Ischemic placental disorders (IPDs), particularly pre-eclampsia and fetal growth restriction (FGR), are major contributors to maternal and perinatal morbidity and mortality worldwide. These conditions are associated with abnormal placentation, impaired uteroplacental blood flow, and inadequate delivery of oxygen and nutrients to the developing fetus. Although pre-eclampsia and FGR have distinct clinical manifestations, they share several underlying pathophysiological mechanisms, particularly defective trophoblastic invasion, inadequate remodelling of the maternal spiral arteries, increased uteroplacental vascular resistance, and placental dysfunction. The consequences of these abnormalities extend beyond pregnancy, contributing to adverse maternal cardiovascular outcomes and long-term health risks in affected offspring. Early identification of pregnancies at increased risk of ischemic placental disorders is therefore essential to facilitate timely preventive interventions, optimise antenatal surveillance, and improve maternal and fetal outcomes. Despite advances in obstetric imaging, biochemical testing, and predictive modelling, the accurate and early prediction of these conditions remains challenging, highlighting the need for further research into reliable, accessible, and clinically applicable screening strategies ^[1].

Pre-eclampsia is a multisystem hypertensive disorder of pregnancy that remains a leading cause of preventable maternal and perinatal morbidity and mortality in both developed and developing countries. It can result in severe maternal complications, including eclampsia, stroke, pulmonary oedema, acute kidney injury, hepatic dysfunction, and HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count). In addition, pre-eclampsia is frequently associated with medically indicated preterm birth, placental abruption, fetal growth restriction, and stillbirth. The clinical course can vary considerably, with early-onset disease often associated with more pronounced placental dysfunction and adverse perinatal outcomes. Importantly, the clinical manifestations of pre-eclampsia generally appear after the underlying placental abnormalities have developed. Consequently, relying exclusively on blood pressure measurement and conventional clinical symptoms may limit opportunities for early intervention. Predicting the likelihood of pre-eclampsia during the first trimester may enable the identification of high-risk pregnancies before the onset of clinical disease and provide an opportunity to initiate preventive measures, including low-dose aspirin in eligible women, alongside appropriate maternal and fetal surveillance ^[2][3].

Fetal growth restriction is another important manifestation of placental dysfunction and is associated with substantial perinatal morbidity and mortality. It refers to the failure of a fetus to achieve its genetically determined growth potential, commonly because of placental insufficiency, although maternal, fetal, and genetic factors may also contribute. In pregnancies complicated by placental insufficiency, inadequate uteroplacental perfusion compromises the transfer of oxygen and nutrients, resulting in impaired fetal growth and, in severe cases, fetal hypoxaemia, stillbirth, or neonatal complications. FGR is also associated with preterm delivery, prolonged neonatal intensive care unit (NICU) admission, increased healthcare expenditure, and potential long-term neurodevelopmental and cardiometabolic consequences. Early identification of pregnancies at risk of FGR can facilitate serial fetal growth assessment, Doppler surveillance, appropriate timing of delivery, and preparation for neonatal care. However, distinguishing pathological FGR from constitutionally small fetuses remains a clinical challenge, reinforcing the importance of combining maternal characteristics, placental biomarkers, and ultrasonographic findings to improve prediction ^[4][5].

Maternal history and clinical risk assessment remain fundamental components of screening for ischemic placental disorders. Factors such as a previous history of pre-eclampsia, FGR, stillbirth, or other placenta-mediated complications; chronic hypertension; pre-existing diabetes mellitus; renal disease; autoimmune disorders; obesity; and advanced maternal age may increase the likelihood of adverse pregnancy outcomes. Parity, conception through assisted reproductive techniques, and relevant family and obstetric histories may also contribute to risk assessment. Although these characteristics are readily available and inexpensive to obtain, history-based screening alone has limited predictive accuracy. A substantial proportion of women who develop pre-eclampsia or FGR may not have recognisable conventional risk factors, while many women classified as high risk will have uncomplicated pregnancies. Therefore, maternal characteristics are most useful when integrated with objective biochemical and ultrasonographic parameters in a comprehensive prediction model ^[6].

First-trimester ultrasonography provides an opportunity to assess early placental development and identify pregnancies with an increased likelihood of subsequent placental dysfunction. Uterine artery Doppler assessment, particularly measurement of the uterine artery pulsatility index (UtA-PI), is an important component of this approach. An elevated UtA-PI may reflect increased resistance to blood flow in the uteroplacental circulation, potentially indicating inadequate trophoblastic invasion and incomplete remodelling of the spiral arteries. When measured during the first trimester, UtA-PI can contribute to the prediction of pre-eclampsia and FGR before their clinical manifestations become apparent. Nevertheless, its predictive performance depends on factors such as gestational age, measurement technique, operator expertise, and the characteristics of the population being screened. Consequently, uterine artery Doppler findings should be interpreted alongside maternal risk factors and biochemical markers rather than used as an isolated screening test ^[7][8].

Biochemical biomarkers associated with placental development, angiogenesis, and function have received considerable attention as potential predictors of ischemic placental disorders. Placental growth factor (PlGF), a member of the vascular endothelial growth factor family, plays an important role in placental angiogenesis and vascular development. Reduced maternal serum PlGF concentrations have been associated with impaired placental function and an increased risk of pre-eclampsia, particularly disease requiring early delivery. Pregnancy-associated plasma protein-A (PAPP-A), a placentally derived protein involved in the regulation of insulin-like growth factors, is another biomarker of interest. Low first-trimester PAPP-A concentrations have been associated with adverse pregnancy outcomes, including FGR, pre-eclampsia, and stillbirth, although its predictive performance as a standalone marker is limited. The soluble fms-like tyrosine kinase-1 (sFlt-1), an antiangiogenic factor, is also relevant to the pathogenesis of pre-eclampsia. An imbalance between angiogenic and antiangiogenic factors contributes to endothelial dysfunction and the clinical manifestations of the disorder. Although the sFlt-1/PlGF ratio is particularly useful in the assessment of suspected pre-eclampsia later in pregnancy, its role and performance in early pregnancy prediction differ from those of first-trimester screening markers.

Other biomarkers reflecting placental development, inflammation, oxidative stress, and vascular function may provide additional predictive information. However, their clinical utility depends on reproducibility, availability, cost, and the ability to improve risk classification beyond established predictors. The term "Agly" in the proposed biomarker panel requires clarification before inclusion in a research protocol, as it may refer to a specific analyte or an abbreviation that needs to be defined. Standardised nomenclature, validated laboratory methods, and prespecified thresholds are essential to ensure that biomarker findings can be interpreted reliably and compared across studies.

Given the multifactorial nature of ischemic placental disorders, combining maternal characteristics, uterine artery Doppler indices, and biochemical biomarkers may provide more accurate prediction than any individual parameter. Multimarker screening models integrate information from different biological pathways and may improve discrimination between pregnancies that will and will not develop adverse placental outcomes. First-trimester algorithms incorporating maternal factors, mean arterial pressure, UtA-PI, and PlGF have demonstrated clinical utility in identifying pregnancies at increased risk of preterm pre-eclampsia. The addition of PAPP-A and other relevant biomarkers may offer further value in selected populations, although the incremental benefit should be evaluated rather than assumed. Importantly, predictive models developed in one population may not perform equally well in another because of differences in maternal characteristics, disease prevalence, healthcare access, ethnicity, and clinical practices. Validation in the intended population is therefore essential before routine implementation.

Despite considerable progress, several research gaps remain in the early prediction of ischemic placental disorders. These include the need to establish population-specific reference ranges, determine the independent and combined predictive value of candidate biomarkers, standardise Doppler measurements, and evaluate the sensitivity, specificity, calibration, and clinical utility of multimarker algorithms. Research should also examine whether such models improve maternal and perinatal outcomes when integrated into routine antenatal care and whether their implementation is cost-effective in resource-constrained settings. The feasibility of incorporating these screening approaches into existing first-trimester antenatal services is particularly important in countries with a high burden of maternal and neonatal complications.

In conclusion, the prediction of ischemic placental disorders represents an important opportunity to improve pregnancy outcomes through early risk stratification and targeted preventive care. Pre-eclampsia and FGR share important placental pathophysiological mechanisms, making a combined approach to their prediction scientifically relevant and clinically valuable. Maternal history, first-trimester ultrasonography, uterine artery Doppler assessment, and biomarkers such as PlGF and PAPP-A offer complementary information about maternal risk, placental vascular resistance, and placental function. Integrating these parameters into a validated multimarker model may improve the early identification of pregnancies at risk of placental ischemic complications. Further prospective research is required to establish the optimal combination of predictors, validate their performance in diverse populations, and demonstrate that their use leads to meaningful improvements in maternal and perinatal outcomes.