The neutrophil-to-lymphocyte ratio: a marker for microbial invasion of the amniotic cavity in preterm prelabor rupture of membranes

Article information

Obstet Gynecol Sci. 2026;69(3):183-190

Publication date (electronic) : 2026 April 1

Da Eun Jeong, MD ¹^,^*, Min Jung Lee, MD ¹^,^*, Eun Ji Oh, MD ¹, Young Mi Jung, MD ¹^,², Hyeon Ji Kim, MD,¹^,², Jee Yoon Park, MD, PhD ¹^,², Kyung Joon Oh, MD, PhD ¹^,²

¹Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea

²Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Kyung Joon Oh, MD, PhD, Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea, E-mail: kjohmd@snubh.org, https://orcid.org/0000-0002-4558-7947

*These authors contributed equally to this article.

Received 2026 January 3; Revised 2026 February 24; Accepted 2026 March 22.

Abstract

Objective

This study investigated the relationship between maternal blood neutrophil-to-lymphocyte ratio (NLR), serum C-reactive protein (CRP) levels, and microbial invasion of the amniotic cavity (MIAC) in the context of preterm prelabor rupture of membranes (pPROM).

Methods

This retrospective cohort study included 154 women with pPROM between 20+0 and 33+6 weeks of gestation who underwent transabdominal amniocentesis. MIAC was defined as a positive amniotic fluid culture. Maternal blood samples were collected within 24 hours after amniocentesis. CRP levels and leukocyte differential counts were quantified.

Results

MIAC was diagnosed in 36.4% of patients with pPROM. Patients with MIAC had higher median NLR and CRP levels than those without MIAC (NLR, 6.8 vs. 5.0; CRP, 0.58 mg/dL vs. 0.26 mg/dL; both P=0.007). NLR and CRP exhibited comparable areas under the curve of 0.67 (95% confidence interval [CI], 0.58–0.75) vs. 0.63 (95% CI, 0.54–0.72); P=0.59. Receiver operating characteristic curve analysis was performed to establish diagnostic cutoff values for NLR and CRP (6.2 for NLR and 0.7 mg/dL for CRP). The prevalence of MIAC was highest in patients with both elevated NLR and CRP levels (54.3%) and lowest in those with low values of both parameters (18.8%). Intermediate prevalence rates were observed in patients with discordant NLR and CRP values.

Conclusion

NLR exhibited a positive association with MIAC in patients with pPROM, with diagnostic performance similar to CRP. Nonetheless, the presence of MIAC in 18.8% of patients with low levels of both parameters highlights the limitations of these measures in ruling out MIAC.

Keywords: Perterm premature rupture of membranes; Biomarkers; Chorioamnionitis; C-reactive protein; Neutrophilto-lymphocyte ratio

Introduction

Preterm prelabor rupture of membranes (pPROM) is responsible for approximately 25–30% of preterm births and is a major identifiable factor leading to preterm delivery [1]. Extensive research has shown that microbial invasion of the amniotic cavity (MIAC) is not only the most common cause of pPROM but is also strongly linked to adverse maternal and neonatal outcomes [2–5]. Timely and precise identification of MIAC in women with pPROM is essential, as it facilitates the prediction of preterm birth and the initiation of targeted interventions for preterm infants who face a higher risk of adverse outcomes, including neonatal sepsis, intraventricular hemorrhage, cerebral palsy, and neonatal mortality, compared to infants born to mothers without these complications [6–8]. Furthermore, recent studies have indicated that, in certain cases, MIAC can be effectively managed with a specific combination of antibiotics [9–13].

Although transabdominal amniocentesis is the definitive test for MIAC, it is invasive and carries risks such as miscarriage, multiple insertion attempts, and bloody taps, particularly in cases of pPROM with reduced amniotic fluid (AF) volume [14,15]. Therefore, a non-invasive diagnostic method is needed. C-reactive protein (CRP) is a commonly used inflammatory marker but has limited specificity for detecting MIAC [16–18]. Owing to this limitation, ongoing research aims to identify alternative markers that could either replace or supplement CRP.

Neutrophil-to-lymphocyte ratio (NLR) is gaining attention as an alternative marker because of its association with inflammation and infection [19–22]. However, the relationship between NLR and MIAC remains incompletely understood. This study explored the link between maternal blood NLR and MIAC and compared their diagnostic accuracy with that of CRP levels in patients presenting with pPROM.

Materials and methods

1.Study population and design

This retrospective cohort study included 154 patients with pPROM admitted to our institution between January 2012 and April 2022. The following inclusion criteria were applied: 1) singleton pregnancy; 2) gestational age from 20+0 to 33+6 weeks; and 3) AF obtained by transabdominal amniocentesis to evaluate the microbiological status and fetal lung maturity. In cases where repeated amniocentesis procedures were performed (n=12), only the microbiological and biochemical results from the initial procedure were used for analysis to ensure methodological consistency across the entire study population. No patients were excluded from the analysis based on the results of subsequent procedures or persistent clinical symptoms following the intention-to-treat principle. The exclusion criteria were as follows: 1) cerclage placement before amniocentesis and 2) fetal death in utero. Clinical and pregnancy outcome data were extracted from the medical records. The clinical information collected included maternal age, nulliparity, gestational age at amniocentesis, gestational age at delivery, and cervical length. The assessed pregnancy outcomes included birth weight, 1-minute and 5-minute Apgar scores, cord arterial blood pH, and neonatal intensive care unit (NICU) admission. This study adhered to the ethical standards for human experimentation outlined in the Declaration of Helsinki. The Institutional Review Board (IRB) approved the analysis of the clinical records, which included both AF analysis outcomes and supplementary research data (IRB No. B-2211-790-106). As this was a retrospective study based on a review of the medical records of patients who had already completed treatment and were discharged, the requirement for informed consent was waived by the IRB.

2. AF and maternal blood analysis

pPROM was defined as fluid leakage from the cervix or fluid pooling in the vagina being observed, followed by a nitrazine test for confirmation [23]. Patients with pPROM who were admitted before 34 weeks of gestation underwent transabdominal amniocentesis to assess the microbiological status of AF and/or lung maturity, in line with our institution’s established clinical protocol [24]. Routine assessment involved determining the maternal serum CRP concentrations alongside the white blood cell (WBC) counts. The need for informed consent was waived by the Institutional Review Board of this retrospective study.

AF samples were cultured to detect aerobic and anaerobic bacteria, genital mycoplasmas (Ureaplasma species or Mycoplasma hominis), and fungi. Bacterial culture was performed by placing the AF in BACTEC culture bottles (Becton Dickinson, Franklin Lakes, NJ, USA) containing resin, followed by incubation in a BACTEC FX automated system (Becton Dickinson). Positivity was indicated by an alarm signal. The final culture test results were determined 5 days later. A portion of the AF was transported to a microbiology laboratory, which cultivated genital mycoplasma using Mycoplasma IST-2 (BioMérieux, Marcy l’Etoile, France) for identification. A positive finding of AF was used to define MIAC.

Within a 24-hour period post amniocentesis, maternal blood samples were obtained. A complete blood count, including leukocyte differentials and CRP levels, was performed. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count.

3. Statistical analysis

We analyzed the clinical characteristics and pregnancy outcomes, along with CRP levels and NLR, in relation to the presence of MIAC. Proportional data were analyzed using either the Pearson chi-square test or Fisher’s exact test, while continuous variables were compared using the Mann-Whitney U-test. Statistical significance was defined as a P-value <0.05. To assess diagnostic accuracy, receiver operating characteristic (ROC) curve analysis was conducted to evaluate the specificity and sensitivity of CRP and NLR. The area under the curve (AUC) was calculated and used to obtain the diagnostic cutoff values. Statistical analyses were performed using SPSS software version 27.0 (IBM, Armonk, NY, USA).

Results

This study included 154 consecutive patients hospitalized with a diagnosis of pPROM who met the inclusion criteria. MIAC was found in 36.4% (56/154) of the patients. Among the 56 patients diagnosed with MIAC, the most frequently isolated microorganisms were genital mycoplasmas (n=49; 87.5%), including Ureaplasma species and/or Mycoplasma hominis. Other isolates included Candida albicans (n=2), Lactobacillus species (n=2), Cutibacterium acnes (n=1), Bifidobacterium species (n=1), and viridans streptococci (n=1). Additionally, unidentified Gram-positive rods (n=2) and Gram-positive cocci (n=1) were identified.

The median interval between the diagnosis of pPROM and transabdominal amniocentesis was 10.8 hours (interquartile range [IQR], 5.6–36.7). Data on this interval were available for 153 patients, 68.0% (104/153) of whom underwent the procedure within 24 hours of PROM diagnosis. Table 1 shows the clinical characteristics and outcomes according to whether patients had MIAC. In the MIAC group, gestational age at delivery, birth weight, and 1-minute Apgar score were significantly lower (P<0.05), while the NICU admission rate was significantly higher (P=0.022) than in the non-MIAC group. In contrast, there were no significant differences between the groups regarding maternal age, nulliparity, cervical length, 5-minute Apgar score, and cord arterial blood pH. Table 2 presents the leukocyte differential counts, NLR, and CRP levels for both groups (with or without MIAC). The WBC and neutrophil counts were significantly higher in patients with MIAC compared to those without (12.9 [IQR, 10.8–15.3] vs. 10.3 [IQR, 9.0–12.3]; P<0.001; 10.5 [IQR, 8.5–13.2] vs. 7.9 [IQR, 6.9–10.0]; P<0.001, respectively). There was no significant difference in lymphocyte counts between the two groups. Both NLR and CRP levels were significantly elevated in patients with MIAC compared to those without (6.8 [IQR, 4.8–10.2] vs. 5.0 [IQR, 3.6–7.4]; P=0.001; 0.58 mg/dL [IQR, 0.25–1.6] vs. 0.26 mg/dL [IQR, 0.19–0.87]; P=0.007, respectively) (Table 2).

Table 1

Clinical characteristics and pregnancy outcomes of the study population

Table 2

The levels of maternal blood inflammatory markers according to the presence of microbial invasion of the amniotic cavity

Fig. 1 shows the ROC curve for CRP and NLR. The AUC for NLR was 0.67 (95% CI, 0.58–0.75), while the AUC for CRP was 0.63 (95% CI, 0.54–0.72), with a non-significant P-value of 0.59. The optimal diagnostic cutoff values for NLR and CRP, determined using the ROC curve, were 6.2 for NLR and 0.7 mg/dL for CRP. At the cutoff of NLR ≥6.2, the sensitivity was 64.3%, specificity was 65.3%, positive likelihood ratio was 1.9, and negative likelihood ratio was 0.55. Conversely, at the cutoff of CRP ≥0.7 mg/dL, the sensitivity was 48.2%, specificity was 71.4%, positive likelihood ratio was 1.7, and negative likelihood ratio was 0.7 (Table 3).

Fig. 1

The receiver-operating characteristics analysis comparing C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) for predicting microbial invasion of the amniotic cavity. The area under the curve for NLR was 0.67 (95% CI, 0.58–0.75), while for CRP, it was 0.63 (95% CI, 0.54–0.72), with no statistically significant difference between them (P=0.59). CI, confidence interval.

Table 3

Receiver operating characteristic curves to assess the usefulness of maternal blood inflammatory markers

To further analyze the diagnostic value of NLR in combination with CRP, patients were divided into four groups based on their levels of NLR and CRP, using a cutoff value of 6.2 for NLR and 0.7 mg/dL for CRP. As indicated in Table 4, MIAC was most common in patients with high values for both parameters (54.3% [19/35]) and least common in those with low values for both NLR and CRP (18.8% [12/64]). Intermediate prevalence rates were found in patients with a high NLR but low CRP (48.6% [17/35]) or a low NLR but high CRP (40.0% [8/20]). The group with high NLR and low CRP exhibited a significant association with MIAC (odds ratio [OR], 4.09; 95% CI, 1.64–10.20; P=0.002). In contrast, the coexistence of a low NLR and high CRP was not significantly associated with MIAC. A high NLR combined with an elevated CRP level demonstrated the strongest association with MIAC (OR, 5.15; 95% CI, 2.06–12.84; P<0.0001).

Table 4

Prevalence of microbial invasion of the amniotic cavity according to neutrophil-to-lymphocyte ratio and C-reactive protein levels

The interval between amniocentesis and delivery was available for 133 patients (86.4%). Among them, the median interval was 7 days (IQR, 3–22 days), and the mean±standard deviation was 16.2±21.7 days. The remaining 21 patients were transferred to other tertiary centers for neonatal intensive care due to imminent delivery and limited NICU capacity or at the patients’ request, and their outcome data were not included in this analysis.

Discussion

1. Main findings of the study

The main findings of the present study were as follows: 1) NLR exhibited an independent positive association with MIAC in patients with pPROM; 2) NLR and CRP showed comparable diagnostic performance for detecting MIAC; and 3) patients with high values for both parameters showed the strongest association with MIAC. Nonetheless, it should be kept in mind that 18.8% (12/64) of patients with low NLR and low CRP had MIAC.

2. NLR and intra-amniotic infection

Neutrophils are crucial in defending against infections, and it has been proposed that the NLR can reliably indicate inflammation in various disease conditions [19,20,22,25,26]. A meta-analysis examining leukocyte ratios in peripheral blood for infectious diseases found that patients with bacterial infections exhibited markedly higher NLR levels [27]. Another study assessed maternal serum markers in cases of no placental inflammation, histologic chorioamnionitis, and histologic chorioamnionitis with funisitis among patients who underwent preterm delivery due to preterm labor or pPROM. This study underscored the effectiveness of NLR in diagnosing placental inflammatory responses and reported that it achieved the highest AUC value of 0.80 for predicting these responses. With a cutoff value of 6.5, the NLR showed a sensitivity of 71% and a specificity of 78% [28]. Consistent with these findings, our study demonstrated that patients with pPROM with MIAC had significantly higher WBC counts and NLR in maternal blood than those without MIAC.

3. Comparative diagnostic performance of NLR and CRP

Maternal CRP levels are one of the most widely used clinical parameters for assessing inflammation [11,26,29]. As maternal CRP secretion increases in response to intra-amniotic inflammation, it has been established as a marker for MIAC [16,30].

Multiple studies have demonstrated that NLR has a diagnostic value for predicting intra-amniotic inflammation that is comparable to or even greater than that of CRP [20,28,31]. In our study, ROC curve analysis revealed that maternal serum NLR and CRP have similar diagnostic effectiveness, reinforcing the potential of NLR as a predictive marker for MIAC on par with CRP. Additionally, when patients were categorized into four subgroups based on high or low levels of NLR and CRP, the highest incidence of MIAC was observed in the subgroup with elevated NLR and CRP levels. Notably, the subgroup with high NLR and low CRP showed a significantly higher rate of MIAC than the subgroup with low NLR and high CRP, indicating that the NLR may offer additional predictive value beyond CRP in diagnosing MIAC.

4. Strength and weakness

The strength of this study lies in its meticulous diagnostic approach, as MIAC was confirmed through direct sampling of AF via transabdominal amniocentesis, followed by culturing. This gold standard method significantly reduces diagnostic uncertainty. Maternal blood was obtained within 24 hours of amniocentesis to ensure that the results from both maternal blood and AF accurately reflected the infection status at the same time. Additionally, by directly comparing biomarkers such as NLR and CRP with a definitive MIAC diagnosis, this study delivers reliable and clinically meaningful results that can guide patient management.

One limitation of this study is that it involved patients from a single hospital, which may have restricted the generalizability of the findings. Additionally, the use of AF culture for diagnosing MIAC presents a limitation, potentially underestimating MIAC diagnosis rates, as molecular techniques, such as polymerase chain reaction, were not employed [32]. Our study focused primarily on the diagnostic accuracy of maternal markers for MIAC. We were unable to obtain outcome data for 21 patients who were transferred to other institutions because of imminent delivery, unavailable NICU beds, or patient preferences, as our IRB approval did not extend to data from external institutions. Although this resulted in missing data for gestational latency, we believe that it did not affect our primary findings regarding the independent association between maternal NLR and MIAC.

5. Clinical implications

Numerous markers in maternal blood have been studied as noninvasive methods for the diagnosis of MIAC. Although analyzing maternal blood offers valuable clinical insights, the definitive diagnosis of MIAC still depends on amniocentesis to collect and analyze the AF. The limitation of noninvasive tests lies in the fact that a negative result cannot exclude the presence of MIAC because maternal blood tests do not directly reflect the condition of the amniotic cavity [16,28,33].

Consistent with other studies that utilized maternal CRP levels, our research determined that using an NLR cutoff value of 6.2 and a CRP cutoff level of 0.7 mg/dL, MIAC was diagnosed in 18.8% (12/64) of patients with low NLR and low CRP. These findings suggest that although NLR and CRP levels can be valuable predictors of MIAC, the presence of MIAC cannot be ruled out based on the low levels of both markers.

Notes

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of our institution (IRB No. B-2211-790-106).

Patient consent

Informed consent was waived by the Institutional Review Board because of the retrospective design of the study and the use of anonymized clinical data. All patient data were fully anonymized before analysis, and no identifiable personal information was included in this study.

Funding information

This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare and the Ministry of Science and ICT, Republic of Korea (Grant No. HI22C1859). The funders had no role in the design of the study, data collection, analysis, or interpretation of the data in this manuscript.

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Variable	MIAC (+) (n=56)	MIAC (−) (n=98)	P-value
Maternal age (yr)	33.0 (31.0–36.0)	32.5 (29.8–35.0)	0.303
Nulliparity	37/56 (66.1)	57/98 (58.2)	0.333
Gestational age at amniocentesis (weeks)	29.1 (27.0–32.2)	29.2 (24.6–32.4)	0.984
Gestational age at delivery (weeks)^a	30.9 (28.1–32.5)	33.3 (30.3–34.1)	0.001
Cervical length (cm)	2.3 (1.3–3.3)	2.8 (2.0–3.3)	0.103
Cesarean delivery	17/50 (34.0)	31/83 (37.3)	0.714
Birth weight (g)^a	1,585 (1,160–1,930)	1,950 (1,440–2,265)	0.004
APGAR score at 1 minute^a	6 (5–7)	7 (5–8)	0.047
APGAR score at 5 minutes^a	8 (7–9)	8 (7–9)	0.175
Cord arterial blood pH^a	7.33 (7.29–7.36)	7.31 (7.27–7.34)	0.147
Fetal death in utero^a	2/50 (4.0)	3/83 (3.6)	1.000
Immediate neonatal death in delivery room^a	1/50 (2.0)	3/83 (3.6)	1.000
NICU admission^a,b	47/47 (100.0)	69/77 (89.6)	0.022

Marker	MIAC (+) (n=56)	MIAC (−) (n=98)	P-value
White blood cells (×10⁹/L)	12.9 (10.8–15.3)	10.3 (9.0–12.3)	<0.001
Neutrophils (×10⁹/L)	10.5 (8.5–13.2)	7.9 (6.9–10.0)	<0.001
Lymphocytes (×10⁹/L)	1.5 (1.2–1.9)	1.6 (1.2–2.0)	0.240
Neutrophil-to-lymphocyte ratio	6.8 (4.8–10.2)	5.0 (3.6–7.4)	0.001
C-reactive protein (mg/dL)	0.58 (0.25–1.6)	0.26 (0.19–0.87)	0.007

Group	MIAC prevalence	Odds ratio	95% CI	P-value
Low NLR/low CRP	18.8% (12/64)	Reference
Low NLR/high CRP	40.0% (8/20)	2.89	0.97–8.62	0.057
High NLR/low CRP	48.6% (17/35)	4.09	1.64–10.20	0.002
High NLR/high CRP	54.3% (19/35)	5.15	2.06–12.84	<0.0001

Marker	Cut-off	Sensitivity (%)	Specificity (%)	AUC	95% CI
Neutrophil-to-lymphocyte ratio	6.2	64.3	65.3	0.67	0.58–0.75
C-reactive protein (mg/dL)	0.7	48.2	71.4	0.63	0.54–0.72