Association of Preoperative Neutrophil-to-Lymphocyte Ratio With Post-Dural Puncture Headache After Cesarean Delivery

Introduction

Post-dural puncture headache (PDPH) is one of the most common and distressing complications associated with spinal anesthesia, particularly in pregnant women undergoing cesarean delivery [1]. It is characterized by a postural headache attributed to cerebrospinal fluid (CSF) leakage through a dural puncture, which leads to intracranial hypotension and compensatory cerebral vasodilation [2]. Although the incidence of PDPH in the general population is relatively low, pregnant women undergoing cesarean delivery are at higher risk than non-obstetric populations [3,4]. This elevated risk has been shown to be associated with demographic factors such as younger age and female sex, as well as with pregnancy-related physiological differences, including increased intra-abdominal pressure and potentially reduced baseline CSF volume [5].

Despite advances in spinal anesthesia techniques – most notably the use of atraumatic (pencil-point) needles, attention to bevel alignment, and single-attempt procedures performed by experienced anesthesiologists – PDPH remains a persistent clinical challenge [6]. This persistence suggests that procedural- and coagulation-related factors alone do not fully account for its occurrence. Emerging evidence indicates that systemic inflammatory responses and individual immunological profiles can influence tissue healing capacity, including the closure of dural defects [7].

In addition to acute discomfort, PDPH is also associated with prolonged hospital stays, increased healthcare costs, delayed maternal–infant bonding, and overall postpartum morbidity for pregnant women undergoing cesarean delivery under spinal anesthesia [8]. These downstream consequences underscore the need to preoperatively identify at-risk patients and to implement targeted preventive or early interventional strategies.

Hematological indices derived from routine complete blood counts – such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) – have gained attention as surrogate markers of systemic inflammation in many conditions [9,10]. A recent study by Park et al found that lower NLR values in patients with spontaneous intracranial hypotension were associated with the need for repeated epidural blood patch procedures, suggesting inadequately mediated healing in the setting of diminished inflammatory activity [11]. An insufficient inflammatory response can impede fibroblast activation, extracellular matrix deposition, and effective tissue sealing, all of which are critical for dural repair. Considered alongside the standardized nature of neuraxial anesthesia, these observations raise the possibility that baseline inflammatory status contributes to PDPH susceptibility. Previous studies in pregnant women have yielded inconsistent results regarding the association between preoperative inflammatory markers and post-dural puncture headache. In particular, Sargin et al did not find a significant relationship between NLR and PDPH in their cohort, suggesting that the predictive value of systemic inflammatory indices may be population- or methodology-dependent [12].

Accordingly, this study aimed to determine whether preoperative systemic inflammatory indices – particularly NLR, PLR, and MLR – are associated with the development of PDPH in a homogeneous cohort of pregnant women undergoing elective cesarean delivery under spinal anesthesia. Our second aim was to identify a clinically relevant cutoff value. Given the persistent occurrence of PDPH despite standardized atraumatic techniques, we sought to clarify whether baseline systemic inflammatory status – serving as a pragmatic surrogate of reparative capacity and dural healing – contributes to PDPH susceptibility in this specific population, while also defining a clinically applicable NLR cutoff. Thus, we aim to contribute to a biomarker-based personalized approach to anesthesia in pregnant women, going beyond traditional risk prediction based solely on demographic and technical factors.

Material and Methods

STUDY DESIGN AND ETHICS APPROVAL:

This retrospective, single-center cohort study was conducted at a tertiary university hospital to investigate the predictive value of preoperative inflammatory markers derived from complete blood counts (CBC) for the development of post-dural puncture headache (PDPH) in pregnant women undergoing cesarean section under spinal anesthesia. The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the İstinye University Clinical Research Ethics Committee (Decision No. 2025-101). Due to its retrospective design, individual patient consent was not required, and all data were analyzed in an anonymized manner. Although retrospective in nature, the study was prospectively registered at ClinicalTrials.gov (Identifier: NCT07075874, registered on July 17, 2025). The study was reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. To reduce potential sources of bias, consecutive patient recruitment and standardized data collection methods were used.

PATIENT POPULATION:

All consecutive pregnant women undergoing elective cesarean delivery under spinal anesthesia between January 2020 and December 2024 were screened for eligibility.

Exclusion criteria were:

After applying these criteria, patients with complete data and confirmed clinical follow-up were included in the final analysis.

ANESTHETIC TECHNIQUE:

Spinal anesthesia was performed according to our standard institutional protocol. Briefly, all patients undergoing cesarean delivery under spinal anesthesia were monitored with non-invasive blood pressure, electrocardiography, and pulse oximetry. An intravenous line was established with an 18–20 G peripheral cannula, and each patient received at least 500 mL of isotonic crystalloid solution 1 hour prior to the procedure as prehydration.

With the patient in the sitting position, the lumbar area was disinfected with povidone–iodine solution and covered with sterile drapes. After local infiltration of the skin with 1–2 mL of 2% lidocaine, a 26-gauge atraumatic pencil-point spinal needle (Whitacre type) was introduced via the midline approach at the L4–L5 interspace. The bevel was aligned parallel to dural fibers to minimize tissue trauma. Following free flow of cerebrospinal fluid (CSF), 10 mg of 0.5% hyperbaric bupivacaine was slowly injected intrathecally, without aspiration or barbotage. The needle was carefully withdrawn, and the patient was positioned supine with left uterine displacement to avoid aortocaval compression.

All spinal anesthesia procedures were performed by attending anesthesiologists with at least 3 years of experience using a standardized technique. No combined spinal-epidural or epidural techniques were used.

DIAGNOSIS OF PDPH:

The diagnosis of PDPH was established based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) [13]. Diagnostic criteria included headache onset within 5 days of dural puncture, worsened in the upright position, relieved by recumbency, and frequently accompanied by neck stiffness, photophobia, tinnitus, or nausea. All postural headaches fulfilling these criteria, including mild or non-disabling cases, were recorded.

Diagnoses were confirmed by attending anesthesiologists during the hospital stay and supplemented by follow-up records when necessary.

DATA COLLECTION:

Data were retrieved from the hospital’s electronic medical record system. Demographics: age, body mass index (BMI).

Hematological indices: complete blood count values obtained within 24 hours before surgery were used to calculate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and sSystemic inflammation response index (SIRI). According to institutional routine practice, all preoperative blood samples were drawn before labor onset and before any antenatal corticosteroid administration for fetal lung maturation.

STATISTICAL ANALYSIS:

All analyses were performed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA). The normality of continuous data was assessed with the Shapiro-Wilk test. Normally distributed variables were expressed as mean±standard deviation (SD), and non-normally distributed variables as median with interquartile range (IQR). Categorical variables were summarized as numbers and percentages.

For group comparisons, we used the t test or Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. In correlation analysis, Spearman’s rank correlation coefficients were used to explore associations between hematological indices and PDPH occurrence.

In regression analysis, univariate logistic regression was performed for potential predictors (age, BMI, NLR, PLR, MLR, SIRI). Variables with P<0.10 were entered into a multivariate logistic regression model to identify independent predictors, expressed as odds ratios (OR) with 95% confidence intervals (CI).

Receiver operating characteristic (ROC) curves were generated for significant independent predictors. The Youden index was used to define optimal cutoff values. Diagnostic performance was quantified using area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LR⁺, LR⁻).

A 2-tailed P value <0.05 was considered statistically significant. No formal sample size calculation was performed, as all eligible patients during the study period were included. As this was a retrospective study, all eligible patients during the study period were included, thus obviating the need for a priori sample size calculation.

Results

PATIENT SCREENING AND INCLUSION:

A total of 902 pregnant women who underwent cesarean section with spinal anesthesia between January 2020 and December 2024 were assessed for this study. During screening, 81 patients who met the exclusion criteria were removed from the dataset. Consequently, 821 patients remained for the final analysis. Among these, 133 patients (16.2%) developed post-dural puncture headache (PDPH), while 688 patients (83.8%) did not exhibit PDPH symptoms and were categorized as asymptomatic (Figure 1).

DEMOGRAPHIC CHARACTERISTICS AND PREOPERATIVE INFLAMMATORY MARKER LEVELS:

There were no statistically significant differences between the 2 groups in terms of age (P=0.114), BMI (P=0.188), PLR (P=0.729), or MLR (P=0.889). In contrast, the median NLR values of patients in the PDPH (+) group were significantly lower compared with those in the non-PDPH group (2.63 [IQR: 2.25–3.13] vs 3.82 [IQR: 3.22–4.61], P<0.001) (Table 1).

Figure 2 illustrates that median NLR values are notably lower in patients with PDPH compared to those without the condition. In contrast, the distributions of other parameters, including PLR, MLR, age, and BMI, appear largely similar between the groups, reflecting no statistically significant differences. SIRI values were also lower in the PDPH group; however, the overlap between groups was greater than that observed for NLR.

CORRELATION BETWEEN INFLAMMATORY INDICES AND PDPH:

Spearman rank correlation analysis conducted to evaluate the relationship between preoperative hematological parameters and the development of PDPH showed a moderate negative correlation of NLR (ρ=−0.41, P<0.001) and SIRI (ρ=−0.252, P<0.001) with PDPH. These findings indicate that lower NLR and SIRI values are associated with PDPH. In contrast, no significant correlation was found between PDPH and PLR, MLR, age, and BMI (Table 2).

UNIVARIATE AND MULTIVARIATE LOGISTIC REGRESSION ANALYSIS:

Uunivariate and multivariate logistic regression analyses were performed to evaluate the association of preoperative hematological parameters and demographic variables with PDPH. These analyses were conducted to evaluate independent associations and control for potential confounding (Tables 3, 4).

In the univariate analysis (Table 3), there was no statistically significant association between age, BMI, PLR, or MLR and the development of PDPH (all P values >0.1). In contrast, NLR and SIRI showed a statistically significant inverse association with PDPH (OR=0.54; 95% CI: 0.42–0.68; P<0.001, and OR=0.66; 95% CI: 0.52–0.83; P<0.001, respectively) (Table 3). These results suggest that lower NLR and SIRI levels are associated with PDPH.

In the multivariate logistic regression analysis (Table 4), where all variables were evaluated together, NLR remained the only variable significantly associated with PDPH (adjusted OR=0.51; 95% CI: 0.39–0.66; P<0.001). SIRI, PLR, MLR, age, and BMI were not associated with PDPH and did not maintain significance in the model (all P>0.05). These results demonstrate that NLR remained independently associated with PDPH after adjustment.

Although SIRI demonstrated a significant association with PDPH in the univariate analysis, this association was no longer significant in the multivariate analysis (P=0.069). This suggests that the effect of SIRI on the development of PDPH diminishes when evaluated alongside a stronger predictor such as NLR. It is likely that SIRI is related to NLR due to the inclusion of neutrophil and lymphocyte counts in its calculation, suggesting that NLR provides a more robust and independent signal than SIRI in the adjusted analysis.

ROC CURVE ANALYSIS FOR NLR PREDICTION VALUE:

We performed receiver operating characteristic (ROC) analysis (Figure 3) to assess the discriminatory performance of preoperative NLR values, which remained independently associated with PDPH in multivariate regression analysis. As a result of the analysis, the area under the curve (AUC) was calculated as 0.76, indicating moderate discriminatory performance (95% CI: 0.72–0.80, P<0.001). Using the Youden index, the optimal cutoff point was determined to be ≤3.14, with a sensitivity of 88.7% and a specificity of 66.2% for this value. Additionally, at this threshold, the positive predictive value (PPV) was calculated to be 65.4%, and the negative predictive value (NPV) was 92.1%. The clinical benefit of NLR in identifying patients at high risk for PDPH is supported by a positive likelihood ratio (LR+) of 2.5 and a negative likelihood ratio (LR−) of 0.2.

Discussion

LIMITATIONS:

This study has several limitations. Its retrospective, single-center design may limit generalizability. PDPH was diagnosed using clinical criteria, reflecting routine practice. Dynamic perioperative changes in inflammatory markers and molecular or immunophenotypic analyses were not assessed, and potential confounders such as postoperative mobilization, hydration, caffeine intake, and analgesic use were not systematically captured. In addition, the proposed NLR cutoff was not internally validated (eg, using bootstrapping or cross-validation) and should be considered exploratory until confirmed in prospective, multicenter studies with internal and external validation.

Conclusions

Lower preoperative NLR values were associated with PDPH and may be a practical marker for perioperative risk assessment. In contrast to SIRI, age, BMI, PLR, and MLR, which showed no independent predictive value in our cohort, NLR offers a straightforward and practical tool for guiding perioperative management. These findings provide a foundation for future investigations into preventive and therapeutic approaches in high-risk patients and support the integration of NLR into obstetric anesthesia practice. A deeper understanding of how pregnancy-related physiology, systemic inflammatory tone, and dural repair mechanisms interact may open pathways to novel therapeutic targets, tailored prophylactic strategies, and improved maternal outcomes.