In manifold calculus, there are various analyticity estimates which run into trouble for codimension two embeddings. For instance, the functor $Emb(M,N)$ is analytic in $M$ if $dim M \leq dim N - 3$. Another example is given by the usual multiple disjunction lemma, which gives estimates on connectivity so long as we study the disjunction of manifolds $L_i$ which have dimension $\leq \dim N-3$. 

At the same time, when I think of codimension 2 embeddings, I think of introducing $\pi_1$ complications. (For instance, think of a 3-manifold, and removing a link. More simply: Remove a point from $\mathbb{R}^2$.) And as a general philosophy of topology, spaces with $\pi_1 \neq 0$ are more difficult to study.

This is a somewhat vague question: Are these two complications related in an obvious or philosphical way, deeper than what I've said here? That is, is there a specific sense in which the codimension-two complications of manifold calculus are a manifestation of a general viewpoint, that non-simply-connected spaces are complicated?