Maternal and fetal cellular programs orchestrate pregnancy complications and placental tolerance

The placenta is a transient organ that orchestrates maternal-fetal interactions essential for healthy pregnancy, yet the multicellular principles governing placental dysfunction remain poorly understood. Here, we present a multimodal single-cell atlas of the human placenta, profiling over 1.2 million cells from 68 donors using paired single-cell RNA sequencing, CITE-seq, and T cell receptor sequencing across spontaneous preterm birth, preterm and term preeclampsia, fetal growth restriction, type 1 diabetes, and healthy term and preterm pregnancies. We define 115 placental cell populations, including previously unrecognized maternal and fetal subsets, revealing unexpected cellular diversity across immune, vascular, trophoblast and stromal compartments. Cross-disease analyses demonstrate that maternal-fetal myeloid imbalance spans nearly all disease states, while trophoblasts, fetal macrophages, and fetal endothelial cells show marked, condition-specific dysregulation. We further identify conserved interferon-stimulated macrophage populations that function as constitutive homeostatic sentinels, and define candidate multicellular immune regulatory niches associated with placental T cell clonal expansion across healthy and complicated pregnancies. Together, these findings establish a comprehensive cellular framework for placental function and dysfunction that can guide precision diagnostic and therapeutic strategies across major obstetric disorders.