Infertility is defined as the inability of a couple to achieve pregnancy after engaging in unprotected regular sexual intercourse for a year or longer, necessitating medical intervention for diagnosis and treatment. It affects around 15–25% of couples worldwide, and a significant portion of cases are classified as unexplained infertility (UI), where standard diagnostic procedures fail to identify clear causes [1, 2]. Despite the availability of advanced diagnostic tools, UI remains a significant challenge, highlighting the need for innovative prognostic tools to predict and improve the outcomes of treatments like in-vitro-fertilization (IVF) [3, 4].

The prognostic nutritional index (PNI), originally evaluates cancer patients’ nutrition and immune condition, has recently been studied for its potential to predict outcomes in various medical fields, including reproductive medicine [5, 6]. It combines serum albumin and lymphocyte measurements, which reflect nutrition status and systemic function, two factors critical to reproductive health [7]. Incorporating systemic markers into IVF outcomes can improve the accuracy of predicting IVF success and personalize treatment approaches, potentially reducing the physical, emotional, and financial burden associated with infertility treatments [8]. In that term, novel researches are expected to explain the interplay between overall health and reproductive success, offering a new framework in reproductive medicine [9, 10]. Ultimately, this could lead to more comprehensive treatment approaches that address the reproductive system and other aspects of patients’ overall health.

This study examined the PNI and inflammatory hematological parameters in non-obese couples undergoing IVF for UI by assessing embryo quality. By focusing on this well-defined group of participants, the research aimed to establish the relationship between these systemic markers and IVF success rates, with the hypothesis that optimal PNI scores and balanced hematological parameters are associated with improved reproductive outcomes.

The study focused on the significance of PNI and hematological inflammatory profiles in forecasting the outcomes of IVF interventions among non-obese couples who are grappling with unexplained infertility. Optimum nutritional and immunological status, gauged by well-balanced hematological parameters and PNI, is strongly linked to enhanced embryo quality and IVF triumph. These observations corroborate the considerable influence of overall health on reproductive outcomes and suggest that incorporating comprehensive health assessments could fortify patient classification and tailor treatment strategies within reproductive medicine.

In the context of IVF, immune inflammation is critical in the prognosis of multiple cancers and reproductive medicine. A 2024 cohort study of women undergoing IVF with a gonadotropin-releasing hormone (GnRH) antagonist protocol found that elevated SII values were significantly associated with poorer outcomes—including lower biochemical pregnancy, clinical pregnancy, implantation, and live birth rates—even after adjusting for age, BMI, AMH, and stimulation parameters. Notably, women in the highest SII quartile had the worst IVF outcomes, suggesting that a higher pre-IVF inflammatory state may negatively impact implantation and pregnancy success [14]. Indices such as PNI, SIRI, and SII [15]—typically studied within the framework of oncological research—offer information about the immune and nutritional factors that affect IVF. PNI effectively combines albumin with lymphocytes and reflects an individual’s nutrition and immunological status [16]. The immune environment of the endometrium holds considerable sway over the success rate of embryo implantation. Lymphocytes are pivotal in maintaining the immune equilibrium required for successful implantation and early pregnancy [9, 17].

SIRI and SII—a systemic inflammation marker derived from platelet, neutrophil, and lymphocyte counts in peripheral blood—may possess relevant implications for reproductive health assessment [18, 19]. Elevated systemic inflammation levels, denoted by a high SII, can unfavorably impact ovarian function, embryo quality, and endometrial receptivity [19]. In a 2024 retrospective cohort, investigators evaluated various baseline inflammatory markers [including NLR, platelet count, PLR, C-reactive protein (CRP), etc.] in IVF patients [20]. They found that lower NLR was strongly predictive of successful pregnancy outcomes after IVF. In multivariate analysis, NLR emerged as an independent predictor of achieving pregnancy with higher NLR associated with decreased odds of pregnancy, whereas other markers like PLR or CRP did not retain independent. NLR is a robust prognostic indicator for IVF success, reinforcing the idea that a lower systemic inflammatory state lower NLR favors implantation. Another research published on UI provides insight into immune-nutritional indices in IVF. That study reported that higher levels of systemic inflammation indices were associated with poorer oocyte and embryo development in IVF. Women with elevated SII/SIRI had higher rates of embryo arrest and required higher gonadotropin doses, indicating an adverse intra-ovarian environment [21].

As an index, PNI was validated as a prognostic potential in oncology studies [19, 22]. However, their potential role in predicting IVF success brings about an intriguing convergence of nutrition, inflammation, and reproductive medicine. In our analysis, PNI demonstrated noteworthy variations, while most biochemical markers did not exhibit significant differences across groups. The decline in PNI from high to low embryo quality implies a direct association between nutritional and immunological well-being and embryo viability. Our regression analyses supported this inverse relationship between PNI and embryo quality, indicating that a lower PNI, indicative of inferior nutritional and immune status, is linked to diminished embryo quality. This index may be attributed to the pivotal functions of albumin and lymphocytes, components of PNI, in establishing a favorable physiological environment for embryo implantation and development.

Moreover, our stepwise regression models demonstrate the robust predictive capacity of PNI in comparison to other inflammatory indices. The NLR, MLR, SII, SIRI, and PLR failed to meet the inclusion criteria due to limited explanatory power, underscoring the utility of PNI as a comprehensive and predictive index for IVF outcomes. The logistic regression findings further corroborate the significant impact of embryo quality on PNI classifications. Because PNI was measured on the day of oocyte retrieval and therefore precedes embryo assessment, the observed association indicates that lower PNI reflects a less favorable nutritional and immune profile that is subsequently linked with poorer embryo quality—rather than embryo quality exerting any influence on PNI. From a clinical standpoint, monitoring it could be helpful to as a valuable tool for embryo quality and comprehending the overall health status of IVF patients.

The primary strength of this study lies in its systematic approach to investigating the interplay between nutritional and immunological statuses represented by PNI and their influence on IVF outcomes. Our findings underscore the intrinsic connection between systemic health and reproductive success by controlling for confounding and comorbidities. However, it is important to acknowledge several limitations. One limitation of our model is the exclusion of hormone levels measured on the trigger day, such as serum estradiol or LH, which may have potential predictive value. These parameters were not available for all cases, limiting their inclusion in a multivariate framework. Longitudinal studies would better determine the temporal relationship and causal pathways. Additionally, while we controlled for various demographic and clinical variables, other unmeasured confounders may impact nutritional and reproductive outcomes, including lifestyle factors, dietary habits, or genetic predispositions. Given that prolactin levels showed no statistically significant variation among the embryo-quality groups, the current findings do not support any inference about its regulatory or predictive relevance in this context. It is also important to note that the study population may not represent all IVF patients, potentially limiting the generalizability. Future longitudinal studies are necessary to investigate the long-term effects of PNI on pregnancy success, neonatal health, and live birth outcomes, which would broaden the clinical relevance.

The study underscored PNI in monitoring the outcomes of IVF treatments among non-obese couples experiencing unexplained infertility. PNI was directly correlated with embryo quality, and a low PNI, indicative of poor nutritional and immune status, was associated with reduced embryo quality. In contrast, other inflammatory indices such as NLR, MLR, SII, SIRI, and PLR exhibited limited effectiveness compared to the potential of PNI. Clinically, monitoring PNI can serve as a valuable and predictive parameter for analysis of embryo quality and understanding the overall health status of IVF patients.

The data supporting the findings are available from the corresponding author upon reasonable request.

AY, TG and HCO designed and conceptualized the study, as well as conducted data collection and analysis. AY prepared the initial manuscript draft, while TG and HCO reviewed and approved the final version. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

IRB Registration: Reviewed and approved by the Non-Interventional Research Ethics Committee of Bezmialem University. The ethical approval number is E-54022451-050.04-153868, dated 10 June 2022. Informed consent was obtained from all participants included in the study. The study was carried out in accordance with the guidelines of the Declaration of Helsinki.

Not applicable.

This research received no external funding.

The authors declare no conflicts of interest.

During the preparation of this manuscript, the authors utilized ChatGPT-3.5 solely for grammar and language polishing. The authors thoroughly reviewed, edited, and revised the manuscript and take full responsibility for its content.