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

Researchers at Oxford University Hospitals compared the PlGF and sFlt-1 assays from Revvity with those from Roche, the latter being widely used across the United Kingdom and internationally. The study, led by Tim James and colleagues including Rebecca Marr and Alexandra Cerdeira, analysed more than 600 clinical specimens obtained from routine practice, covering the full range of concentrations encountered in daily testing. The work was published in the British Journal of Biomedical Science and represents a pragmatic head-to-head evaluation conducted in a real clinical setting rather than a controlled laboratory exercise.

The precision of the Revvity assays proved reassuring. Intermediate imprecision, assessed using quality control material during the evaluation, ranged from 3.2 to 9.0 percent coefficient of variation for PlGF and from 1.1 to 9.0 percent for sFlt-1, figures that fall comfortably within accepted analytical performance criteria for immunoassays. Even more convincing, the researchers constructed precision profiles from more than 500 clinical specimens measured in duplicate, showing median coefficients of variation of 1.9 percent for PlGF and 1.1 percent for sFlt-1 across the clinically relevant concentration ranges. As with most immunoassays, precision was somewhat poorer at low concentrations, but the overall analytical performance of the Revvity platform was solid.

Agreement between the two manufacturers’ assays, however, told a more complicated story. Using Bland-Altman analysis, the researchers found that the Revvity PlGF assay gave systematically higher results than the Roche assay, with a mean bias of approximately 20 percent across the concentration range. For sFlt-1, the direction of bias reversed: the Revvity assay gave systematically lower results than the Roche assay, with a mean bias of roughly minus 20 percent. These proportional biases were consistent across the measuring range, meaning that the discrepancy between the two platforms was not confined to extreme concentrations but persisted throughout routine clinical testing.

Passing-Bablok regression analysis confirmed these findings and revealed that the relationship between the two platforms was not perfectly proportional. For PlGF, the regression equation showed a slope greater than one with a negative intercept, indicating that the proportional bias increased at higher concentrations. For sFlt-1, the slope was less than one with a positive intercept, meaning the negative bias became more pronounced as concentrations rose. The researchers also found that the calculated sFlt-1-to-PlGF ratio, a parameter increasingly used in clinical decision-making, differed systematically between the two platforms, with the ratio derived from Revvity results being substantially lower than that derived from Roche results.

Despite these analytical differences, the clinical concordance between the two platforms proved remarkably good. When specimens were classified according to the National Institute for Health and Care Excellence (NICE) thresholds for ruling preeclampsia in or out, the two platforms agreed on the clinical category in the overwhelming majority of cases. Using the NICE rule-out threshold of a sFlt-1-to-PlGF ratio of 38 or below, the two platforms showed almost perfect agreement, with only a small proportion of specimens falling into discordant categories. The researchers calculated that the clinical sensitivity and specificity for ruling out preeclampsia were essentially identical between the two manufacturers when appropriate platform-specific thresholds were applied.

The explanation for the analytical bias lies in the different calibration systems and antibody specificities used by the two manufacturers. Roche calibrators are traceable to a specific reference material, while Revvity uses its own internal reference preparation, and the two companies employ different monoclonal antibody pairs that may recognise different epitopes on the target molecules. PlGF exists in multiple molecular forms, and sFlt-1 is a complex glycoprotein with considerable structural heterogeneity, so antibodies raised against different epitopes can yield systematically different quantitative results even when both are analytically valid. The researchers also noted that the freeze-thaw cycle used in specimen preparation may have contributed to some of the observed differences, although a subgroup analysis of fresh versus frozen specimens suggested this was not a major factor.

The practical message for laboratories is that assay-specific decision thresholds are essential. The researchers demonstrated that when the NICE rule-out threshold derived from Roche-based studies was applied directly to Revvity results, the clinical performance deteriorated, with a small but measurable loss of sensitivity. However, when platform-specific thresholds were calculated using the regression equations from this study, the Revvity assays achieved clinical performance equivalent to the Roche platform. This finding underscores a broader principle in laboratory medicine: quantitative results from different immunoassay platforms are not interchangeable, and clinical decision limits must be validated for each specific assay system before implementation.

For patients, the reassuring news is that both platforms deliver clinically reliable answers when used correctly. The angiogenic markers have established themselves as among the most powerful predictors in obstetric medicine, and the Oxford evaluation confirms that the Revvity assays, despite giving systematically different numerical results from the Roche platform, provide equivalent clinical discrimination when appropriate thresholds are used. The researchers emphasise that their findings should not be interpreted as a criticism of either manufacturer but rather as a demonstration of the challenges inherent in measuring complex biological molecules and the importance of rigorous validation before clinical implementation.

The Oxford team acknowledges some limitations of their work. The evaluation was conducted at a single centre, and the specimens analysed were obtained from a specific clinical population, so the findings may not generalise to all patient groups. The researchers also note that they did not assess the clinical performance of the assays against confirmed diagnostic outcomes, relying instead on established NICE thresholds as the reference standard. Nevertheless, the study represents one of the most comprehensive comparisons of commercial angiogenic assays conducted to date, and its findings should inform laboratory validation protocols and clinical implementation strategies for these increasingly important obstetric biomarkers. As the use of angiogenic markers continues to expand in routine practice, the message from Oxford is clear: rigorous platform-specific validation is not optional but essential for delivering safe and effective clinical care.

Subject of Research: Laboratory evaluation of angiogenic biomarker assays for preeclampsia

Article Title: Evaluation of analytical performance of the Revvity sFlt-1 and PlGF methods for the assessment of preeclampsia

Article References: Marr, R., Cerdeira, A. S., Smith, I., Vatish, M., & James, T. (2026). Evaluation of analytical performance of the Revvity sFlt-1 and PlGF methods for the assessment of preeclampsia. British Journal of Biomedical Science, 83, Article 15950. https://doi.org/10.3389/bjbs.2026.15950

Image Credits: AI Generated

DOI: 10.3389/bjbs.2026.15950

Keywords: preeclampsia, angiogenic markers, sFlt-1, PlGF, immunoassay, laboratory medicine, pregnancy, biomarkers, Evaluation, analytical, performance, Revvity

The new analysis, led by Kai-Yang Chen of Chang Gung Memorial Hospital in Taiwan, together with Hoi-Chun Chan of China Medical University and Chi-Ming Chan of Cardinal Tien Hospital and Fu Jen Catholic University, was prospectively registered with PROSPERO and conducted according to the PRISMA 2020 reporting guidelines. The team searched PubMed, Scopus, Web of Science, ScienceDirect, and the Cochrane Library from inception through April 21, 2026, screening more than 1,200 records to identify 25 eligible studies spanning in vitro experiments, animal models, and early- to late-phase human trials.

The biological rationale is compelling. Diabetic retinopathy alone affects approximately 22 percent of people with diabetes, roughly 103 million adults as of 2020, and is projected to reach 160 million by 2045. Neovascular age-related macular degeneration shares a common final pathway: VEGF-driven pathological angiogenesis and breakdown of the blood-retinal barrier, producing macular edema, capillary nonperfusion, and progressive retinal damage. Current anti-VEGF injections suppress these processes only transiently, requiring repeated administration and carrying procedural risks including endophthalmitis, elevated intraocular pressure, and cataract. Gene therapy, typically delivered via adeno-associated viral (AAV) vectors, aims to turn the eye itself into a factory for therapeutic proteins, achieving sustained pathway-level disease control after a single procedure.

The preclinical results are striking. Across eight animal and in vitro studies, gene therapy significantly reduced pathological neovascularization, with a pooled standardized mean difference of −1.16 (95 percent confidence interval, −1.48 to −0.84; p < 0.001), meaning the reduction exceeded one full standard deviation compared with controls. Remarkably, heterogeneity was negligible, with an I² of 0 percent, indicating extraordinary consistency despite differences in vector platforms, transgenes, and disease models. Within the oxygen-induced retinopathy subgroup, the effect was even larger, with a standardized mean difference of approximately −1.29, reflecting robust suppression of ischemia-driven retinal angiogenesis by constructs including soluble VEGF receptor sFLT-1, pigment epithelium-derived factor (PEDF), angiostatin, and the antioxidant enzyme MnSOD.

Vascular leakage, the other hallmark of these diseases, was also significantly reduced. Three preclinical experimental studies using AAV- and adenovirus-mediated gene transfer showed a pooled mean difference of 0.215 on a directionally harmonized scale (95 percent CI, 0.178 to 0.251; p < 0.001), again with zero heterogeneity. Complementary mechanistic work showed that sFLT-1 expression reduced VEGF-induced endothelial permeability by roughly 40 to 60 percent while preserving tight junction proteins, and antioxidant gene transfer reduced oxidative stress-driven barrier breakdown. In vivo, fluorescein leakage scores fell by 30 to 70 percent following anti-VEGF or PEDF gene delivery, while antioxidant therapy reduced acellular capillaries by approximately 40 to 60 percent, indicating preservation of the retinal microvasculature beyond angiogenesis alone.

The clinical evidence, though still early-stage, points in the same direction. Across eight clinical cohorts, ocular gene therapy produced a statistically significant reduction in central subfield thickness of −55.30 micrometers (95 percent CI, −72.58 to −38.03; p < 0.001), a meaningful anatomical improvement reflecting reduced macular edema and fluid accumulation. In the phase 1 trial of intravitreal AAV2-sFLT01 reported by Heier and colleagues, individual eyes showed central thickness reductions of up to roughly 600 micrometers at week 18 and 860 micrometers by week 52, while the phase 2a trial of subretinal rAAV.sFLT-1 by Constable and colleagues demonstrated stabilization of retinal thickness over 52 weeks.

Perhaps the most clinically consequential finding concerns treatment burden. Across seven clinical cohorts, the pooled logit event rate of 0.62 (95 percent CI, 0.20 to 1.04; p = 0.0039) corresponds to approximately 65 percent of participants meeting study-specific criteria for reduced supplemental anti-VEGF injections after gene therapy. Heterogeneity was low, at roughly 11 percent, despite differences between AAV and lentiviral platforms, delivery routes, and dosing regimens. This outcome directly addresses the central weakness of current standard care: the cumulative burden and adherence challenges of repeated intravitreal injections.

The analysis also situates these findings within a rapidly advancing clinical pipeline. Next-generation programs including ABBV-RGX-314, ADVM-022 (ixo-vec), and 4D-150 have progressed into phase II/III trials for neovascular retinal diseases, with early data showing reductions in anti-VEGF injection burden of up to 80 to 97 percent alongside stable visual and anatomical outcomes. Notably, 4D-150 employs dual inhibition of VEGF-A and VEGF-C, an evolution beyond earlier single-target constructs, while ADVM-022 offers intravitreal delivery that avoids surgery, and RGX-314 has shown durability across both subretinal and suprachoroidal routes. The concordance between these emerging results and the meta-analysis findings reinforces the biological validity of sustained intraocular VEGF suppression.

The authors are careful to acknowledge limitations. Some functional outcomes were drawn from trials of non-angiogenic inherited retinal disorders, including Leber hereditary optic neuropathy, RPE65-associated Leber congenital amaurosis, and X-linked retinitis pigmentosa, and were interpreted as proof of concept for gene delivery and durability rather than anti-angiogenic efficacy. The XIRIUS phase 2/3 trial of cotoretigene toliparvovec in X-linked retinitis pigmentosa, for example, missed its primary endpoint, underscoring the importance of disease context, dose selection, and intervention timing. Animal models, meanwhile, do not fully reproduce the chronic metabolic milieu of human diabetic retinopathy. Publication bias analyses were largely reassuring, though small-study effects were flagged for central subfield thickness and injection burden outcomes, and trim-and-fill sensitivity analyses supported the robustness of the primary estimates.

Safety data across translational stages suggest an acceptable early profile, with adverse events largely procedure-related or reflecting transient ocular inflammation. However, the authors caution that limited sample sizes, heterogeneous reporting, and incomplete long-term follow-up constrain safety conclusions, particularly given the potential irreversibility of ocular gene transfer. The path forward, they argue, requires adequately powered, disease-specific randomized trials, standardized outcome definitions, harmonized optical coherence tomography metrics, and long-term surveillance of transgene durability and immunogenicity. If those trials confirm the signals synthesized here, ocular gene therapy could shift the treatment of neovascular retinal disease from a lifetime of monthly injections toward long-acting or single-administration therapy, fundamentally changing the outlook for the hundreds of millions at risk of preventable vision loss worldwide.

Subject of Research: Ocular gene therapy targeting retinal angiogenesis and vascular leakage in neovascular retinal diseases

Article Title: Ocular gene therapy targeting retinal angiogenesis and vascular leakage: translational and clinical evidence from a systematic review and meta-analysis

Article References: Chen, K.-Y., Chan, H.-C., & Chan, C.-M. (2026). Ocular gene therapy targeting retinal angiogenesis and vascular leakage: translational and clinical evidence from a systematic review and meta-analysis. Angiogenesis, 29(4), Article 66. https://doi.org/10.1007/s10456-026-10050-y

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10050-y

Keywords: ocular gene therapy, retinal angiogenesis, vascular leakage, anti-VEGF, adeno-associated virus, neovascular age-related macular degeneration, diabetic retinopathy, systematic review, meta-analysis, sFLT-1, central subfield thickness, retinal disease