The genetic–environmental interactome in maternal cardiopulmonary disease: A systematic review of multi-omics, placental crosstalk and transgenerational cardiovascular programming

Maternal cardiopulmonary disease is still a major contributing but mechanistically disparate cause of pregnancy complications and, perhaps more so, an underrecognised sufferer of increased lifetime cardiovascular risk in the progeny. To fill this gap across these domains, we performed a systematic review, following PRISMA 2020 reporting guidance on the interplay of genetic susceptibility and environmental exposures that converge through multi-omics pathways at the maternal–placental–fetal interface. A search through five databases (PubMed/MEDLINE, Embase, Scopus, Web of Science and Cochrane Library) and additional sources for supplement records resulted in 1334 records. After duplicates were removed and predefined exclusion papers applied, 897 records were screened, resulting in 35 studies assessed for qualitative synthesis. While not always clearly articulated in the original reports, a common pattern across the diverse range of study designs emerged. Maternal cardiovascular and respiratory disorders appear to operate within a shared hierarchical genetic–environmental interactome rather than as isolated clinical entities. Markers of hypoxia, inflammation, angiogenic imbalance and metabolic stress repeatedly converged at the placental level, where the placenta often acted as an active integrator rather than a passive interface in many studies (78). While the depth and standardisation of multi-omics data varied, there was a concerted effort to identify convergent mechanisms that could explain epigenetic modulation, transcriptomic reprogramming and proteomic signaling leading to fetal cardiovascular adaptation. What is harder and harder to dismiss within this body of research, though, is the lasting nature of these effects beyond birth. The data are suggestive of some form of transgenerational imprinting as demonstrated by evidence linking intrauterine exposure to subsequent cardiometabolic and vascular phenotypes, but the details are not fully elucidated. Although we still find some limitations due to study design or substantial heterogeneity and bias, the synthesis adds support for a conceptual move toward a genetic–environmental interactome framework. This transition has a tremendous impact on both risk stratification and early intervention in this new world of precision perinatology.