Rethinking the placenta: why fetal oxygen demand may matter more than maternal symptoms

For decades, obstetric medicine has judged the health of the placenta largely through the mother. If a woman develops pre-eclampsia, the placenta is presumed dysfunctional; if her blood pressure remains normal and the fetus keeps growing, the organ is presumed to be doing its job. A provocative new hypothesis paper published in Frontiers in Physiology argues that this entire framework rests on a logical flaw, and proposes a radical reframing in which placental sufficiency is defined not by any single clinical sign but by a dynamic balance between how much oxygen the fetus needs and how much the integrated maternal–placental–fetal system can actually deliver. The consequences of accepting that view could reshape how clinicians screen, monitor and interpret gestational disease.

The article, authored by obstetricians Maria Cezara Mureşan of Victor Babeş University of Medicine and Pharmacy and Marius Bogdan Mureşan of the Fetal Medicine Center in Timişoara, Romania, addresses what the authors call the single-endpoint problem. Current tools for predicting placental disease—competing-risks models and angiogenic biomarkers such as placental growth factor, or PlGF—were calibrated to forecast the maternal syndrome of pre-eclampsia. They do that well. But when their output is implicitly read as evidence that the fetus is safe, an instrument built to report on one actor’s response is being asked a question it was never designed to answer. A latent state with more than one possible expression is being read through only one of them.

The core of the proposal is a formal demand–supply relation expressed on a common oxygen scale. The authors denote the fetus’s unadapted oxygen requirement as Co(t) and the effective capacity of the whole oxygen-transfer chain, assessed at the fetal receiving end, as Os(t). Their difference, Δ(t) = Co(t) − Os(t), defines the instantaneous imbalance. When Δ is positive, the integrated system can no longer meet the fetal requirement—whatever the cause. Crucially, both quantities are latent: no current bedside measurement recovers them directly. Supply capacity integrates maternal oxygen content, uterine blood flow, intervillous perfusion, placental exchange surface, the placenta’s own oxygen consumption and umbilical flow, while fetal haemoglobin and the oxygen-dissociation curve modify what can ultimately be used.

This framing yields a counterintuitive insight: an organ that is structurally unremarkable can still become functionally insufficient, and a placenta that was adequate for a small fetus at 30 weeks may be inadequate for the same fetus at 39. The authors distinguish three trajectories to insufficiency. The familiar supply-driven route begins with defective placentation—incomplete spiral artery remodelling, infarction or vascular maldevelopment—which lowers the supply ceiling before rising demand reaches it. A second, less recognised route is demand-driven: an initially adequate placenta is overtaken by the fetus’s normally increasing requirement, with no previously detectable abnormality. Most real cases, the authors argue, are mixtures of the two.

The demand-driven trajectory is grounded in a rough physiological budget. Doppler and Fick estimates place term fetal oxygen uptake at roughly 6.6 millilitres per kilogram per minute, about 22 millilitres per minute for a 3.4-kilogram fetus, while the placenta itself consumes approximately 40 percent of the oxygen taken up by the gravid uterus at term. Longitudinal studies show that although absolute uterine artery blood flow roughly doubles between 20 and 38 weeks, flow normalised to fetal weight declines, and weight-normalised umbilical venous flow also falls in late gestation. The margin between supply and demand therefore narrows selectively—in fetuses with elevated demand or blunted per-mass supply—without any universal convergence of the two curves.

Labour, in this model, is not the origin of insufficiency but its great unmasking. Uterine contractions intermittently slash uteroplacental perfusion, and a fetus entering labour with ample reserve recovers fully between contractions. When demand already sits close to the supply ceiling, the same contraction pattern repeatedly drives the system into positive imbalance, consuming myocardial and metabolic reserve until compensatory heart-rate responses fail. This is essentially the phenomenon recently described as relative uteroplacental insufficiency of labour, which explains why intrapartum compromise can strike pregnancies classified as low risk hours earlier.

The paper’s most specific and falsifiable claim concerns PlGF, one half of the sFlt-1/PlGF angiogenic ratio used in pre-eclampsia testing. The authors advance a biphasic, oxygen-sparing hypothesis. In the first phase of a sustained imbalance, the highly oxidative placenta preserves its own consumption while the fetus bears much of the emerging deficit, compensating by redistributing cardiac output and slowing growth. If the mismatch persists, placental metabolism may reprogramme toward glycolysis, sparing oxygen for fetal transfer but generating hypoxic, energetic and endoplasmic-reticulum stress. Experimental work shows that hypoxia suppresses PlGF through HIF-2α, and that the stress proteins ATF4 and ATF6β negatively regulate PlGF transcription. On this account, a gestational-age-inappropriate decline in PlGF is a delayed signal of sustained demand–supply mismatch—not a direct measure of fetal demand, and not necessarily evidence of a pre-existing lesion.

From the divergence of the two halves of the angiogenic ratio flows the framework’s most clinically consequential claim: maternal and fetal expressions of the same placental state are only incompletely coupled. Excess sFlt-1 sequesters VEGF and PlGF and can produce maternal endothelial dysfunction, but the resulting phenotype depends on a host-specific maternal response the authors call Vm. A strong placental signal may produce florid pre-eclampsia in one woman and near silence in another. Likewise, fetal compensation—cardiovascular redistribution, reduced activity, growth slowing—lowers realised consumption without touching the underlying requirement, so a normally grown fetus is not proof of adequate support. Fetal decompensation can unfold over minutes to hours during labour, while maternal syndromes evolve over days to weeks, meaning fetal jeopardy can develop during relative maternal silence.

The authors therefore propose that the reference endpoint for placental oxygen-transfer function should shift from the maternal syndrome to the adequacy of fetal support, with maternal and fetal morbidity remaining co-equal outcomes. Testing this demands endpoints graded by independence from clinical management: cord metabolic acidaemia defined by prespecified thresholds, neonatal encephalopathy and death—adjudicated against acute extraplacental causes—rather than operative delivery for suspected compromise, which depends heavily on local practice. They also caution that interventions targeting the angiogenic signal rather than the imbalance, such as pilot trials of sFlt-1 removal, may improve maternal markers without restoring transfer capacity, so trials must report objective fetal endpoints.

What lends the paper credibility is its unusual epistemic discipline. The authors prespecify a single primary estimand—a 36-week landmark model combining free-PlGF multiples of the median and its 32-to-36-week slope, interpreted with total PlGF and sFlt-1, tested against an adjudicated fetal-compromise composite in an external validation cohort—and they enumerate, level by level, exactly what would falsify the framework: failure of the landmark signature, failure to demonstrate placental metabolic reprogramming under sustained imbalance, or failure of PlGF to track fetal endpoints. They also acknowledge close antecedents, from the two-stage model of pre-eclampsia to the capacity–load model of placental adaptation and prior proposals that pre-eclampsia may be a response to fetal hypoxia rather than its cause. Their claimed novelty lies in the combination: a latent demand–supply balance, three separated levels of causation and expression, host-dependent divergence, and a delayed biphasic PlGF mechanism. If the prespecified predictions replicate, the field may be pushed toward a conclusion with real clinical bite—that the question ‘is the placenta doing its job?’ can only be answered by asking whether the fetus, not the mother, is being adequately served.

Subject of Research: A demand–supply framework defining placental sufficiency by fetal oxygen requirement versus maternal–placental–fetal supply capacity

Article Title: Placental sufficiency is relational: a demand–supply hypothesis for divergent maternal and fetal expressions of gestational disease

Article References: Mureşan, M. C., & Mureşan, M. B. (2026). Placental sufficiency is relational: a demand–supply hypothesis for divergent maternal and fetal expressions of gestational disease. Frontiers in Physiology, 17, Article 1963994. https://doi.org/10.3389/fphys.2026.1963994

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1963994

Keywords: placenta, placental insufficiency, fetal oxygen demand, pre-eclampsia, placental growth factor, PlGF, sFlt-1, fetal growth restriction, intrapartum compromise, hypoxia, angiogenic biomarkers, placental metabolism