Preeclampsia (PE) is one of the most significant hypertensive conditions unique to pregnancy, affecting roughly 2%−8% of pregnancies worldwide (1). It remains a major driver of maternal death, serious complications, early delivery, fetal growth restriction, and long-term cardiovascular risk for both mothers and their children (2). Despite extensive research, PE continues to pose difficulties for clinicians because its onset is hard to predict, its symptoms vary widely, and its biological mechanisms are multifactorial (3). Traditionally, PE is diagnosed when a pregnant individual develops new hypertension after 20 weeks of gestation, along with proteinuria or evidence of maternal organ dysfunction (4). Increasingly, however, it is viewed as a syndrome encompassing several distinct subtypes, such as early-onset and late-onset forms, as well as placental, immune-related, and metabolic phenotypes (5).

The prevailing model describes PE as developing through two major stages (6). The first involves inadequate trophoblast invasion and poor remodeling of the uterine spiral arteries, which leads to defective placentation and persistent placental hypoxia (6). The second stage reflects the maternal response to this placental stress—characterized by endothelial dysfunction, oxidative stress, exaggerated inflammatory activity, and imbalanced angiogenic signaling (6, 7). These disturbances culminate in the clinical features of hypertension and multi-organ involvement. Even with this framework, PE remains highly diverse, influenced by maternal genetics, immune adaptation, cardiometabolic health, and environmental factors (1).

Since the condition can only be resolved after delivery of the placenta, prevention is essential. Low-dose aspirin (LDA) is currently the only pharmacological measure with consistent evidence for lowering PE risk in individuals considered high-risk (8). However, many eligible patients either show limited benefit or still develop PE despite prophylaxis (9–12). Growing research suggests that maternal genetic variations, platelet activity profiles, and angiogenic biomarkers may affect both predisposition to PE and responsiveness to LDA (13).

This article is a narrative review synthesizing translational, observational, and mechanistic studies; it is not a systematic review. Literature was identified through targeted searches of PubMed and EMBASE focusing on aspirin, preeclampsia, genetic, platelet, and angiogenic biomarkers.

Low-dose aspirin (LDA) is currently the most effective and widely recommended pharmacologic strategy to decrease the risk of preeclampsia, particularly forms that develop early in pregnancy (14). Its primary action involves the selective, irreversible inhibition of platelet cyclooxygenase-1 (COX-1), which lowers the production of thromboxane A₂ (TxA₂)—a molecule that promotes vasoconstriction and platelet aggregation. At low doses, aspirin spares endothelial cyclooxygenase activity, allowing continued production of prostacyclin (PGI₂), a vasodilator that counteracts platelet activation (15). By restoring the TxA₂/PGI₂ balance, LDA supports healthier uteroplacental blood flow (15).

Clinical trials and meta-analyses consistently support its benefit (15–17). The ASPRE trial demonstrated that starting 150 mg of aspirin before 16 weeks' gestation in women identified as high risk reduced the incidence of early-onset PE by more than 60% (18). Earlier pooled analysis reported an overall reduction of roughly 10%−20% in PE onset, with the most pronounced benefit occurring when treatment begins between 11 and 16 weeks, coinciding with the critical period of spiral artery remodeling (19). This suggests that aspirin may exert its primary protective effect by influencing placental development and attenuating inflammation before irreversible pathology occurs (20).

Despite strong evidence for its use, several issues complicate optimal implementation. International organizations offer differing recommendations: ACOG advises 81 mg daily, whereas FIGO and NICE suggest doses between 100 and 150 mg (21). Additionally, the standard single-dose approach does not address the considerable variability in how individuals process and respond to aspirin. Factors such as maternal body mass index, platelet turnover, genetic variants affecting aspirin metabolism, and preexisting platelet hyperactivity can all alter the degree of COX-1 inhibition achieved (22).

Such variability contributes to the problem of “aspirin resistance,” observed in up to one-third of high-risk pregnancies (23). Persistent platelet activity despite LDA use is associated with a heightened risk of PE, implying that fixed dosing may not be appropriate for all patients. Higher doses—typically 100–150 mg—have been proposed for individuals with elevated BMI or increased platelet activation, yet these strategies are not consistently incorporated into clinical guidelines (24).

Another major challenge is accurately identifying who will benefit most from prophylaxis. Current recommendations are based largely on clinical risk factors such as prior PE, chronic hypertension, diabetes, or multifetal gestation (25). Although useful, these criteria have limited predictive accuracy: many individuals who develop PE are not classified as high risk, while some who are deemed high risk never develop the disease. Incorporating biomarkers—particularly angiogenic markers and platelet function assays—may strengthen prediction models and support more targeted aspirin use (26). In summary, while LDA remains central to PE prevention, its effectiveness is constrained by uniform dosing approaches and broad inclusion criteria. Integrating genetic, biochemical, and physiological markers into clinical decision-making could refine aspirin prophylaxis and enable a shift toward personalized prevention strategies (27). However, no randomized trials have demonstrated improved outcomes using biomarker-guided aspirin dosing in pregnancy.

Genetic variation plays a significant role in both the development of preeclampsia (PE) and the differing responses to low-dose aspirin among pregnant individuals. PE is known to have a heritable component, with contributions from maternal, fetal, and paternal genomes. Large genomic studies, such as GWAS, have identified numerous loci linked to angiogenic signaling, immune modulation, endothelial function, and placental biology (28). Variants in genes such as FLT1, HLA-G, ENG, ACVR2A, and FGG have been associated with impaired placental vascularization, increased inflammatory activity, and disruptions in immune tolerance—key elements of PE pathogenesis (29, 30).

Genetic differences may also influence how effectively aspirin prevents PE. Since aspirin works through irreversible COX-1 inhibition, polymorphisms in the PTGS1 gene can reduce platelet sensitivity to aspirin and lead to incomplete thromboxane suppression (31). Variants in platelet receptor genes, such as ITGA2 and GP1BA, may heighten baseline platelet activity, meaning higher or earlier dosing could be needed to achieve adequate inhibition (32).

Polymorphisms in enzymes such as CES1 and PON1, which help hydrolyze aspirin, can modulate how quickly the drug is converted into salicylic acid, thereby influencing systemic exposure and effectiveness (33). Genetic differences in endothelial and oxidative stress pathways—for example, NOS3 variants—may further modify aspirin's impact on vascular function (33).

Growing research suggests that genetics may help determine which patients benefit most from LDA. Certain FLT1 or HLA-G alleles are associated with unique angiogenic patterns and distinct PE risk profiles, which may alter responsiveness to antiplatelet therapy (34). Although routine genetic testing is not yet clinically recommended, incorporating polygenic risk scores, platelet-related genotypes, and placental gene expression signatures may ultimately enhance risk stratification. These findings support further investigation into genetically informed prevention strategies; however, routine genetic testing to guide aspirin use is not currently recommended and remains a research priority (35).

Platelet activation plays a key role in the development of preeclampsia (PE) and contributes to interindividual variability in response to low-dose aspirin (LDA) (22). In PE, heightened platelet reactivity—driven by increased thromboxane A₂ production, systemic inflammation, and endothelial dysfunction—promotes vasoconstriction, impaired placental perfusion, and activation of coagulation pathways (15). Platelet-related biomarkers, therefore, provide mechanistic insight into PE pathophysiology and aspirin pharmacodynamics; however, their role in guiding clinical management during pregnancy remains investigational (22).

Disruption of angiogenic balance is a central feature of preeclampsia (PE), making angiogenic biomarkers—particularly soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)—important tools for understanding placental dysfunction. sFlt-1 acts as a decoy receptor that reduces circulating vascular endothelial growth factor (VEGF) and PlGF, impairing angiogenic signaling and contributing to widespread endothelial dysfunction (46). In contrast, PlGF supports placental vascular development and maternal cardiovascular adaptation. The sFlt-1/PlGF ratio is an established marker of placental health and is widely used for diagnosis and prognosis of PE later in pregnancy, particularly for predicting early-onset disease (46, 47).

Bringing biological insights into clinical practice represents the next major step in optimizing aspirin use for PE prevention. A personalized prevention model combines maternal clinical risk factors with genetic predisposition, platelet function profiles, and angiogenic biomarker data, creating a more dynamic and individualized approach rather than applying a uniform dosing strategy to all patients. Figure 1 provides an integrated conceptual model in which genetic markers (e.g., F2/F5/PTGS1 variants), platelet function indices, and angiogenic biomarkers (such as PlGF and sFlt-1) collectively inform individualized decisions regarding aspirin initiation, dosage adjustment, and monitoring throughout pregnancy.

Translating biological insights into improved prevention strategies represents an important goal in preeclampsia (PE) research. Integrative approaches that combine maternal clinical risk factors with genetic, platelet, and angiogenic biomarkers have been proposed as a means of better understanding interindividual variability in aspirin responsiveness. The framework described below is presented as a conceptual model to illustrate potential future research directions rather than a clinical decision-making algorithm. Figure 1 depicts this integrative model, in which genetic markers (e.g., F2, F5, PTGS1 variants), platelet function indices, and angiogenic biomarkers (such as PlGF and sFlt-1) are considered alongside clinical risk factors to generate hypotheses regarding heterogeneity in aspirin response.

Personalized aspirin strategies offer significant potential, but several challenges remain to their widespread adoption. A major hurdle is the lack of standardization for biomarkers like sFlt-1, PlGF, and platelet aggregation (54, 55). Assay variability and inconsistent cut-off values across different labs complicate their use in clinical settings. Establishing validated thresholds through large multicenter studies is essential for reliable application in decision-making.

Low-dose aspirin remains the cornerstone of pharmacological prevention for preeclampsia in pregnancies identified as high risk using established clinical criteria. Growing interest in genetic, platelet, and angiogenic biomarkers reflects recognition of the biological heterogeneity underlying both preeclampsia pathogenesis and variability in aspirin responsiveness. This narrative review highlights the potential of these biomarkers to enhance mechanistic understanding and to inform future research aimed at refining risk stratification and preventive strategies.

However, current evidence supporting biomarker-guided approaches to aspirin prophylaxis is predominantly derived from mechanistic studies, genetic association analyses, and observational cohorts. Genetic profiling and platelet function testing lack validation in pregnant populations, standardized thresholds, and randomized evidence, demonstrating improved maternal or perinatal outcomes. Similarly, while angiogenic biomarkers have an established diagnostic and prognostic role later in pregnancy, their use for first-trimester risk stratification and for guiding aspirin initiation or dose modification remains investigational.

Importantly, no randomized controlled trials have evaluated biomarker-guided aspirin dosing or monitoring strategies in pregnancy. Until such evidence becomes available, the use of aspirin for preeclampsia prevention should continue to follow current guideline-based recommendations regarding patient selection, timing, and dosage. Biomarker-informed strategies should be regarded as a future research direction rather than a component of routine clinical care.

Future studies should prioritize well-designed prospective cohorts and randomized trials to evaluate whether integrating biomarkers with clinical risk assessment can meaningfully improve outcomes without increasing harm. Such evidence will be essential before precision-based approaches to aspirin prophylaxis can be responsibly translated into clinical practice.