Revisiting placental hypoxia in assisted reproduction: from molecular signatures to functional consequences

The global expansion of assisted reproductive technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), has raised concerns regarding the impact on placental development and susceptibility to pregnancy complications. Oxygen tension is a central regulator of placental biology, acting both as a physiological developmental signal and, when dysregulated, as a driver of pathology. Early placentation occurs in a naturally low-oxygen environment that is essential for trophoblast specification, invasion, immune-vascular crosstalk, and angiogenesis. These processes are coordinated by hypoxia-inducible factor (HIF) signaling and related oxygen-sensing pathways.

This review examines the dual role of oxygen in placental development and disease, with particular emphasis on the molecular mechanisms that regulate hypoxia responses during normal and pathological placentation. We further evaluate emerging evidence that ART alters early embryonic and placental programming and propose a mechanistic framework in which ART-induced developmental reprogramming increases susceptibility to hypoxic maladaptation later in pregnancy.

Literature searches were conducted in PubMed and Google Scholar up to June 2026 using combinations of the terms 'hypoxia,' 'placenta,' 'HIF signaling,' 'assisted reproductive technology,' 'in vitro fertilization,' and 'embryo culture.' Studies were limited to English-language publications, with emphasis on human studies and mechanistic investigations in experimental animal and stem cell models.

Oxygen tension emerges as a master regulator of placental development. Genetic and experimental studies demonstrate that precise temporal and spatial regulation of HIF signaling, including distinct contributions of HIF-1α and HIF-2α, is essential for trophoblast differentiation, placental morphogenesis, vascular development, and fetal viability. Physiological hypoxia orchestrates normal placentation, whereas sustained or dysregulated activation of hypoxia-responsive pathways contributes to an angiogenic imbalance, inflammation, oxidative stress, mitochondrial dysfunction, regulated cell death, and placental insufficiency. Increasing evidence suggests that ART may perturb this tightly regulated developmental program at its earliest stages. Exposure of preimplantation embryos to non-physiological culture conditions can alter their metabolic state, redox homeostasis, epigenetic regulation, and trophectoderm gene expression. These early perturbations may persist into placental development, resulting in impaired trophoblast differentiation and invasion, altered angiogenic signaling, and heightened sensitivity to hypoxic stress. Collectively, findings from experimental models, human placental studies, and emerging single-cell and spatial omics approaches support a model in which ART-induced developmental reprogramming predisposes the placenta to hypoxic maladaptation, thereby increasing susceptibility to disorders such as preeclampsia and fetal growth restriction.

ART-associated placental hypoxia may originate from altered embryonic programming during preimplantation development rather than arising solely from placental pathology that develops later in pregnancy. Integrating developmental biology, oxygen-sensing pathways, and multi-omic approaches may facilitate the identification of early biomarkers, optimization of embryo culture conditions, and development of targeted strategies to improve maternal and fetal health.

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