The Maternal Cardiopulmonary–Placental Axis: A Systematic Review of Maternal Physiology, Placental Function, and Fetal Vulnerability

Abstract Clinical experience has shown that fetal status may deteriorate in pregnancies complicated by maternal cardiopulmonary disease despite only mild symptoms being evident in the mother. However, the physiological relationships beneath this discrepancy remain largely unstudied in a unified approach. To fill this knowledge gap, we performed a systematic review using 2020 PRISMA guidelines to aggregate evidence on the relationship between maternal cardiopulmonary reserve, placental microvascular adaptation, and fetal responses. An extensive search for primary studies was conducted in major bibliographic databases and clinical trial registries with no date limits. Of the 2005 records screened, we included reviews of clinical, experimental, and mechanistic studies that met the eligibility criteria. Even with the diversity in study designs and populations, a familiar theme emerged. More modest decreases in maternal cardiac output or oxygen delivery were commonly associated with placental malperfusion, altered villous development, angiogenic imbalance, prooxidant/antioxidant activation, and evidence of fetal hypoxemia. Many reports describe severe fetal compromise in the setting of apparently stable maternal status, and imply that the placental circulation may be extremely vulnerable to even subtle changes in physiology. Evidence from human cohorts, animal models, and molecular studies converged into a unified biological conceptual framework where the placenta is no longer seen as a passive conduit between mother and fetus but an active intermediary translating maternal cardiopulmonary strain into fetal consequences. Taken together, these findings provide evidence for an integrated Maternal Cardiopulmonary–Placental Axis that explains the discrepancy between maternal and fetal phenotypes and provides a physiologic rationale to evaluate pregnancy risk beyond a binary approach.