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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.
The "always Void portal after Mega Satan" mod is also known to prevent all Mega Satan unlocks. If you have it, disable it.
If instead you have the in-game unlocks but you're just missing Steam achievements for some reason, checking the in-game secrets menu should fix this inconsistency.