noteworthy vs. the film/filmmakers. (I'm imagining a hypothetical film made in the 1960s whose raison d'etre would've been to depict the changing attitudes of the times.)

knocked up

have no idea but i suspect there are probably pre-code examples of this?

It's also hard to tell in retrospect what a film thinks is noteworthy. Like, is the sex in Breathless being depicted as illicit?

Otto Preminger's The Moon is Blue (1953) is generally considered to be the first American movie to break at least some of the cinematic taboos surrounding pre-marital sex:

http://en.wikipedia.org/wiki/The_Moon_Is_Blue

not the first but John & Mary from 1969 comes to mind

knocked up

That was the first thing that came to my mind too. Or The Sin of Nora Moran.

I think it's very heavily implied if not made crystal clear that Bogart nails Dorothy Malone's bookshop proprietor in The Big Sleep and very little is made of it.

I guess there must have been some pre-Hays Code movies which played fast and loose, but can't think of one at the moment.

This site http://www.filmsite.org/sexualfilms2.html would suggest 'Our Dancing Daughters' from 1928 starring Joan Crawford.

as noted, dozens of pre-hayes code stuff, pick one, how about this

https://www.youtube.com/watch?v=eDfRzke3R9E

it takes a real man to tame this kind of female lol