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- Seeds (except a few special ones)
- Challenges (except for their reward obviously).
- Daily Runs.
- Reruns and Victory Laps (except for a few specific unlocks).
- Any active mod from the mod menu before Mom is killed once on that save (no matter what they do, other saves are irrelevant).
- Enabling the console before Mom is killed once on that save (even if you don't use it).
- Paranoid antivirus programs (or missing rights) preventing the game from creating/editing its save file.
Otherwise, if you still unlock things in-game but Steam achievements don't pop-up, it might just be a sync issue. Checking the secrets menu (in stats) should fix it.
The options file is located here (this exact file path, nowhere else, any other option file will be ignored):
C:\Users\[your name]\Documents\My Games\Binding of Isaac Repentance
(On AB+, the console is automatically disabled if all mods are disabled. On Rebirth/Afterbirth, the console doesn't exist at all.)