Association of Systemic Inflammation Markers with Early Pregnancy Loss in the First Trimester: A Retrospective Study

Association of Systemic Inflammation Markers with Early Pregnancy Loss in the First Trimester: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of Systemic Inflammation Markers with Early Pregnancy Loss in the First Trimester: A Retrospective Study Cem Inceoglu, Refaettin Sahin, Veysel Tahiroglu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6779110/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This study aimed to investigate whether hematologic inflammatory markers derived from routine complete blood count (CBC) are associated with early pregnancy loss during the first trimester. Methods In this retrospective case-control study, 217 women diagnosed with missed abortion and 192 healthy pregnant women who gave birth at term were included. Data were obtained from patient records at the Obstetrics and Gynecology Clinic of Sirnak State Hospital between January 2022 and April 2025. Inflammatory indices—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)—were calculated from CBC parameters and compared between the groups. Results Gravida, parity, and body mass index (BMI) were significantly higher in the missed abortion group (p < 0.001), while maternal age and gestational week showed no significant difference. Hematologic parameters, including hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, and platelets, were significantly elevated in the missed abortion group (p < 0.05). Inflammatory markers such as NLR, SII, SIRI, and AISI were significantly higher in this group, while PLR showed no statistical difference (p = 0.128). Among these, SII (AUC = 0.74), SIRI (AUC = 0.73), and AISI (AUC = 0.67) demonstrated the strongest discriminative performance in ROC analysis. Conclusion First-trimester inflammatory indices, particularly SII, SIRI, and AISI, may serve as accessible, low-cost biomarkers for identifying pregnancies at risk of early loss. Further prospective studies are needed to validate their clinical utility. Early pregnancy loss systemic inflammation SIRI AISI SII missed abortion Figures Figure 1 Introduction Early pregnancy loss (EPL) is defined as the absence of embryonic or fetal cardiac activity within the intrauterine gestational sac before 12 weeks of gestation. It is a common obstetric complication, affecting approximately 10% of all clinically recognized pregnancies, with nearly 80% of these losses occurring in the first trimester [[ 1 ],[ 2 ]]. In addition to the emotional burden it places on couples, EPL also presents significant clinical challenges in early pregnancy management. The etiology of early pregnancy loss is multifactorial, involving genetic abnormalities, infections, endocrine dysfunctions, anatomical anomalies, and immune-related implantation failures. However, in up to 40% of cases, the exact cause remains unknown [[ 3 ],[ 4 ]]. Recently, increasing evidence has highlighted the potential role of systemic inflammation in the pathogenesis of EPL [ 5 ]. Inflammatory processes play a crucial role in embryo implantation, trophoblastic invasion, and the development of the placenta. An imbalance in maternal immune response—either insufficient or exaggerated—may disrupt these processes and lead to adverse pregnancy outcomes. Therefore, inflammatory markers derived from routine hematological parameters have gained attention as possible predictors of EPL. Complete blood count (CBC)-based indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) are considered indirect indicators of systemic inflammation. These indices are advantageous because they are inexpensive, easily accessible, and non-invasive tools widely available in clinical practice [[ 6 ],[ 7 ]]. While such inflammatory markers have been evaluated in conditions like preeclampsia, gestational diabetes, intrahepatic cholestasis, and gynecological malignancies, their diagnostic value in early pregnancy loss remains underexplored. This study aims to investigate the association between first-trimester CBC-derived inflammatory markers and early pregnancy loss, to identify potential biomarkers that may assist in early detection. In light of this information, our study aimed to evaluate the potential of inflammation markers obtained from complete blood count results to predict early pregnancy loss in first trimester pregnant women. In this way, it is aimed to identify pregnancies at risk of miscarriage at an early stage and to determine appropriate clinical approaches. Materials and Methods This retrospective case-control study was conducted at the Obstetrics and Gynecology Clinic of Sirnak State Hospital, Turkey, between January 1, 2022, and April 1, 2025. Ethical approval was obtained from the Ethics Committee of Sirnak University (Approval No: 130554 − 050.04.-E.74546226), and all procedures complied with the Declaration of Helsinki. Institutional permission was granted prior to data collection. The study included pregnant women aged 18–45 years. The case group comprised 217 women diagnosed with early pregnancy loss (EPL), defined as the absence of fetal cardiac activity in an intrauterine gestational sac before 12 weeks of gestation. The control group included 192 healthy pregnant women who delivered at term (≥ 37 weeks) without obstetric complications. Exclusion criteria were multiple gestation, recurrent miscarriage, infertility, thrombophilia, systemic disease, uterine anomalies, chronic medication use, active smoking, and pregnancy-related complications. Demographic and clinical data—including age, gravidity, parity, gestational age at assessment, and body mass index (BMI)—were extracted from hospital records. Hematological parameters were obtained from venous blood samples collected in K3-EDTA tubes. In the case group, samples were drawn at the time of EPL diagnosis; in the control group, during the first antenatal visit following confirmation of fetal viability. Analyses were performed within 15 minutes using an automated hematology analyzer. From complete blood count data, inflammation-based indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII = platelet count × neutrophil count/lymphocyte count), systemic inflammation response index (SIRI = neutrophil count × monocyte count / lymphocyte count), and aggregate index of systemic inflammation (AISI = neutrophil count × monocyte count × platelet count/lymphocyte count). Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation or median with interquartile range, depending on distribution. Normality was assessed using the Kolmogorov–Smirnov test. Group comparisons were made using the independent samples t-test or Mann–Whitney U test as appropriate. Diagnostic performance of the inflammatory indices was evaluated using receiver operating characteristic (ROC) analysis, and area under the curve (AUC), sensitivity, specificity, and optimal cut-off values were reported. A two-tailed p-value < 0.05 was considered statistically significant. Results A total of 409 pregnant women met the inclusion criteria and were analyzed in this study. Of these, 217 constituted the missed abortion group, and 192 comprised the healthy control group who delivered at term. The two groups were similar in terms of maternal age, with no statistically significant difference observed (29.65 ± 5.39 vs. 30.31 ± 6.23 years; p = 0.312). However, the missed abortion group had significantly higher obstetric history markers. Gravidity (2.87 ± 1.69 vs. 1.42 ± 0.50; p < 0.001) and parity (1.27 ± 1.27 vs. 0.15 ± 0.36; p < 0.001) were both elevated in the EPL group. Similarly, mean body mass index (BMI) was significantly higher in women who experienced early pregnancy loss (27.82 ± 4.78 vs. 26.10 ± 3.65 kg/m²; p < 0.001). Gestational age at evaluation, however, did not differ significantly between groups (8.95 ± 2.28 vs. 9.02 ± 1.68 weeks; p = 0.401), indicating that the timing of clinical assessment was comparable, are shown in Table 1 . Table 1 Demographic and Clinical Parameters Parameter Missed Abortion (Mean ± SD) Missed Abortion (Median [min–max]) Control (Mean ± SD) Control (Median [min–max]) p-value Age 29.65 ± 5.39 29.0 [20, 45] 30.31 ± 6.23 30.0 [19, 43] 0.312 Gravida 2.87 ± 1.69 3.0 [ 1 , 10 ] 1.42 ± 0.50 1.0 [ 1 , 2 ] < 0.001 Parity 1.27 ± 1.27 1.0 [0, 5] 0.15 ± 0.36 0.0 [0, 1] < 0.001 BMI 27.82 ± 4.78 27.0 [20, 45] 26.10 ± 3.65 26.0 [18, 42] < 0.001 Gestational Week 8.95 ± 2.28 9.0 [ 4 , 12 ] 9.02 ± 1.68 9.0 [ 6 , 12 ] 0.401 Comprehensive hematological evaluation revealed several significant differences between the groups. Women in the missed abortion group exhibited higher levels of hemoglobin (12.27 ± 1.32 vs. 10.17 ± 1.21 g/dL; p < 0.001), white blood cell count (9.75 ± 2.67 vs. 8.04 ± 2.34 ×10³/mm³; p < 0.001), and platelet count (264.47 ± 64.52 vs. 236.04 ± 66.10 ×10³/mm³; p < 0.001) compared to the control group. In addition, monocyte (0.70 ± 0.70 vs. 0.56 ± 0.19 ×10³/mm³; p = 0.030), neutrophil (6.58 ± 2.45 vs. 5.54 ± 1.91 ×10³/mm³; p < 0.001), and lymphocyte counts (2.22 ± 0.71 vs. 2.07 ± 0.64 ×10³/mm³; p = 0.015) were significantly elevated in the missed abortion group. Although mean C-reactive protein (CRP) levels appeared numerically similar across groups (5.23 ± 4.56 vs. 5.62 ± 1.80 mg/L), the p-value was < 0.001, suggesting a distributional discrepancy likely due to greater variance in the EPL group, are shown in Table 2 Table 2 Hematological and Inflammatory Parameters Parameter Missed Abortion (Mean ± SD) Missed Abortion (Median [min–max]) Control (Mean ± SD) Control (Median [min–max]) p-value HB (g/dL) 12.27 ± 1.32 12.30 [8.30, 15.30] 10.17 ± 1.21 10.10 [7.37, 14.10] < 0.001 WBC (×10³/mm³) 9.75 ± 2.67 9.52 [4.07, 19.58] 8.04 ± 2.34 7.73 [3.62, 18.01] < 0.001 PLT (×10³/mm³) 264.47 ± 64.52 262.00 [137.00, 697.00] 236.04 ± 66.10 234.00 [77.00, 458.00] < 0.001 CRP (mg/L) 5.23 ± 4.56 5.00 [0.50, 46.00] 5.62 ± 1.80 5.50 [2.00, 11.00] < 0.001 Monocytes 0.70 ± 0.70 0.59 [0.17, 6.84] 0.56 ± 0.19 0.55 [0.05, 1.25] 0.030 Neutrophils 6.58 ± 2.45 6.16 [2.29, 16.75] 5.54 ± 1.91 5.22 [2.20, 14.72] < 0.001 Lymphocytes 2.22 ± 0.71 2.13 [0.38, 4.59] 2.07 ± 0.64 2.02 [0.57, 4.75] 0.015 NLR 3.45 ± 2.80 2.88 [0.80, 27.24] 2.90 ± 1.25 2.77 [0.93, 8.88] 0.037 PLR 132.80 ± 70.23 121.52 [51.87, 704.92] 124.81 ± 56.32 116.03 [33.48, 510.53] 0.128 AISI 660.43 ± 1020.70 413.75 [95.72, 10338.13] 377.83 ± 244.85 331.89 [61.43, 1447.68] < 0.001 SIRI 2.58 ± 4.20 1.68 [0.28, 43.26] 1.60 ± 0.89 1.43 [0.23, 5.77] 0.005 SII 868.21 ± 589.86 763.07 [218.58, 6427.89] 682.15 ± 360.10 619.79 [93.07, 2373.24] < 0.001 When inflammation-based composite indices were evaluated, significant elevations were observed in most markers within the missed abortion group. Neutrophil-to-lymphocyte ratio (NLR) was higher in the EPL group (3.45 ± 2.80 vs. 2.90 ± 1.25; p = 0.037), reflecting a relative neutrophilia and/or lymphopenia often associated with systemic inflammatory responses. Similarly, systemic immune-inflammation index (SII), which integrates platelet, neutrophil, and lymphocyte data, was significantly increased (868.21 ± 589.86 vs. 682.15 ± 360.10; p < 0.001). Systemic inflammation response index (SIRI), calculated from neutrophil, monocyte, and lymphocyte counts, was also higher in the EPL group (2.58 ± 4.20 vs. 1.60 ± 0.89; p = 0.005), suggesting a heightened innate immune response. Aggregate index of systemic inflammation (AISI), a newer marker incorporating neutrophils, monocytes, and platelets normalized to lymphocyte count, was markedly elevated as well (660.43 ± 1020.70 vs. 377.83 ± 244.85; p < 0.001). In contrast, the platelet-to-lymphocyte ratio (PLR) did not show a statistically significant difference between the groups (132.80 ± 70.23 vs. 124.81 ± 56.32; p = 0.128), are shown in Table 2 , indicating that this marker may have limited discriminatory capacity in this context. The diagnostic performance of these inflammatory indices was assessed using receiver operating characteristic (ROC) curve analysis. Among all evaluated markers, SII demonstrated the strongest discriminative ability for identifying women at risk for early pregnancy loss, with an area under the curve (AUC) of 0.74, providing 85% specificity and 51% sensitivity. SIRI followed closely with an AUC of 0.73, 91% specificity, and 55% sensitivity. AISI yielded an AUC of 0.67, with the specificity of 94% and a sensitivity of 53%. These findings suggest that while these markers are highly specific, their sensitivities remain modest, underscoring the need for them to be interpreted in conjunction with clinical findings. NLR and PLR had lower AUC values (0.63 and 0.56, respectively), are shown in Fig. 1, indicating relatively poor performance in isolation. Taken together, the results suggest that systemic inflammation markers—particularly SII, SIRI, and AISI—are elevated in women experiencing missed abortion and may serve as useful adjuncts in risk stratification during early pregnancy. Detailed data related to demographic and clinical parameters are presented in Table 1 , while hematologic and inflammatory indices are summarized in Table 2 . ROC curve findings illustrating the diagnostic potential of these markers are shown in Fig. 1. Discussion Systemic inflammatory markers derived from routine blood counts have gained increasing attention in recent years as potential tools to predict adverse pregnancy outcomes. Inflammation plays a critical role in early pregnancy processes such as implantation, trophoblast invasion, and placental development. Disruption in this immunological balance, whether through excessive or inadequate response, has been implicated in early pregnancy loss (EPL). Numerous studies have aimed to explore the diagnostic utility of hematologic inflammation indices like NLR, PLR, SII, SIRI, and AISI in detecting pregnancies at risk for miscarriage. While findings in the literature often support the clinical value of these indices, some inconsistencies remain, likely due to differences in methodology, population characteristics, and biomarker variability. In the following section, we compare our findings with previously published studies to highlight both the parallels and distinctions and to discuss the potential reasons for these differences. A retrospective case-control study conducted in 2018 at Süleyman Demirel University in Turkey investigated the diagnostic value of complete blood count-derived markers in predicting spontaneous abortion. The study included 325 patients with spontaneous abortion and 245 healthy pregnant women. The researchers found that both the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were significantly elevated in the miscarriage group. These findings align with our study in terms of NLR, which also demonstrated a statistically significant difference. However, PLR did not show statistical significance in our cohort, possibly due to differences in sample size, population characteristics, or marker sensitivity [ 8 ]. In a retrospective case-control study conducted in Istanbul, Turkey, the authors evaluated the role of the systemic immune-inflammation index (SII) and systemic inflammatory response index (SRI) in early pregnancy loss. This study, which included 535 individuals were enrolled in this retrospective analysis, reported that both indices were significantly elevated in the miscarriage group. These findings are consistent with our results, where SII and SIRI demonstrated strong diagnostic performance. Unlike the previous study, our research also evaluated the aggregate index of systemic inflammation (AISI), which emerged as a promising marker. This additional parameter adds a novel perspective to the literature and may explain the broader diagnostic scope of our findings [ 9 ]. A study from Foshan Women and Children’s Hospital in China, published in 2022, retrospectively analyzed 200 patients with missed abortion and 200 controls to assess the diagnostic value of NLR and PLR. Both markers were found to be significantly higher in the miscarriage group, with NLR showing stronger discriminatory power. This result is in line with our study regarding NLR. However, the discrepancy in PLR outcomes may stem from ethnic, environmental, or physiological differences between the Chinese and Turkish populations[ 10 ]. In another Turkish study conducted in 2020 at Kütahya Health Sciences University, 40 women with missed abortion and 40 healthy pregnant women were evaluated. The study aimed to assess the utility of NLR and PLR in predicting miscarriage. Both markers were significantly elevated in the case group. The agreement with our findings concerning NLR is notable, whereas the inconsistency in PLR results may be due to the relatively small sample size and local population characteristics [ 11 ]. A 2023 case-control study from Iran included 120 women with spontaneous abortion and 120 controls. The research focused on determining whether NLR and PLR measured in the first trimester could predict pregnancy loss. Both markers were significantly higher in the miscarriage group. While our results agree regarding NLR, PLR did not show a significant difference in our study. This variation could be related to differing analytical methods, laboratory standards, or population-based differences[ 12 ]. A retrospective study conducted in China in 2021 evaluated 67 patients who experienced second-trimester pregnancy loss alongside a control group of healthy pregnant women. The researchers assessed levels of high-sensitivity C-reactive protein (hs-CRP), NLR, and PLR, all of which were significantly elevated in the miscarriage group. Consistent with these findings, our study also demonstrated significantly increased CRP and NLR levels in patients with pregnancy loss. However, the inconsistent results observed for PLR across different studies suggest that its diagnostic utility may be influenced by variations in sample characteristics or testing protocols [ 13 ]. A retrospective observational study conducted in Greece evaluated the prognostic value of first-trimester NLR in predicting pregnancy outcomes among 129 women with spontaneous conception, including 65 with live births and 64 who experienced first-trimester miscarriage. Although mean NLR values did not significantly differ between the live birth and miscarriage groups (2.5 ± 1.0 vs. 2.9 ± 1.5, p = 0.167), NLR levels exceeding 5.8 were observed exclusively in the miscarriage group (p = 0.028). This finding suggests that while NLR may not serve as a universal predictor of pregnancy outcome, markedly elevated NLR levels could help identify a small subset of women at high risk of early pregnancy loss The inconsistency in PLR findings across studies might be attributed to limited statistical power in smaller cohorts or variable cutoff values [ 14 ]. In contrast to the aforementioned findings, our study included a larger sample size and a more comprehensively screened patient population. Consistent with the existing literature, we found that NLR was significantly elevated in women with early pregnancy loss. Furthermore, novel inflammatory markers such as the SII, SIRI, and AISI were also significantly higher in the miscarriage group, suggesting their potential utility as prognostic indicators and paving the way for future research. Finally, a 2024 meta-analysis comprising 14 studies demonstrated that the pooled mean neutrophil-to-lymphocyte ratio (NLR) was significantly higher in women who experienced pregnancy loss compared to those with healthy pregnancies. In contrast, no significant difference was observed in the platelet-to-lymphocyte ratio (PLR) between the two groups. Consistent with these findings, our study also identified elevated NLR levels in the miscarriage group. However, the persistent inconsistency in PLR outcomes across studies suggests that its diagnostic utility may be influenced by variations in sample characteristics or testing methodologies.[ 15 ] Conclusion This study demonstrates that systemic inflammatory markers derived from complete blood counts—particularly the systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)—are significantly elevated in women experiencing early pregnancy loss during the first trimester. These findings support the hypothesis that subclinical inflammation may play a role in the pathophysiology of early pregnancy loss. Among the evaluated indices, SII and SIRI showed the highest diagnostic performance in distinguishing between healthy and miscarrying pregnancies, although their sensitivity remains modest. Importantly, these markers are cost-effective, easily obtainable, and widely accessible in clinical settings, making them valuable adjuncts in the early identification of high-risk pregnancies. However, given their moderate predictive power, they should be interpreted in combination with clinical findings rather than used in isolation. Our results align with several previous studies, particularly about NLR, SII, and SIRI, yet discrepancies in PLR and other parameters across studies highlight the need for standardization and further investigation. Future research should focus on large-scale, multicenter, prospective studies to validate these indices and establish clinically applicable cut-off values. Incorporating these biomarkers into routine antenatal assessment protocols may improve early detection and facilitate timely interventions, ultimately contributing to the reduction of preventable pregnancy losses. Study Limitations This study has certain limitations. Its retrospective and single-center design may limit the generalizability of the findings. Additionally, inflammatory markers were assessed at a single time point, which may not fully capture the dynamic nature of systemic inflammation. Despite strict exclusion criteria, unmeasured confounding factors cannot be entirely excluded. Declarations Ethical Approval and Participant Consent Written informed consent was obtained from all participants before inclusion in the study. This study was conducted by the principles of the Declaration of Helsinki, and approval was obtained from Şırnak University (Approval date: 19 April 2025; Decision No: 130554-050.04.-E.74546226). Consent for publication Written informed consent was obtained from all participants for publication of this study. Data Availability Statement Data availability statement: the datasets used and analysed in this study are available upon contact with the corresponding author. Conflict of Interest The authors declare that they have no conflict of interest. Funding The authors declare that they have not received any funding, grants, or other support during this study. Author Contributions All authors contributed to the conceptualisation and design of the study. Material preparation, data collection, and analysis were carried out by Cem İnceoğlu. Rafaettin Şahin designed the study and critically revised the manuscript. The first draft of the manuscript was written by Rafaettin Şahin, and Veysel Tahiroğlu commented on earlier versions and supervised the work. All authors read and approved the final manuscript. Acknowledgments We thank the patients who participated in this study and the dedicated staff members involved. References Obstetricians ACo, Gynecologists. ACOG practice bulletin no. 200: early pregnancy loss. Obstetrics and gynecology. 2018;132(5):e197-e207. Kolte A, Bernardi L, Christiansen O, Quenby S, Farquharson R, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Human reproduction. 2015;30(3):495-8. Shorter JM, Atrio JM, Schreiber CA. Management of early pregnancy loss, with a focus on patient centered care. Seminars in perinatology: Elsevier; 2019. p. 84-94. Pinar MH, Gibbins K, He M, Kostadinov S, Silver R. Early pregnancy losses: review of nomenclature, histopathology, and possible etiologies. Fetal and pediatric pathology. 2018;37(3):191-209. Calleja-Agius J, Jauniaux E, Pizzey AR, Muttukrishna S. Investigation of systemic inflammatory response in first trimester pregnancy failure. Hum Reprod. 2012;27(2):349-57. doi: 10.1093/humrep/der402. Oğlak SC, Aydın MF. Are neutrophil to lymphocyte ratio and platelet to lymphocyte ratio clinically useful for the prediction of early pregnancy loss? Ginekologia Polska. 2020;91(9):524-7. Ata N, Kulhan M, Kulhan NG, Turkler C. Can neutrophil-lymphocyte and platelet-lymphocyte ratios predict threatened abortion and early pregnancy loss? Ginekologia polska. 2020;91(4):210-5. Bas FY, Tola EN, Sak S, Cankaya BA. The role of complete blood inflammation markers in the prediction of spontaneous abortion. Pakistan journal of medical sciences. 2018;34(6):1381. Çallıoğlu N, Gül DK, Arslan İÖ, Geyikoğlu İ, Demirçivi E. Inflammatory markers in systemic immune-inflammatory index and inflammatory response index to predict early pregnancy loss. Saudi Medical Journal. 2024;45(8):808. Liu D, Huang X, Xu Z, Chen M, Wu M. Predictive value of NLR and PLR in missed miscarriage. Journal of Clinical Laboratory Analysis. 2022;36(3):e24250. Biyik I, Albayrak M, Keskin F. Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in missed abortion. Revista Brasileira de Ginecologia e Obstetrícia/RBGO Gynecology and Obstetrics. 2020;42(05):235-9. Yazdizadeh M, Hivehchi N, Ghaemi M, Azizi S, Saeedzarandi M, Afrooz N, et al. Platelet to lymphocyte and neutrophil to lymphocyte ratios in the first trimester of pregnancy, are they useful for predicting spontaneous miscarriage? A case-control study. International Journal of Reproductive Biomedicine. 2023;21(6):463. Zhang L, Hong H, Duan B, Zhang Y, Shao C, Wang L, et al. Neutrophil-lymphocyte ratio and hypersensitive C-reaction protein are associated with miscarriage during the second trimester of pregnancy. Journal of Biological Regulators and Homeostatic Agents. 2021;35(3):889-900. Christoforaki V, Zafeiriou Z, Daskalakis G, Katasos T, Siristatidis C. First trimester neutrophil to lymphocyte ratio (NLR) and pregnancy outcome. Journal of Obstetrics and Gynaecology. 2020;40(1):59-64. Hantoushzadeh S, Gargar OK, Jafarabady K, Rezaei MM, Asadi F, Eshraghi N, et al. Diagnostic value of neutrophil‐to‐lymphocyte and platelet‐to‐lymphocyte ratio to predict recurrent pregnancy loss and abortion; a systematic review and meta‐analysis. Immunity, Inflammation and Disease. 2024;12(3):e1210. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6779110","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":465961039,"identity":"e263e434-5e6c-40d4-95b9-50e8fb735c97","order_by":0,"name":"Cem Inceoglu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYJCCA2CSHYg/ADEbO9FamBkYGGeAtDATbRdQJTMPlIEX8Ld3Jx4uqLGRk3fmMZO2+bVNno+ZgfHDxxzcWiTOnN1weMaxNGPDw0AtuX23DduYGZglZ27DrcVAInfDYd6Gw4kbm0Faem4zArWwMfPi0yL/FqTlP0SLZc9te8JaJHhBWg4kzmcGamH4cTuRoBaJM0CH8RxLNjZgZiu27G24ndzGzNiM1y/87Wc3f+apsZOTb2/eeOPHn9u289ubD374iEcLwoUHgARjG4jJ2ECEeiCQB6v7Q5ziUTAKRsEoGFkAAN55TF0Njl2SAAAAAElFTkSuQmCC","orcid":"","institution":"Turkish Ministry of Sirnak State Hospital","correspondingAuthor":true,"prefix":"","firstName":"Cem","middleName":"","lastName":"Inceoglu","suffix":""},{"id":465961040,"identity":"e2c84ced-586d-4ab3-bcc7-d247c5469548","order_by":1,"name":"Refaettin Sahin","email":"","orcid":"","institution":"Turkish Ministry of Sirnak State Hospital","correspondingAuthor":false,"prefix":"","firstName":"Refaettin","middleName":"","lastName":"Sahin","suffix":""},{"id":465961041,"identity":"4ab9a9ee-5afe-40eb-bf79-e21cae789847","order_by":2,"name":"Veysel Tahiroglu","email":"","orcid":"","institution":"Şırnak University","correspondingAuthor":false,"prefix":"","firstName":"Veysel","middleName":"","lastName":"Tahiroglu","suffix":""}],"badges":[],"createdAt":"2025-05-29 19:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6779110/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6779110/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84197582,"identity":"f9d7b53c-6aae-4deb-97e0-e79660509c4b","added_by":"auto","created_at":"2025-06-09 08:00:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":167818,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6779110/v1/7d18f03773de77dfea97a547.png"},{"id":90326750,"identity":"908ed30b-539b-488c-886b-a17f4c0c88ae","added_by":"auto","created_at":"2025-09-01 12:17:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":716684,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6779110/v1/4c1eebd8-6b8d-408e-8405-abc59aa681a5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of Systemic Inflammation Markers with Early Pregnancy Loss in the First Trimester: A Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEarly pregnancy loss (EPL) is defined as the absence of embryonic or fetal cardiac activity within the intrauterine gestational sac before 12 weeks of gestation. It is a common obstetric complication, affecting approximately 10% of all clinically recognized pregnancies, with nearly 80% of these losses occurring in the first trimester [[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e],[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]]. In addition to the emotional burden it places on couples, EPL also presents significant clinical challenges in early pregnancy management.\u003c/p\u003e \u003cp\u003eThe etiology of early pregnancy loss is multifactorial, involving genetic abnormalities, infections, endocrine dysfunctions, anatomical anomalies, and immune-related implantation failures. However, in up to 40% of cases, the exact cause remains unknown [[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e],[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]]. Recently, increasing evidence has highlighted the potential role of systemic inflammation in the pathogenesis of EPL [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInflammatory processes play a crucial role in embryo implantation, trophoblastic invasion, and the development of the placenta. An imbalance in maternal immune response\u0026mdash;either insufficient or exaggerated\u0026mdash;may disrupt these processes and lead to adverse pregnancy outcomes. Therefore, inflammatory markers derived from routine hematological parameters have gained attention as possible predictors of EPL.\u003c/p\u003e \u003cp\u003eComplete blood count (CBC)-based indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) are considered indirect indicators of systemic inflammation. These indices are advantageous because they are inexpensive, easily accessible, and non-invasive tools widely available in clinical practice [[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e],[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]].\u003c/p\u003e \u003cp\u003eWhile such inflammatory markers have been evaluated in conditions like preeclampsia, gestational diabetes, intrahepatic cholestasis, and gynecological malignancies, their diagnostic value in early pregnancy loss remains underexplored. This study aims to investigate the association between first-trimester CBC-derived inflammatory markers and early pregnancy loss, to identify potential biomarkers that may assist in early detection.\u003c/p\u003e \u003cp\u003eIn light of this information, our study aimed to evaluate the potential of inflammation markers obtained from complete blood count results to predict early pregnancy loss in first trimester pregnant women. In this way, it is aimed to identify pregnancies at risk of miscarriage at an early stage and to determine appropriate clinical approaches.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis retrospective case-control study was conducted at the Obstetrics and Gynecology Clinic of Sirnak State Hospital, Turkey, between January 1, 2022, and April 1, 2025. Ethical approval was obtained from the Ethics Committee of Sirnak University (Approval No: 130554\u0026thinsp;\u0026minus;\u0026thinsp;050.04.-E.74546226), and all procedures complied with the Declaration of Helsinki. Institutional permission was granted prior to data collection.\u003c/p\u003e \u003cp\u003eThe study included pregnant women aged 18\u0026ndash;45 years. The case group comprised 217 women diagnosed with early pregnancy loss (EPL), defined as the absence of fetal cardiac activity in an intrauterine gestational sac before 12 weeks of gestation. The control group included 192 healthy pregnant women who delivered at term (\u0026ge;\u0026thinsp;37 weeks) without obstetric complications. Exclusion criteria were multiple gestation, recurrent miscarriage, infertility, thrombophilia, systemic disease, uterine anomalies, chronic medication use, active smoking, and pregnancy-related complications.\u003c/p\u003e \u003cp\u003eDemographic and clinical data\u0026mdash;including age, gravidity, parity, gestational age at assessment, and body mass index (BMI)\u0026mdash;were extracted from hospital records. Hematological parameters were obtained from venous blood samples collected in K3-EDTA tubes. In the case group, samples were drawn at the time of EPL diagnosis; in the control group, during the first antenatal visit following confirmation of fetal viability. Analyses were performed within 15 minutes using an automated hematology analyzer.\u003c/p\u003e \u003cp\u003eFrom complete blood count data, inflammation-based indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII\u0026thinsp;=\u0026thinsp;platelet count \u0026times; neutrophil count/lymphocyte count), systemic inflammation response index (SIRI\u0026thinsp;=\u0026thinsp;neutrophil count \u0026times; monocyte count / lymphocyte count), and aggregate index of systemic inflammation (AISI\u0026thinsp;=\u0026thinsp;neutrophil count \u0026times; monocyte count \u0026times; platelet count/lymphocyte count).\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median with interquartile range, depending on distribution. Normality was assessed using the Kolmogorov\u0026ndash;Smirnov test. Group comparisons were made using the independent samples t-test or Mann\u0026ndash;Whitney U test as appropriate. Diagnostic performance of the inflammatory indices was evaluated using receiver operating characteristic (ROC) analysis, and area under the curve (AUC), sensitivity, specificity, and optimal cut-off values were reported. A two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 409 pregnant women met the inclusion criteria and were analyzed in this study. Of these, 217 constituted the missed abortion group, and 192 comprised the healthy control group who delivered at term. The two groups were similar in terms of maternal age, with no statistically significant difference observed (29.65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39 vs. 30.31\u0026thinsp;\u0026plusmn;\u0026thinsp;6.23 years; p\u0026thinsp;=\u0026thinsp;0.312). However, the missed abortion group had significantly higher obstetric history markers. Gravidity (2.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69 vs. 1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and parity (1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.27 vs. 0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were both elevated in the EPL group. Similarly, mean body mass index (BMI) was significantly higher in women who experienced early pregnancy loss (27.82\u0026thinsp;\u0026plusmn;\u0026thinsp;4.78 vs. 26.10\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65 kg/m\u0026sup2;; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Gestational age at evaluation, however, did not differ significantly between groups (8.95\u0026thinsp;\u0026plusmn;\u0026thinsp;2.28 vs. 9.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68 weeks; p\u0026thinsp;=\u0026thinsp;0.401), indicating that the timing of clinical assessment was comparable, are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and Clinical Parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissed Abortion (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMissed Abortion (Median [min\u0026ndash;max])\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl (Median [min\u0026ndash;max])\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e29.65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.0 [20, 45]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e30.31\u0026thinsp;\u0026plusmn;\u0026thinsp;6.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30.0 [19, 43]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.312\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGravida\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.0 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0 [0, 5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0 [0, 1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e27.82\u0026thinsp;\u0026plusmn;\u0026thinsp;4.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.0 [20, 45]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e26.10\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.0 [18, 42]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational Week\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.95\u0026thinsp;\u0026plusmn;\u0026thinsp;2.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e9.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.0 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComprehensive hematological evaluation revealed several significant differences between the groups. Women in the missed abortion group exhibited higher levels of hemoglobin (12.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32 vs. 10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21 g/dL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), white blood cell count (9.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67 vs. 8.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34 \u0026times;10\u0026sup3;/mm\u0026sup3;; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and platelet count (264.47\u0026thinsp;\u0026plusmn;\u0026thinsp;64.52 vs. 236.04\u0026thinsp;\u0026plusmn;\u0026thinsp;66.10 \u0026times;10\u0026sup3;/mm\u0026sup3;; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to the control group. In addition, monocyte (0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70 vs. 0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 \u0026times;10\u0026sup3;/mm\u0026sup3;; p\u0026thinsp;=\u0026thinsp;0.030), neutrophil (6.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45 vs. 5.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91 \u0026times;10\u0026sup3;/mm\u0026sup3;; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and lymphocyte counts (2.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71 vs. 2.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64 \u0026times;10\u0026sup3;/mm\u0026sup3;; p\u0026thinsp;=\u0026thinsp;0.015) were significantly elevated in the missed abortion group. Although mean C-reactive protein (CRP) levels appeared numerically similar across groups (5.23\u0026thinsp;\u0026plusmn;\u0026thinsp;4.56 vs. 5.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80 mg/L), the p-value was \u0026lt;\u0026thinsp;0.001, suggesting a distributional discrepancy likely due to greater variance in the EPL group, are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHematological and Inflammatory Parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissed Abortion (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMissed Abortion (Median [min\u0026ndash;max])\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl (Median [min\u0026ndash;max])\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHB (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.30 [8.30, 15.30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.10 [7.37, 14.10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (\u0026times;10\u0026sup3;/mm\u0026sup3;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.52 [4.07, 19.58]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e8.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.73 [3.62, 18.01]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT (\u0026times;10\u0026sup3;/mm\u0026sup3;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e264.47\u0026thinsp;\u0026plusmn;\u0026thinsp;64.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e262.00 [137.00, 697.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e236.04\u0026thinsp;\u0026plusmn;\u0026thinsp;66.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e234.00 [77.00, 458.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.23\u0026thinsp;\u0026plusmn;\u0026thinsp;4.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.00 [0.50, 46.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.50 [2.00, 11.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.59 [0.17, 6.84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.55 [0.05, 1.25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.16 [2.29, 16.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.22 [2.20, 14.72]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.13 [0.38, 4.59]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e2.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.02 [0.57, 4.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNLR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.45\u0026thinsp;\u0026plusmn;\u0026thinsp;2.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.88 [0.80, 27.24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.77 [0.93, 8.88]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e132.80\u0026thinsp;\u0026plusmn;\u0026thinsp;70.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e121.52 [51.87, 704.92]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e124.81\u0026thinsp;\u0026plusmn;\u0026thinsp;56.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e116.03 [33.48, 510.53]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAISI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e660.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1020.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e413.75 [95.72, 10338.13]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e377.83\u0026thinsp;\u0026plusmn;\u0026thinsp;244.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e331.89 [61.43, 1447.68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSIRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.68 [0.28, 43.26]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.43 [0.23, 5.77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e868.21\u0026thinsp;\u0026plusmn;\u0026thinsp;589.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e763.07 [218.58, 6427.89]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e682.15\u0026thinsp;\u0026plusmn;\u0026thinsp;360.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e619.79 [93.07, 2373.24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen inflammation-based composite indices were evaluated, significant elevations were observed in most markers within the missed abortion group. Neutrophil-to-lymphocyte ratio (NLR) was higher in the EPL group (3.45\u0026thinsp;\u0026plusmn;\u0026thinsp;2.80 vs. 2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25; p\u0026thinsp;=\u0026thinsp;0.037), reflecting a relative neutrophilia and/or lymphopenia often associated with systemic inflammatory responses. Similarly, systemic immune-inflammation index (SII), which integrates platelet, neutrophil, and lymphocyte data, was significantly increased (868.21\u0026thinsp;\u0026plusmn;\u0026thinsp;589.86 vs. 682.15\u0026thinsp;\u0026plusmn;\u0026thinsp;360.10; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Systemic inflammation response index (SIRI), calculated from neutrophil, monocyte, and lymphocyte counts, was also higher in the EPL group (2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20 vs. 1.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89; p\u0026thinsp;=\u0026thinsp;0.005), suggesting a heightened innate immune response. Aggregate index of systemic inflammation (AISI), a newer marker incorporating neutrophils, monocytes, and platelets normalized to lymphocyte count, was markedly elevated as well (660.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1020.70 vs. 377.83\u0026thinsp;\u0026plusmn;\u0026thinsp;244.85; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, the platelet-to-lymphocyte ratio (PLR) did not show a statistically significant difference between the groups (132.80\u0026thinsp;\u0026plusmn;\u0026thinsp;70.23 vs. 124.81\u0026thinsp;\u0026plusmn;\u0026thinsp;56.32; p\u0026thinsp;=\u0026thinsp;0.128), are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, indicating that this marker may have limited discriminatory capacity in this context.\u003c/p\u003e \u003cp\u003eThe diagnostic performance of these inflammatory indices was assessed using receiver operating characteristic (ROC) curve analysis. Among all evaluated markers, SII demonstrated the strongest discriminative ability for identifying women at risk for early pregnancy loss, with an area under the curve (AUC) of 0.74, providing 85% specificity and 51% sensitivity. SIRI followed closely with an AUC of 0.73, 91% specificity, and 55% sensitivity. AISI yielded an AUC of 0.67, with the specificity of 94% and a sensitivity of 53%. These findings suggest that while these markers are highly specific, their sensitivities remain modest, underscoring the need for them to be interpreted in conjunction with clinical findings. NLR and PLR had lower AUC values (0.63 and 0.56, respectively), are shown in Fig.\u0026nbsp;1, indicating relatively poor performance in isolation.\u003c/p\u003e \u003cp\u003eTaken together, the results suggest that systemic inflammation markers\u0026mdash;particularly SII, SIRI, and AISI\u0026mdash;are elevated in women experiencing missed abortion and may serve as useful adjuncts in risk stratification during early pregnancy. Detailed data related to demographic and clinical parameters are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, while hematologic and inflammatory indices are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. ROC curve findings illustrating the diagnostic potential of these markers are shown in Fig.\u0026nbsp;1.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSystemic inflammatory markers derived from routine blood counts have gained increasing attention in recent years as potential tools to predict adverse pregnancy outcomes. Inflammation plays a critical role in early pregnancy processes such as implantation, trophoblast invasion, and placental development. Disruption in this immunological balance, whether through excessive or inadequate response, has been implicated in early pregnancy loss (EPL). Numerous studies have aimed to explore the diagnostic utility of hematologic inflammation indices like NLR, PLR, SII, SIRI, and AISI in detecting pregnancies at risk for miscarriage. While findings in the literature often support the clinical value of these indices, some inconsistencies remain, likely due to differences in methodology, population characteristics, and biomarker variability. In the following section, we compare our findings with previously published studies to highlight both the parallels and distinctions and to discuss the potential reasons for these differences.\u003c/p\u003e \u003cp\u003eA retrospective case-control study conducted in 2018 at S\u0026uuml;leyman Demirel University in Turkey investigated the diagnostic value of complete blood count-derived markers in predicting spontaneous abortion. The study included 325 patients with spontaneous abortion and 245 healthy pregnant women. The researchers found that both the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were significantly elevated in the miscarriage group. These findings align with our study in terms of NLR, which also demonstrated a statistically significant difference. However, PLR did not show statistical significance in our cohort, possibly due to differences in sample size, population characteristics, or marker sensitivity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a retrospective case-control study conducted in Istanbul, Turkey, the authors evaluated the role of the systemic immune-inflammation index (SII) and systemic inflammatory response index (SRI) in early pregnancy loss. This study, which included 535 individuals were enrolled in this retrospective analysis, reported that both indices were significantly elevated in the miscarriage group. These findings are consistent with our results, where SII and SIRI demonstrated strong diagnostic performance. Unlike the previous study, our research also evaluated the aggregate index of systemic inflammation (AISI), which emerged as a promising marker. This additional parameter adds a novel perspective to the literature and may explain the broader diagnostic scope of our findings [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA study from Foshan Women and Children\u0026rsquo;s Hospital in China, published in 2022, retrospectively analyzed 200 patients with missed abortion and 200 controls to assess the diagnostic value of NLR and PLR. Both markers were found to be significantly higher in the miscarriage group, with NLR showing stronger discriminatory power. This result is in line with our study regarding NLR. However, the discrepancy in PLR outcomes may stem from ethnic, environmental, or physiological differences between the Chinese and Turkish populations[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn another Turkish study conducted in 2020 at K\u0026uuml;tahya Health Sciences University, 40 women with missed abortion and 40 healthy pregnant women were evaluated. The study aimed to assess the utility of NLR and PLR in predicting miscarriage. Both markers were significantly elevated in the case group. The agreement with our findings concerning NLR is notable, whereas the inconsistency in PLR results may be due to the relatively small sample size and local population characteristics [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA 2023 case-control study from Iran included 120 women with spontaneous abortion and 120 controls. The research focused on determining whether NLR and PLR measured in the first trimester could predict pregnancy loss. Both markers were significantly higher in the miscarriage group. While our results agree regarding NLR, PLR did not show a significant difference in our study. This variation could be related to differing analytical methods, laboratory standards, or population-based differences[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA retrospective study conducted in China in 2021 evaluated 67 patients who experienced second-trimester pregnancy loss alongside a control group of healthy pregnant women. The researchers assessed levels of high-sensitivity C-reactive protein (hs-CRP), NLR, and PLR, all of which were significantly elevated in the miscarriage group. Consistent with these findings, our study also demonstrated significantly increased CRP and NLR levels in patients with pregnancy loss. However, the inconsistent results observed for PLR across different studies suggest that its diagnostic utility may be influenced by variations in sample characteristics or testing protocols [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA retrospective observational study conducted in Greece evaluated the prognostic value of first-trimester NLR in predicting pregnancy outcomes among 129 women with spontaneous conception, including 65 with live births and 64 who experienced first-trimester miscarriage. Although mean NLR values did not significantly differ between the live birth and miscarriage groups (2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 vs. 2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5, p\u0026thinsp;=\u0026thinsp;0.167), NLR levels exceeding 5.8 were observed exclusively in the miscarriage group (p\u0026thinsp;=\u0026thinsp;0.028). This finding suggests that while NLR may not serve as a universal predictor of pregnancy outcome, markedly elevated NLR levels could help identify a small subset of women at high risk of early pregnancy loss The inconsistency in PLR findings across studies might be attributed to limited statistical power in smaller cohorts or variable cutoff values [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In contrast to the aforementioned findings, our study included a larger sample size and a more comprehensively screened patient population. Consistent with the existing literature, we found that NLR was significantly elevated in women with early pregnancy loss. Furthermore, novel inflammatory markers such as the SII, SIRI, and AISI were also significantly higher in the miscarriage group, suggesting their potential utility as prognostic indicators and paving the way for future research.\u003c/p\u003e \u003cp\u003eFinally, a 2024 meta-analysis comprising 14 studies demonstrated that the pooled mean neutrophil-to-lymphocyte ratio (NLR) was significantly higher in women who experienced pregnancy loss compared to those with healthy pregnancies. In contrast, no significant difference was observed in the platelet-to-lymphocyte ratio (PLR) between the two groups. Consistent with these findings, our study also identified elevated NLR levels in the miscarriage group. However, the persistent inconsistency in PLR outcomes across studies suggests that its diagnostic utility may be influenced by variations in sample characteristics or testing methodologies.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates that systemic inflammatory markers derived from complete blood counts\u0026mdash;particularly the systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)\u0026mdash;are significantly elevated in women experiencing early pregnancy loss during the first trimester. These findings support the hypothesis that subclinical inflammation may play a role in the pathophysiology of early pregnancy loss. Among the evaluated indices, SII and SIRI showed the highest diagnostic performance in distinguishing between healthy and miscarrying pregnancies, although their sensitivity remains modest.\u003c/p\u003e \u003cp\u003eImportantly, these markers are cost-effective, easily obtainable, and widely accessible in clinical settings, making them valuable adjuncts in the early identification of high-risk pregnancies. However, given their moderate predictive power, they should be interpreted in combination with clinical findings rather than used in isolation.\u003c/p\u003e \u003cp\u003eOur results align with several previous studies, particularly about NLR, SII, and SIRI, yet discrepancies in PLR and other parameters across studies highlight the need for standardization and further investigation. Future research should focus on large-scale, multicenter, prospective studies to validate these indices and establish clinically applicable cut-off values. Incorporating these biomarkers into routine antenatal assessment protocols may improve early detection and facilitate timely interventions, ultimately contributing to the reduction of preventable pregnancy losses.\u003c/p\u003e"},{"header":"Study Limitations","content":"\u003cp\u003eThis study has certain limitations. Its retrospective and single-center design may limit the generalizability of the findings. Additionally, inflammatory markers were assessed at a single time point, which may not fully capture the dynamic nature of systemic inflammation. Despite strict exclusion criteria, unmeasured confounding factors cannot be entirely excluded.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Participant Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants before inclusion in the study. This study was conducted by the principles of the Declaration of Helsinki, and approval was obtained from Şırnak University (Approval date: 19 April 2025; Decision No: 130554-050.04.-E.74546226).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants for publication of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData availability statement: the datasets used and analysed in this study are available upon contact with the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have not received any funding, grants, or other support during this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conceptualisation and design of the study. Material preparation, data collection, and analysis were carried out by Cem İnceoğlu. Rafaettin Şahin designed the study and critically revised the manuscript. The first draft of the manuscript was written by Rafaettin Şahin, and Veysel Tahiroğlu commented on earlier versions and supervised the work. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients who participated in this study and the dedicated staff members involved.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eObstetricians ACo, Gynecologists. ACOG practice bulletin no. 200: early pregnancy loss. Obstetrics and gynecology. 2018;132(5):e197-e207.\u003c/li\u003e\n\u003cli\u003eKolte A, Bernardi L, Christiansen O, Quenby S, Farquharson R, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Human reproduction. 2015;30(3):495-8.\u003c/li\u003e\n\u003cli\u003eShorter JM, Atrio JM, Schreiber CA. Management of early pregnancy loss, with a focus on patient centered care. Seminars in perinatology: Elsevier; 2019. p. 84-94.\u003c/li\u003e\n\u003cli\u003ePinar MH, Gibbins K, He M, Kostadinov S, Silver R. Early pregnancy losses: review of nomenclature, histopathology, and possible etiologies. Fetal and pediatric pathology. 2018;37(3):191-209.\u003c/li\u003e\n\u003cli\u003eCalleja-Agius J, Jauniaux E, Pizzey AR, Muttukrishna S. Investigation of systemic inflammatory response in first trimester pregnancy failure. Hum Reprod. 2012;27(2):349-57. doi: 10.1093/humrep/der402.\u003c/li\u003e\n\u003cli\u003eOğlak SC, Aydın MF. Are neutrophil to lymphocyte ratio and platelet to lymphocyte ratio clinically useful for the prediction of early pregnancy loss? Ginekologia Polska. 2020;91(9):524-7.\u003c/li\u003e\n\u003cli\u003eAta N, Kulhan M, Kulhan NG, Turkler C. Can neutrophil-lymphocyte and platelet-lymphocyte ratios predict threatened abortion and early pregnancy loss? Ginekologia polska. 2020;91(4):210-5.\u003c/li\u003e\n\u003cli\u003eBas FY, Tola EN, Sak S, Cankaya BA. The role of complete blood inflammation markers in the prediction of spontaneous abortion. Pakistan journal of medical sciences. 2018;34(6):1381.\u003c/li\u003e\n\u003cli\u003e\u0026Ccedil;allıoğlu N, G\u0026uuml;l DK, Arslan İ\u0026Ouml;, Geyikoğlu İ, Demir\u0026ccedil;ivi E. Inflammatory markers in systemic immune-inflammatory index and inflammatory response index to predict early pregnancy loss. Saudi Medical Journal. 2024;45(8):808.\u003c/li\u003e\n\u003cli\u003eLiu D, Huang X, Xu Z, Chen M, Wu M. Predictive value of NLR and PLR in missed miscarriage. Journal of Clinical Laboratory Analysis. 2022;36(3):e24250.\u003c/li\u003e\n\u003cli\u003eBiyik I, Albayrak M, Keskin F. Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in missed abortion. Revista Brasileira de Ginecologia e Obstetr\u0026iacute;cia/RBGO Gynecology and Obstetrics. 2020;42(05):235-9.\u003c/li\u003e\n\u003cli\u003eYazdizadeh M, Hivehchi N, Ghaemi M, Azizi S, Saeedzarandi M, Afrooz N, et al. Platelet to lymphocyte and neutrophil to lymphocyte ratios in the first trimester of pregnancy, are they useful for predicting spontaneous miscarriage? A case-control study. International Journal of Reproductive Biomedicine. 2023;21(6):463.\u003c/li\u003e\n\u003cli\u003eZhang L, Hong H, Duan B, Zhang Y, Shao C, Wang L, et al. Neutrophil-lymphocyte ratio and hypersensitive C-reaction protein are associated with miscarriage during the second trimester of pregnancy. Journal of Biological Regulators and Homeostatic Agents. 2021;35(3):889-900.\u003c/li\u003e\n\u003cli\u003eChristoforaki V, Zafeiriou Z, Daskalakis G, Katasos T, Siristatidis C. First trimester neutrophil to lymphocyte ratio (NLR) and pregnancy outcome. Journal of Obstetrics and Gynaecology. 2020;40(1):59-64.\u003c/li\u003e\n\u003cli\u003eHantoushzadeh S, Gargar OK, Jafarabady K, Rezaei MM, Asadi F, Eshraghi N, et al. Diagnostic value of neutrophil‐to‐lymphocyte and platelet‐to‐lymphocyte ratio to predict recurrent pregnancy loss and abortion; a systematic review and meta‐analysis. Immunity, Inflammation and Disease. 2024;12(3):e1210.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Early pregnancy loss, systemic inflammation, SIRI, AISI, SII, missed abortion","lastPublishedDoi":"10.21203/rs.3.rs-6779110/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6779110/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to investigate whether hematologic inflammatory markers derived from routine complete blood count (CBC) are associated with early pregnancy loss during the first trimester.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective case-control study, 217 women diagnosed with missed abortion and 192 healthy pregnant women who gave birth at term were included. Data were obtained from patient records at the Obstetrics and Gynecology Clinic of Sirnak State Hospital between January 2022 and April 2025. Inflammatory indices\u0026mdash;including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)\u0026mdash;were calculated from CBC parameters and compared between the groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGravida, parity, and body mass index (BMI) were significantly higher in the missed abortion group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while maternal age and gestational week showed no significant difference. Hematologic parameters, including hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, and platelets, were significantly elevated in the missed abortion group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Inflammatory markers such as NLR, SII, SIRI, and AISI were significantly higher in this group, while PLR showed no statistical difference (p\u0026thinsp;=\u0026thinsp;0.128). Among these, SII (AUC\u0026thinsp;=\u0026thinsp;0.74), SIRI (AUC\u0026thinsp;=\u0026thinsp;0.73), and AISI (AUC\u0026thinsp;=\u0026thinsp;0.67) demonstrated the strongest discriminative performance in ROC analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFirst-trimester inflammatory indices, particularly SII, SIRI, and AISI, may serve as accessible, low-cost biomarkers for identifying pregnancies at risk of early loss. Further prospective studies are needed to validate their clinical utility.\u003c/p\u003e","manuscriptTitle":"Association of Systemic Inflammation Markers with Early Pregnancy Loss in the First Trimester: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 08:00:49","doi":"10.21203/rs.3.rs-6779110/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a4bad059-6252-4d03-bfc3-5c934b47ec39","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T12:09:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-09 08:00:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6779110","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6779110","identity":"rs-6779110","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}