Preeclampsia is a hypertensive disorder of pregnancy associated with severe maternal and fetal complications. Typically manifesting after the 20th week of gestation, it is characterized by new-onset hypertension and proteinuria and remains a leading cause of maternal and perinatal morbidity and mortality worldwide [1]. Although its pathophysiology has not been fully elucidated, placental dysfunction, systemic inflammation, and vascular dysregulation are considered central mechanisms [2]. These interconnected processes contribute to endothelial injury, oxidative stress, and the activation of inflammatory pathways, ultimately leading to the clinical manifestations of the disease.

Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), have been extensively investigated in the context of preeclampsia, as they reflect underlying systemic inflammation and immune dysregulation [3, 4]. Among these, NLR has emerged as a particularly promising indicator, with several studies demonstrating its predictive value for disease onset and adverse maternal-fetal outcomes [3, 4, 5]. Nevertheless, while NLR and related indices offer important pathophysiological insights, they do not capture the multifactorial nature of preeclampsia, which also involves metabolic and nutritional alterations.

The Naples Prognostic Score (NPS), originally developed in oncology, integrates inflammatory (NLR, LMR) and nutritional (serum albumin, total cholesterol) parameters to predict clinical prognosis [6, 7, 8, 9, 10]. Its ability to concurrently reflect systemic inflammation, immune competence, and nutritional status makes it theoretically well-suited for assessing pregnancy-related complications, in which these physiological domains play pivotal roles. A higher NPS indicates a less favorable prognostic profile. Despite its theoretical relevance, the clinical utility of NPS in obstetric populations remains underexplored, and pregnancy-specific reference values have yet to be established.

In this study, we examined the association between mid-trimester NPS and the subsequent development of preeclampsia. We hypothesized that NPS would demonstrate clinically meaningful predictive performance and that its individual components—particularly the NLR—would independently correlate with the risk of developing preeclampsia.

The primary finding of this study is that mid-trimester NPS demonstrated a strong association with the subsequent development of preeclampsia and exhibited strong discriminative ability (AUC = 0.886). However, in multivariate modeling, the composite NPS was not retained as an independent predictor. Instead, its key inflammatory and nutritional components—elevated NLR, reduced lymphocyte count, decreased serum albumin, and lower total cholesterol—were independently associated with preeclampsia, indicating that the underlying mechanistic drivers lie within these specific pathophysiological pathways.

The central role of the NLR observed in this study is consistent with the well-established inflammatory pathophysiology of preeclampsia. Our findings identify NLR as a robust early predictor, representing the strongest independent determinant of preeclampsia (aOR = 4.127) and exhibiting good standalone diagnostic performance (AUC = 0.809). These results are consistent with previous literature. For instance, a meta-analysis by Kang et al. [3] reported that elevated NLR values are significantly associated with an increased risk of preeclampsia. Furthermore, studies evaluating second-trimester NLR for preeclampsia prediction have reported AUC values ranging from 0.75 to 0.82, which are directly comparable to our findings [4, 5]. Collectively, these data reinforce the reliability and reproducibility of NLR as a key inflammatory biomarker for early screening of preeclampsia.

Similarly, a lower LMR, another marker of systemic inflammation, was significant in our initial analyses, consistent with previous studies emphasizing the role of lymphocyte-monocyte interactions in the inflammatory cascade of preeclampsia [12]. However, its predictive power was ultimately superseded by stronger variables in the final multivariate model. More importantly, a reduced lymphocyte count (lymphopenia) was retained as an independent predictor (aOR = 0.266), highlighting the immune dysregulation central to the pathogenesis of preeclampsia. This relative decline in lymphocytes, together with systemic neutrophil activation, shifts the immune balance toward the pro-inflammatory state characteristic of the disease.

The observed association between low serum albumin levels and increased preeclampsia risk (aOR = 0.412) may reflect not only potential nutritional insufficiency but also increased vascular permeability and subclinical protein loss that precede the clinical onset of proteinuria. Conversely, the finding of lower total cholesterol contrasts with some reports in established preeclampsia. Possible explanations include sampling during the mid-trimester—prior to the full metabolic adaptations of late pregnancy—differences in cohort characteristics, and the use of non-pregnancy-specific NPS cutoffs. We acknowledge this limitation as important and emphasize the need to establish and validate pregnancy-specific thresholds in future research.

From a clinical perspective, the NPS is appealing as a well-established prognostic tool originally developed and extensively validated in oncology to capture systemic inflammation and nutritional status [7, 8, 9, 10]. Its potential utility in obstetrics stems from the same principle—it integrates routine, low-cost laboratory parameters obtainable during the 20–24-week visit, thereby offering an accessible approach for risk stratification. NPS may also serve as a complementary screening method in settings where assays such as the soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio are unavailable or cost-prohibitive. We emphasize that NPS should be considered a screening rather than a diagnostic tool until further external validation and pregnancy-specific cutoff values are established.

The clinical applicability of NPS should be considered within the broader context of existing first- and second-trimester screening modalities for preeclampsia. The search for reliable blood-based biomarkers to predict preeclampsia remains a major focus of ongoing research, and our findings contribute to this growing body of evidence [13, 14, 15, 16]. Biomarkers such as the sFlt-1/PlGF ratio and uterine artery Doppler velocimetry have demonstrated strong predictive performance, particularly for early-onset preeclampsia [17]. However, their widespread implementation is often limited by cost, the need for specialized equipment, and operator expertise—constraints that are especially relevant in resource-limited settings.

In contrast, the NPS is derived from parameters routinely measured in standard antenatal care, including the complete blood count and basic biochemical profile. Thus, NPS should not be considered a replacement for established biomarkers such as the sFlt-1/PlGF ratio, but rather a potentially valuable, universally accessible, and cost-effective first-line tool for risk stratification. Its simplicity and accessibility could facilitate broader population-level screening to identify women at increased risk who may benefit from closer monitoring or advanced testing. Future prospective studies are warranted to directly compare the predictive performance of NPS with that of established obstetric biomarkers.

Mid-trimester NPS is significantly associated with the subsequent development of preeclampsia and demonstrates good screening performance. Its independent predictive value appears to derive primarily from its inflammatory and nutritional components—particularly the NLR—highlighting their mechanistic relevance in disease pathogenesis. Following validation with pregnancy-specific thresholds and in external cohorts, NPS may serve as a practical, noninvasive, and cost-effective screening tool for early identification of women at increased risk of preeclampsia.

Datasets are available from the corresponding author upon reasonable request.

Conceptualization: TKK, YK; Data curation: YK; Formal analysis/Statistics: TKK; Methodology: TKK; Writing—original draft: TKK; Writing—review & editing: TKK, YK; Supervision: YK. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Approved by the Giresun University Ethics Committee for Human Research (Approval number: 30/10/2024-147). The study complied with the Declaration of Helsinki; informed consent was waived due to the retrospective design.

We thank the peer reviewers for their constructive comments and the clinical records team for assistance with data retrieval.

This research received no external funding.

The authors declare no conflict of interest.