Two changes in the setup for downfall can cause instant losses, which may not be what you want.

1. Rolling 'Ectoplasm' from the boss relic swap. This relic should be removed from the boss relic random start pool. You literally cannot get to Neow anymore should you roll this.

2. Having elites on all paths within 1 combat. Especially hexaghost has a very hard time beating elites with her starter deck. The slime boss and the snecko can sometimes beat them, while guardian pretty much can always do so due to defensive mode. Essentially a setup like this (if the game did not give you the '2 free combats' option boils down to 'you lose' at the start. Sure, the regular game can do this (on Silent, you receive 3 card choices with no attacks, then Lagavulin appears), but it is much less common: elites can only appear from floor 5 onward.