The value of angiogenic biomarkers in determining preeclampsia-related perinatal deaths: a cross-sectional study in a high burden setting of southern Mozambique

BackgroundEstimating the contribution of preeclampsia (PE) to perinatal mortality in low-resource settings remains difficult due to limited diagnostic capacity. Lack of specific histopathologic changes in stillbirth, foetuses and/or placenta often hampers assignment of PE as cause of death. While PE angiogenic biomarkers (sFlt-1, PlGF) predict adverse pregnancy outcomes, their post-mortem diagnostic utility is unclear. We evaluated the potential role of these biomarkers in identifying PE-related perinatal deaths. MethodsThis cross-sectional study was conducted among pregnant women who delivered a stillborn infant or experienced an early neonatal death at Maputo Central Hospital in Mozambique. Concentrations of sFlt-1, PlGF and their ratio (sFlt-1/PlGF) were assessed in maternal blood and post-mortem foetal/neonatal and placental blood. Causes of death were determined via minimally invasive tissue sampling (MITS) and diagnostic accuracy was assessed using ROC curves for standardized and optimal biomarker cut-offs. ResultsA total of 100 women with perinatal deaths (98 stillbirths and 2 early neonatal deaths) were included in the study between March 2021 and April 2022. Maternal sFlt-1/PlGF ratios showed the highest diagnostic accuracy for PE-related deaths (area under curve [AUC]=82%), followed by placental (AUC=75%) and foetal blood (AUC=61%). PlGF levels were significantly reduced in PE-associated deaths. sFlt-1/PlGF cutoffs of [≥]85 and [≥]110 in maternal and placental blood were reliable cut-offs for identifying PE-related foetal/neonatal deaths. Optimal ratio cut-offs were [≥]50 (maternal blood), [≥]230 (placental blood), and [≥]140 (foetal blood), with maternal and placental sFlt-1/PlGF ratios showing significant associations with PE-related death (OR=10.58 and 5.98 respectively). Sensitivity and specificity in maternal and placental blood were 84% and 73%, and 67% and 78%, respectively, with a positive predictive value (PPV) of 84% in both. ConclusionsMaternal and placental angiogenic biomarkers enable reliable identification of preeclampsia-related perinatal deaths and could significantly enhance cause-of-death determination in low-resource, high-burden settings. These findings underscore the potential value of biomarker measurement for both risk stratification and mortality surveillance. Research in contextO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIsFlt-1, PlGF, and their ratio, are well-established in predicting and diagnosing preeclampsia during pregnancy. C_LIO_LIHowever, their utility in identifying preeclampsia-related perinatal deaths particularly in postmortem investigations such as minimally invasive tissue sampling (MITS) samples, is underexplored. C_LI What this study addsO_LIThis study is the first to evaluate diagnostic accuracy of these biomarkers using postmortem placental and foetal/neonatal blood samples from MITS to identify preeclampsia-related perinatal deaths. C_LIO_LIWe show that maternal and placental sFlt-1/PlGF ratios can reliably identify preeclampsia-related perinatal deaths at standardized ratio cutoffs of [≥]85 and [≥]110 respectively. Whilst significantly reduced PlGF concentrations, lower placental and perinatal anthropometric measurements were hallmark features of PE-related deaths. C_LIO_LIThe study suggests optimal sFlt-1/PlGF ratio cut-offs for maternal ([≥]50) and placental ([≥]230) blood, providing robust diagnostic thresholds for use in perinatal mortality surveillance and antenatal risk stratification in high-burden settings. C_LI How this study might affect research, practice or policyO_LIThe use of preeclampsia biomarker analysis in determining causes of perinatal death offers a feasible, scalable, and objective method that may help overcome challenges in accurate cause of death attribution in LMICs. C_LIO_LIThis has important implications for mortality surveillance system monitoring and pregnancy risk assessments, where autopsy is rare and clinical records are often incomplete. C_LIO_LIIncorporating biomarker-based diagnostics into existing perinatal death investigations could significantly improve mortality data and guide targeted health interventions. C_LI