We’d likely be going to a mid-sized city in the Midwest (think Ohio/Indiana sort of area),
I lived in the US for 6 months and travelled widely there on holiday so have some experience but was only ever living there temporarily.
I would say if you definitely approach it on a temporary basis - agree set number of years absolute maximum whatever happens (obviously fewer years may happen naturally if you don't like it or your DH loses his job) so when your oldest would be moving into senior school - then experiencing a different culture is a good thing and interesting. If you know its temporary then it gives you more of a a 'holiday' mindset so you get more out of it - doing the tourist stuff, travelling more locally that kind of thing - that if you think its forever you never do because you always think you can do it tomorrow.
100% make sure healthcare insurance is sorted for the whole family. You have to pay for everything including the pill.
I would absolutely want to go to check out the "mid-sized city in the Midwest" because (sorrty about this - may be offensive to some but its my honest opinion based on my experience) once you get off the beaten track (by which I mean big cosmopolitan cities - usually ones that match up with centres of tourism and international travel and international education) there are a lot of places in the US that are shockingly backward - in terms of poverty, rich/poor divide, racism and zero culture. You want to know what you are letting yourself in for and you won't get a sense of that without visiting the place. If you are white, wealthy and don't care about culture, then it maybe you can pass through life without noticing any of this wherever you are but like I said anything other than New York, DC etc, I would be going to check it out first.
If you have travelled in the states anywhere in that centre block of states (the square between top left Idaho to top right Minnesota to bottom right Louisiana to bottom left Arizona) outside of the main tourist spots (so I don't mean New Orleans or Las Vegas - you would know what I meant but if you haven't, definitely go to see. Its hard to explain but it is very very different from those bigger cities some of which are very like London in vibe - New York for example is so similar to London in many ways. You can travel to some places where they are totally blindsided by an English accent even someone out of state is a big deal - so you need to see that for yourself.
Finally (trivia I know) the whole lunch culture is another world. There is no equivalent of M&S or Pret or a place where you can just grab a nice, small normal sized good quality sandwich. It's all big subs, McDonalds or massive salads.
I would say provided the basic location is ok and has enough for you and your family to have a 2 -4 year adventure, go for it BUT don't sell your house, rent it out and plan (agree with your DH) a definite plan to come back.
Oh - and one more thing - how old are both your parents? If they are younger and healthy, now is a good time to do this because when they get older and are facing the end of their life, you are likely to want to be around/closer to them.