# Relationship between Platelet-to-Lymphocyte Ratio and Lymphocyte-to-Monocyte Ratio with Spontaneous Preterm Birth: A Systematic Review and Meta-analysis

Authors: Liang Peng; Baodi Cao; Fangpeng Hou; Baolin Xu; Hong Zhou; Luyi Liang; Yu Jiang; Xiaohui Wang; Jingjian Zhou
Journal: Journal of Immunology Research
 (2023)

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## Abstract

Background. Spontaneous preterm birth is one of the most common pregnancy complications in obstetric clinical practice, and its etiology is complex. The problems of low survival and high morbidity rates of premature infants need to be solved urgently. The platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) are two novel biomarkers of inflammation, and several studies have linked PLR and LMR to spontaneous preterm birth. These systematic review and meta-analysis are aimed at analyzing the relationship between PLR and LMR in patients with spontaneous preterm birth to provide new ideas for the early prevention and treatment of spontaneous preterm births. Methods. Cochrane Library, EMBASE, PubMed, and China National Knowledge Infrastructure databases were inspected to gather PLR and LMR in patients with spontaneous preterm birth, all from the database to February 2022. Interstudy heterogeneity was evaluated using Cochran’s Q test and I2 statistic. Differences in PLR and LMR between patients with spontaneous preterm birth and full-term controls were evaluated by computing standardized mean differences and 95% confidence intervals. Publication bias and sensitivity analyses were also performed. Results. Nine studies were included in the meta-analysis based on the inclusion and exclusion criteria. The meta-analysis showed that serum PLR values were remarkably larger for patients with spontaneous preterm birth than for full-term controls (SMD=0.49, 95% CI: 0.13 to 0.84, P=0.007), whereas the difference between serum LMR in patients with spontaneous preterm birth and full-term controls was not statistically significant (SMD: 0.35, 95% CI: -0.18, 0.88, P=0.199). The results of Begg’s and Egger’s tests revealed that the publication bias of the meta-analysis was not significant. The outcomes of the sensitivity analysis showed that the individual studies did not influence the meta-analysis results. Conclusions. Current evidence shows that PLR is strongly associated with spontaneous preterm birth, whereas LMR is not. PLR has a certain clinical value in diagnosing and treating spontaneous preterm births, and our research will provide strong theoretical support for clinical work. In the future, it will be necessary to further explore the reasons for the increased PLR in the serum of patients with spontaneous preterm birth and other mechanisms inducing spontaneous preterm birth.


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## Body

## 1. Introduction

According to its definition, preterm labor refers to pregnancy termination before 37 weeks of gestation. It is one of a common complication in obstetrics [1]. The incidence of preterm birth exceeds 10% worldwide, affecting more than 15 million births each year [2, 3]. A study that analyzed data from 107 countries estimated the global preterm birth rate to be 10.6% in 2014. Complications from preterm birth were the biggest culprit of death in children aged under five [4]. After preterm birth, problems include chronic respiratory disease, neurodevelopmental disorders, and long-term cognitive impairment, whose effects can last a lifetime, burdening families, society, and medical institutions [5].According to etiology, preterm labor is divided into spontaneous and therapeutic preterm labor, with spontaneous preterm labor accounting for the majority of preterm births [6]. Spontaneous preterm birth is the unexpected occurrence of threatened preterm birth, preterm labor, and preterm delivery before 37 weeks of pregnancy, including premature delivery and preterm premature rupture of membranes [7]. The lack of specificity of preterm birth makes it difficult to distinguish actual preterm birth from false preterm birth, which can easily lead to over diagnosis and over treatment. In addition, some preterm births occur without noticeable clinical symptoms, making it easy to miss the diagnosis [8]. Therefore, it is essential to fully understand the mechanism of spontaneous preterm birth and to be able to forecast the incidence of preterm birth as soon as possible so that clinicians can timely and effectively intervene in the incidence of preterm birth; the morbidity and mortality of fetuses and newborns can be diminished [9].The etiology and mechanisms of spontaneous preterm labor are intricate. These include infection, uteroplacental ischemia, meconium hemorrhage, maternal immune tolerance to the fetus, excessive uterine volume (e.g., multiple pregnancies with excessive amniotic fluid), cervical insufficiency, and hormonal abnormalities. Despite several etiologies of preterm labor, the most typical culprits of spontaneous preterm labor are infection and inflammation [10, 11]. PLR and LMR have become new biomarkers of inflammation because of their convenience in detecting and reflecting the level of inflammation in the body. At present, PLR and LMR have been reported in tumors [12, 13], rheumatic diseases [14], erectile dysfunction [15], and other diseases and are associated with a variety of poor prognoses under different conditions. They are associated with various poor prognoses for different diseases. PLR and LMR also have some application value in obstetrics and gynecology. For example, for patients with preeclampsia, PLR levels can be higher than those of pregnant women in good health condition with normal blood pressure, and PLR may help predict the occurrence of preeclampsia [16, 17]. Another study reported that worse overall survival and progression-free survival in patients with ovarian cancer were correlated with lower LMR levels among patients with ovarian cancer. These findings may assist in assessing the prognosis of ovarian cancer [18].To our knowledge, there are several clinical studies that have investigated the potential relationship between PLR, LMR, and spontaneous preterm birth. However, given the limited number of cases in a single study and seemingly contradictory results, a meta-analysis is necessary to aggregate published studies to provide more clues that corroborate the association between NLR, PLR, and spontaneous preterm birth. Therefore, in this study, a systematic review and meta-analysis were performed to evaluate the association and application value of PLR and LMR more objectively and systematically with spontaneous preterm birth.


## 2. Methods

### 2.1. Study Design and Enrollment

The study design adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, which contains 27 items and a flow chart [19].The study was registered on INPLASY, an international platform for system reviews (registration number INPLASY202230092). Detailed plans can be viewed on the website (10.37766/inplasy2022.3.0092). This study was based on the literature published by others. Therefore, ethics committee approval was not required for this study.


### 2.2. Literature Search Strategy

This study was conducted from the establishment of the library on March 10, 2022. Two researchers searched for relevant literature using the CNKI, EMBASE, PubMed, and Cochrane Library databases. No language restrictions were imposed for this study. The search had no language restrictions. The terms used for the search included “preterm birth”, “preterm labor”, “preterm delivery”, “preterm” combined with “neutrophil to lymphocyte ratio”, “lymphocyte to monocyte ratio”, and “haematological parameters”. The search strategy was fine-tuned for a specific database. The most recent or complete literature was included when the same patient population was analyzed in multiple publications.


### 2.3. Inclusion and Exclusion Criteria

Studies were initially filtered based on their titles and abstracts, followed by full-text screening, and those who fulfilled a number of criteria were selected: (1) included patients were clinically diagnosed with spontaneous preterm delivery; (2) the LMR and PLR were tested at admission or during hospitalization for spontaneous preterm delivery; (3) studies that presented the account of cases and controls, the mean, standard deviation, or median and interquartile range of LMR and/or PLR; (4) observational study design; and (5) published full-text articles were included, and gray literature was excluded.The exclusion criteria were (1) nonclinically controlled studies such as reviews, case reports, empirical summaries, primary research, and conference abstracts and (2) duplicate publications or reports of incomplete extracted data.


### 2.4. Data Extraction

The authors (Fangpeng Hou and Baolin Xu) separately screened and evaluated the literature and employed standardized data collection tables for data extraction, with the recorded information covering the first author, year of publication, duration, country of study, type of study, sample size (tests/controls), mean maternal age (tests/controls), time to test for complete blood count, mean and standard deviation, or median and interquartile range of LMR and/or PLR. The extracted data were entered into Microsoft Excel. For missing data, the corresponding authors were contacted via email. Two authors independently searched all the references. In cases of disagreement, all authors were resolved based on the voting results.


### 2.5. Methodological Quality Evaluation

All the included literatures were case-control studies. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the risk of study bias [20]. The NOS scale consists of three dimensions with eight entries: four entries for study subject selection, one entry for between-group comparability, and three entries for outcome measures, with the exception of comparability entry, which received a maximum of 2 stars, and the other entries received a maximum of 1 star, with a score range of 0 to 9 stars. A higher total score in a study implies a better quality. Studies with a score of ≥7 were considered high-quality studies. The evaluation process was carried out independently by both authors (Hong Zhou and Luyi Liang), and when there was disagreement, a consensus was reached through discussion with a third party (Yu Jiang).


### 2.6. Statistical Analysis

All statistical analyses were completed using STATA12.0 software. Because there were studies with inconsistent LMR and/or PLR units, the standardized mean difference (SMD) was selected as the effect size and 95% confidence intervals were selected. The Cochran’sQ test and I2 test were used to assess the heterogeneity between studies. When P was less than 0.1 or I2 was greater than 50%, heterogeneity between studies was regarded significant, and a random-effects model was applied. Conversely, a fixed-effects model was used. Subgroup analysis was leveraged for identifying potential sources of heterogeneity. For the sensitivity analysis, we removed the included studies one after another and observed the change in the combined effect size after excluding one study. To evaluate publication bias, we employed Begg’s rank correlation method and Egger’s regression method. P<0.05 was considered statistically significant.


## 2.1. Study Design and Enrollment

The study design adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, which contains 27 items and a flow chart [19].The study was registered on INPLASY, an international platform for system reviews (registration number INPLASY202230092). Detailed plans can be viewed on the website (10.37766/inplasy2022.3.0092). This study was based on the literature published by others. Therefore, ethics committee approval was not required for this study.


## 2.2. Literature Search Strategy

This study was conducted from the establishment of the library on March 10, 2022. Two researchers searched for relevant literature using the CNKI, EMBASE, PubMed, and Cochrane Library databases. No language restrictions were imposed for this study. The search had no language restrictions. The terms used for the search included “preterm birth”, “preterm labor”, “preterm delivery”, “preterm” combined with “neutrophil to lymphocyte ratio”, “lymphocyte to monocyte ratio”, and “haematological parameters”. The search strategy was fine-tuned for a specific database. The most recent or complete literature was included when the same patient population was analyzed in multiple publications.


## 2.3. Inclusion and Exclusion Criteria

Studies were initially filtered based on their titles and abstracts, followed by full-text screening, and those who fulfilled a number of criteria were selected: (1) included patients were clinically diagnosed with spontaneous preterm delivery; (2) the LMR and PLR were tested at admission or during hospitalization for spontaneous preterm delivery; (3) studies that presented the account of cases and controls, the mean, standard deviation, or median and interquartile range of LMR and/or PLR; (4) observational study design; and (5) published full-text articles were included, and gray literature was excluded.The exclusion criteria were (1) nonclinically controlled studies such as reviews, case reports, empirical summaries, primary research, and conference abstracts and (2) duplicate publications or reports of incomplete extracted data.


## 2.4. Data Extraction

The authors (Fangpeng Hou and Baolin Xu) separately screened and evaluated the literature and employed standardized data collection tables for data extraction, with the recorded information covering the first author, year of publication, duration, country of study, type of study, sample size (tests/controls), mean maternal age (tests/controls), time to test for complete blood count, mean and standard deviation, or median and interquartile range of LMR and/or PLR. The extracted data were entered into Microsoft Excel. For missing data, the corresponding authors were contacted via email. Two authors independently searched all the references. In cases of disagreement, all authors were resolved based on the voting results.


## 2.5. Methodological Quality Evaluation

All the included literatures were case-control studies. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the risk of study bias [20]. The NOS scale consists of three dimensions with eight entries: four entries for study subject selection, one entry for between-group comparability, and three entries for outcome measures, with the exception of comparability entry, which received a maximum of 2 stars, and the other entries received a maximum of 1 star, with a score range of 0 to 9 stars. A higher total score in a study implies a better quality. Studies with a score of ≥7 were considered high-quality studies. The evaluation process was carried out independently by both authors (Hong Zhou and Luyi Liang), and when there was disagreement, a consensus was reached through discussion with a third party (Yu Jiang).


## 2.6. Statistical Analysis

All statistical analyses were completed using STATA12.0 software. Because there were studies with inconsistent LMR and/or PLR units, the standardized mean difference (SMD) was selected as the effect size and 95% confidence intervals were selected. The Cochran’sQ test and I2 test were used to assess the heterogeneity between studies. When P was less than 0.1 or I2 was greater than 50%, heterogeneity between studies was regarded significant, and a random-effects model was applied. Conversely, a fixed-effects model was used. Subgroup analysis was leveraged for identifying potential sources of heterogeneity. For the sensitivity analysis, we removed the included studies one after another and observed the change in the combined effect size after excluding one study. To evaluate publication bias, we employed Begg’s rank correlation method and Egger’s regression method. P<0.05 was considered statistically significant.


## 3. Results

### 3.1. Search Results

Multiple databases were retrieved using search strategies to obtain the original literature of 128 studies. Literature screening was performed using the EndNote X9 software, removing 60 duplicate studies. Next, 57 records were removed by reading the titles and abstracts of the literature. The remaining 11 records were entered into the full-text search, two of which were further excluded because incomplete data according to the inclusion criteria were described above. Finally, 9 studies were screened for subsequent meta-analysis. Figure1 illustrates this process.Figure 1
The literature screening process.


### 3.2. Attributes of Studies Included

The years of publication of the nine included studies were between 2016 and 2021. Among them, four were from China, three were from Turkey, one was from Egypt, and one was from Korea. Two of them were prospective case-control studies, and seven were retrospective case-control studies. Nine studies reported PLR values in 1115 patients with spontaneous preterm delivery and 1222 full-term controls. Five studies reported the LMR values in 297 patients with spontaneous preterm delivery and 767 full-term patients. The attributes of the included studies are listed in Table1.Table 1
The included studies and their attributes.
Study, yearCountryDurationStudy designSample size (T/C)Age (T/C)ParametersCBC testDaglar et al., 2016 [28]Turkey2011-2012Prospective case control30/5326.4±8.2/26.7±8.4PLR, LMRUpon admissionGezer et al., 2018 [29]Turkey2010-2015Retrospective case control229/17825.9±5.1/26.8±5.3PLRUpon admissionJaffar and Feissal Rabie, 2018 [30]EgyptDuring 2017Retrospective case control439/20028.0±3.8/27.9±3.3PLRNot reportedChen et al., 2019 [31]China2016-2017Retrospective case control100/116Not reportedPLR, LMR28-30 weeks of pregnancyOzel et al., 2019 [32]Turkey2016-2017Retrospective case control110/4729.27±5.2/28.1±2.2PLRUpon admissionCha et al., 2020 [33]Korea2015-2017Prospective case control28/30832.1±4.2/33.1±4.8PLR, LMR24-28 weeks of pregnancyMa et al., 2020 [34]ChinaDuring 2017Retrospective case control105/21029.93±4.039/30.07±4.201PLR, LMR20-30 weeks of pregnancyWu et al., 2020 [35]ChinaDuring 2019Retrospective case control34/8036.07±1.16/39.30±0.75PLR, LMRUpon admissionMi and Sun, 2021 [36]China2017-2020Retrospective case control40/3025.5±6.5/25.8±6.6PLRUpon admission


### 3.3. Qualitative Analysis of the Included Studies

We performed a methodological assessment of the literature quality for all included articles, rating two of them as high-quality studies with 7-star NOS ratings. The remaining seven articles were rated six stars with average quality. The results are shown in Additional File 1: Supplementary Table1.


### 3.4. Meta-analysis Results

#### 3.4.1. Analysis of Serum PLR Levels in Patients with Spontaneous Preterm Delivery and Controls

Figure2 presents a forest plot of the association between the PLR and spontaneous preterm delivery. All nine studies reported serum PLR levels in patients with spontaneous preterm delivery and full-term controls. The results of the overall heterogeneity test showed a high degree of heterogeneity among the included studies (P<0.01, I2=92.5%). Therefore, a random-effects model was employed to analyze it, with the resulting pooled effect size manifesting a discrepancy that was statistically significant in serum PLR levels in the spontaneous preterm birth group compared to the control group (SMD=0.49, 95% CI: 0.13 to 0.84, P=0.007).Figure 2
Forest plot of PLR levels in the spontaneous preterm birth group comparing to the control group.We also carried out subgroup analyses regarding their geographical location, with five articles from Asian regions and four articles from non-Asian regions. The results from the Asian region did not consider serum PLR levels in patients with spontaneous preterm birth to be higher than those in controls (SMD=0.77, 95% CI: -0.03 to 1.57, P=0.059), whereas the results of the non-Asian analysis considered serum levels to be higher in patients with spontaneous preterm birth than in controls (SMD=0.28, 95% CI: 0.17 to 0.40, P<0.001). A subgroup analysis was conducted according to sample size, with a sample size of <100 cases for three publications and ≥100 cases for five publications. There was no significant association between serum PLR levels and spontaneous preterm delivery at sample sizes below 100 (SMD=0.94, 95% CI: -0.30 to 2.18, P=0.136) and at sample sizes of 100 or more; higher serum PLR levels were associated with spontaneous preterm delivery (SMD=0.22, 95% CI: 0.06 to 0.38, P<0.01). Additionally, the serum PLR levels in patients with spontaneous preterm delivery outweighed those in full-term controls when complete blood counts were tested at admission (SMD=0.87, 95% CI: 0.11 to 1.62, P<0.01) and in retrospective case-control studies (SMD=0.65, 95% CI: 0.24 to 1.06, P<0.01) (Table 2).Table 2
PLR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia50.77 (-0.03, 1.57)0.05992.5<0.001RandomNon-Asia40.28 (0.17, 0.40)<0.00100.482FixedCase number<10030.94 (-0.30, 2.18)0.13696.5<0.001Fixed≥10050.22 (0.06, 0.38)0.00858.50.047FixedCBC testUpon admission50.87 (0.11, 1.62)0.02595.2<0.001FixedOther40.11 (-0.15, 0.38)0.3992.5<0.001FixedStudy designProspective case control2-0.10 (-0.39, 0.19)0.49900.508FixedRetrospective case control70.65 (0.24, 1.06)0.00293.9<0.001Random


#### 3.4.2. Analysis of Serum LMR Levels in Patients with Spontaneous Preterm Delivery versus Controls

As shown in Figure3, a meta-analysis of the results of the five included studies was conducted. The results revealed that heterogeneity existed among the five works (P<0.01, I2=92%); therefore, a random-effects model was chosen. The combined SMD value was 0.35 (95% CI: -0.18−0.88, P=0.199), and no discrepancy could be considered between the spontaneous preterm birth and control groups regarding serum LMR levels.Figure 3
Forest plot of LMR levels in the spontaneous preterm birth group in comparison to the control group.As shown in Table3, subgroup analyses were performed based on the geographic location, sample size, time of detection of complete blood counts, and study design. Subgroup analysis based on sample size and time of detection of complete blood counts, respectively, revealed that LMR levels in the spontaneous preterm group outweighed those in the control group at sample sizes<100 (SMD=0.44, 95% CI: 0.19 to 0.68, P<0.001); LMR levels were higher in the spontaneous preterm group than in the control group (SMD=0.70, 95% CI: 0.39 to 1.01, P<0.001) when the complete blood count was measured at admission. Subgroup analysis according to geographical location and study design showed no difference in serum LMR levels between the spontaneous preterm birth and control groups (all P>0.05).Table 3
LMR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia40.34 (-0.31, 0.98)0.30593.9<0.001RandomNon-Asia10.41 (-0.05, 0.86)0.079———Case number<10030.44 (0.19, 0.68)<0.00181.10.005Random≥10020.11 (-0.07, 0.29)0.21597.1<0.001RandomCBC testUpon admission20.70 (0.39, 1.01)<0.00167.70.079RandomOther30.10 (-0.07, 0.26)0.24994.3<0.001RandomStudy designProspective case control20.18 (-0.12, 0.47)0.23340.20.196FixedRetrospective case control30.44 (-0.41, 1.29)0.30695.8<0.001Random


### 3.5. Publication Bias

We used Begg’s test and Egger’s test to verify publication bias. An absence of publication bias was observed in nine studies reporting PLR values (P=0.917 for Begg’s test and P=0.305 for Egger’s test). No significant publication bias was observed in five studies that reported LMR values (P=0.806 for Begg’s test and P=0.396 for Egger’s test). The funnel plots of the PLR and LMR are shown in Figure 4.Figure 4
Begg’s funnel plot for assessing publication bias. (a) Begg’s funnel plot for assessing publication bias for PLR. (b) Begg’s funnel plot for evaluating publication bias for LMR.
(a)(b)


### 3.6. Sensitivity Analysis

We conducted a sensitivity analysis employing a one-by-one elimination method to ensure the stability of this study’s findings. The results showed that the combined effect sizes of the meta-analysis did not change significantly after the sequential elimination of any study, suggesting that the stability of the results was good (Figure5).Figure 5
Sensitivity analysis. (a) Sensitivity analysis of PLR. (b) Sensitivity analysis of LMR.
(a)(b)


## 3.1. Search Results

Multiple databases were retrieved using search strategies to obtain the original literature of 128 studies. Literature screening was performed using the EndNote X9 software, removing 60 duplicate studies. Next, 57 records were removed by reading the titles and abstracts of the literature. The remaining 11 records were entered into the full-text search, two of which were further excluded because incomplete data according to the inclusion criteria were described above. Finally, 9 studies were screened for subsequent meta-analysis. Figure1 illustrates this process.Figure 1
The literature screening process.


## 3.2. Attributes of Studies Included

The years of publication of the nine included studies were between 2016 and 2021. Among them, four were from China, three were from Turkey, one was from Egypt, and one was from Korea. Two of them were prospective case-control studies, and seven were retrospective case-control studies. Nine studies reported PLR values in 1115 patients with spontaneous preterm delivery and 1222 full-term controls. Five studies reported the LMR values in 297 patients with spontaneous preterm delivery and 767 full-term patients. The attributes of the included studies are listed in Table1.Table 1
The included studies and their attributes.
Study, yearCountryDurationStudy designSample size (T/C)Age (T/C)ParametersCBC testDaglar et al., 2016 [28]Turkey2011-2012Prospective case control30/5326.4±8.2/26.7±8.4PLR, LMRUpon admissionGezer et al., 2018 [29]Turkey2010-2015Retrospective case control229/17825.9±5.1/26.8±5.3PLRUpon admissionJaffar and Feissal Rabie, 2018 [30]EgyptDuring 2017Retrospective case control439/20028.0±3.8/27.9±3.3PLRNot reportedChen et al., 2019 [31]China2016-2017Retrospective case control100/116Not reportedPLR, LMR28-30 weeks of pregnancyOzel et al., 2019 [32]Turkey2016-2017Retrospective case control110/4729.27±5.2/28.1±2.2PLRUpon admissionCha et al., 2020 [33]Korea2015-2017Prospective case control28/30832.1±4.2/33.1±4.8PLR, LMR24-28 weeks of pregnancyMa et al., 2020 [34]ChinaDuring 2017Retrospective case control105/21029.93±4.039/30.07±4.201PLR, LMR20-30 weeks of pregnancyWu et al., 2020 [35]ChinaDuring 2019Retrospective case control34/8036.07±1.16/39.30±0.75PLR, LMRUpon admissionMi and Sun, 2021 [36]China2017-2020Retrospective case control40/3025.5±6.5/25.8±6.6PLRUpon admission


## 3.3. Qualitative Analysis of the Included Studies

We performed a methodological assessment of the literature quality for all included articles, rating two of them as high-quality studies with 7-star NOS ratings. The remaining seven articles were rated six stars with average quality. The results are shown in Additional File 1: Supplementary Table1.


## 3.4. Meta-analysis Results

### 3.4.1. Analysis of Serum PLR Levels in Patients with Spontaneous Preterm Delivery and Controls

Figure2 presents a forest plot of the association between the PLR and spontaneous preterm delivery. All nine studies reported serum PLR levels in patients with spontaneous preterm delivery and full-term controls. The results of the overall heterogeneity test showed a high degree of heterogeneity among the included studies (P<0.01, I2=92.5%). Therefore, a random-effects model was employed to analyze it, with the resulting pooled effect size manifesting a discrepancy that was statistically significant in serum PLR levels in the spontaneous preterm birth group compared to the control group (SMD=0.49, 95% CI: 0.13 to 0.84, P=0.007).Figure 2
Forest plot of PLR levels in the spontaneous preterm birth group comparing to the control group.We also carried out subgroup analyses regarding their geographical location, with five articles from Asian regions and four articles from non-Asian regions. The results from the Asian region did not consider serum PLR levels in patients with spontaneous preterm birth to be higher than those in controls (SMD=0.77, 95% CI: -0.03 to 1.57, P=0.059), whereas the results of the non-Asian analysis considered serum levels to be higher in patients with spontaneous preterm birth than in controls (SMD=0.28, 95% CI: 0.17 to 0.40, P<0.001). A subgroup analysis was conducted according to sample size, with a sample size of <100 cases for three publications and ≥100 cases for five publications. There was no significant association between serum PLR levels and spontaneous preterm delivery at sample sizes below 100 (SMD=0.94, 95% CI: -0.30 to 2.18, P=0.136) and at sample sizes of 100 or more; higher serum PLR levels were associated with spontaneous preterm delivery (SMD=0.22, 95% CI: 0.06 to 0.38, P<0.01). Additionally, the serum PLR levels in patients with spontaneous preterm delivery outweighed those in full-term controls when complete blood counts were tested at admission (SMD=0.87, 95% CI: 0.11 to 1.62, P<0.01) and in retrospective case-control studies (SMD=0.65, 95% CI: 0.24 to 1.06, P<0.01) (Table 2).Table 2
PLR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia50.77 (-0.03, 1.57)0.05992.5<0.001RandomNon-Asia40.28 (0.17, 0.40)<0.00100.482FixedCase number<10030.94 (-0.30, 2.18)0.13696.5<0.001Fixed≥10050.22 (0.06, 0.38)0.00858.50.047FixedCBC testUpon admission50.87 (0.11, 1.62)0.02595.2<0.001FixedOther40.11 (-0.15, 0.38)0.3992.5<0.001FixedStudy designProspective case control2-0.10 (-0.39, 0.19)0.49900.508FixedRetrospective case control70.65 (0.24, 1.06)0.00293.9<0.001Random


### 3.4.2. Analysis of Serum LMR Levels in Patients with Spontaneous Preterm Delivery versus Controls

As shown in Figure3, a meta-analysis of the results of the five included studies was conducted. The results revealed that heterogeneity existed among the five works (P<0.01, I2=92%); therefore, a random-effects model was chosen. The combined SMD value was 0.35 (95% CI: -0.18−0.88, P=0.199), and no discrepancy could be considered between the spontaneous preterm birth and control groups regarding serum LMR levels.Figure 3
Forest plot of LMR levels in the spontaneous preterm birth group in comparison to the control group.As shown in Table3, subgroup analyses were performed based on the geographic location, sample size, time of detection of complete blood counts, and study design. Subgroup analysis based on sample size and time of detection of complete blood counts, respectively, revealed that LMR levels in the spontaneous preterm group outweighed those in the control group at sample sizes<100 (SMD=0.44, 95% CI: 0.19 to 0.68, P<0.001); LMR levels were higher in the spontaneous preterm group than in the control group (SMD=0.70, 95% CI: 0.39 to 1.01, P<0.001) when the complete blood count was measured at admission. Subgroup analysis according to geographical location and study design showed no difference in serum LMR levels between the spontaneous preterm birth and control groups (all P>0.05).Table 3
LMR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia40.34 (-0.31, 0.98)0.30593.9<0.001RandomNon-Asia10.41 (-0.05, 0.86)0.079———Case number<10030.44 (0.19, 0.68)<0.00181.10.005Random≥10020.11 (-0.07, 0.29)0.21597.1<0.001RandomCBC testUpon admission20.70 (0.39, 1.01)<0.00167.70.079RandomOther30.10 (-0.07, 0.26)0.24994.3<0.001RandomStudy designProspective case control20.18 (-0.12, 0.47)0.23340.20.196FixedRetrospective case control30.44 (-0.41, 1.29)0.30695.8<0.001Random


## 3.4.1. Analysis of Serum PLR Levels in Patients with Spontaneous Preterm Delivery and Controls

Figure2 presents a forest plot of the association between the PLR and spontaneous preterm delivery. All nine studies reported serum PLR levels in patients with spontaneous preterm delivery and full-term controls. The results of the overall heterogeneity test showed a high degree of heterogeneity among the included studies (P<0.01, I2=92.5%). Therefore, a random-effects model was employed to analyze it, with the resulting pooled effect size manifesting a discrepancy that was statistically significant in serum PLR levels in the spontaneous preterm birth group compared to the control group (SMD=0.49, 95% CI: 0.13 to 0.84, P=0.007).Figure 2
Forest plot of PLR levels in the spontaneous preterm birth group comparing to the control group.We also carried out subgroup analyses regarding their geographical location, with five articles from Asian regions and four articles from non-Asian regions. The results from the Asian region did not consider serum PLR levels in patients with spontaneous preterm birth to be higher than those in controls (SMD=0.77, 95% CI: -0.03 to 1.57, P=0.059), whereas the results of the non-Asian analysis considered serum levels to be higher in patients with spontaneous preterm birth than in controls (SMD=0.28, 95% CI: 0.17 to 0.40, P<0.001). A subgroup analysis was conducted according to sample size, with a sample size of <100 cases for three publications and ≥100 cases for five publications. There was no significant association between serum PLR levels and spontaneous preterm delivery at sample sizes below 100 (SMD=0.94, 95% CI: -0.30 to 2.18, P=0.136) and at sample sizes of 100 or more; higher serum PLR levels were associated with spontaneous preterm delivery (SMD=0.22, 95% CI: 0.06 to 0.38, P<0.01). Additionally, the serum PLR levels in patients with spontaneous preterm delivery outweighed those in full-term controls when complete blood counts were tested at admission (SMD=0.87, 95% CI: 0.11 to 1.62, P<0.01) and in retrospective case-control studies (SMD=0.65, 95% CI: 0.24 to 1.06, P<0.01) (Table 2).Table 2
PLR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia50.77 (-0.03, 1.57)0.05992.5<0.001RandomNon-Asia40.28 (0.17, 0.40)<0.00100.482FixedCase number<10030.94 (-0.30, 2.18)0.13696.5<0.001Fixed≥10050.22 (0.06, 0.38)0.00858.50.047FixedCBC testUpon admission50.87 (0.11, 1.62)0.02595.2<0.001FixedOther40.11 (-0.15, 0.38)0.3992.5<0.001FixedStudy designProspective case control2-0.10 (-0.39, 0.19)0.49900.508FixedRetrospective case control70.65 (0.24, 1.06)0.00293.9<0.001Random


## 3.4.2. Analysis of Serum LMR Levels in Patients with Spontaneous Preterm Delivery versus Controls

As shown in Figure3, a meta-analysis of the results of the five included studies was conducted. The results revealed that heterogeneity existed among the five works (P<0.01, I2=92%); therefore, a random-effects model was chosen. The combined SMD value was 0.35 (95% CI: -0.18−0.88, P=0.199), and no discrepancy could be considered between the spontaneous preterm birth and control groups regarding serum LMR levels.Figure 3
Forest plot of LMR levels in the spontaneous preterm birth group in comparison to the control group.As shown in Table3, subgroup analyses were performed based on the geographic location, sample size, time of detection of complete blood counts, and study design. Subgroup analysis based on sample size and time of detection of complete blood counts, respectively, revealed that LMR levels in the spontaneous preterm group outweighed those in the control group at sample sizes<100 (SMD=0.44, 95% CI: 0.19 to 0.68, P<0.001); LMR levels were higher in the spontaneous preterm group than in the control group (SMD=0.70, 95% CI: 0.39 to 1.01, P<0.001) when the complete blood count was measured at admission. Subgroup analysis according to geographical location and study design showed no difference in serum LMR levels between the spontaneous preterm birth and control groups (all P>0.05).Table 3
LMR subgroup analysis.
VariablesNo. of studiesSMD (95% CI)PHeterogeneityModelI2 (%)pHCountryAsia40.34 (-0.31, 0.98)0.30593.9<0.001RandomNon-Asia10.41 (-0.05, 0.86)0.079———Case number<10030.44 (0.19, 0.68)<0.00181.10.005Random≥10020.11 (-0.07, 0.29)0.21597.1<0.001RandomCBC testUpon admission20.70 (0.39, 1.01)<0.00167.70.079RandomOther30.10 (-0.07, 0.26)0.24994.3<0.001RandomStudy designProspective case control20.18 (-0.12, 0.47)0.23340.20.196FixedRetrospective case control30.44 (-0.41, 1.29)0.30695.8<0.001Random


## 3.5. Publication Bias

We used Begg’s test and Egger’s test to verify publication bias. An absence of publication bias was observed in nine studies reporting PLR values (P=0.917 for Begg’s test and P=0.305 for Egger’s test). No significant publication bias was observed in five studies that reported LMR values (P=0.806 for Begg’s test and P=0.396 for Egger’s test). The funnel plots of the PLR and LMR are shown in Figure 4.Figure 4
Begg’s funnel plot for assessing publication bias. (a) Begg’s funnel plot for assessing publication bias for PLR. (b) Begg’s funnel plot for evaluating publication bias for LMR.
(a)(b)


## 3.6. Sensitivity Analysis

We conducted a sensitivity analysis employing a one-by-one elimination method to ensure the stability of this study’s findings. The results showed that the combined effect sizes of the meta-analysis did not change significantly after the sequential elimination of any study, suggesting that the stability of the results was good (Figure5).Figure 5
Sensitivity analysis. (a) Sensitivity analysis of PLR. (b) Sensitivity analysis of LMR.
(a)(b)


## 4. Discussion

Prematurity, the primary cause of infant morbidity and mortality, occurs in 5-18% of pregnancies. Compared with normal newborns, premature babies are born earlier, the physiological functions of fetal organs are not fully developed, and resistance is poor. Consequently, preterm infants have higher morbidity and mortality rates. Spontaneous preterm labor is a common complication of pregnancy. As a type of preterm labor, it accounts for 70% of premature births in pregnant women and is caused by multiple pathological processes [21]. However, the exact pathogenesis of spontaneous preterm birth is not fully understood. Therefore, in order to effectively screen patients for spontaneous preterm birth, investigators have been looking for other potential biomarkers, especially those related to inflammation and infection, as 30-40% of spontaneous preterm births are thought to be caused by intrauterine and systemic infections and inflammation [22]. For example, interleukin-6 in cervicovaginal fluid is strongly associated with spontaneous preterm birth in asymptomatic women [23]. In clinical practice, the complete blood count (CBC) is the simplest and most basic blood test, while the differential blood count (DBC) index between cell populations is a valuable option for obtaining further information about the body’s inflammation. PLR, LMR, and other markers of the systemic inflammatory response can be obtained from the total peripheral blood count, which can be used to predict the occurrence of various diseases such as coronary artery disease, acute ischemic stroke, and gynecological or gastrointestinal malignancy [24–27].As two common markers of inflammation, studies on the relationship between serum PLR and LMR levels and spontaneous preterm labor have gradually increased in recent years. However, there are still limitations that cannot be addressed by a single study, such as the enormous spatial and temporal span of the study population area between studies as well as the accuracy and presentation of results. Therefore, the clinical significance of a single study is limited. Therefore, our study is among the first to systematically assess the relationship between serum PLR and LMR levels and spontaneous preterm birth using meta-analysis.After rigorous screening, a meta-analysis was performed on the nine original papers that met the inclusion criteria. After meta-analysis, this study found that PLR was notably elevated in the serum of patients with spontaneous preterm labor, with a statistically significant difference compared to controls (SMD=0.49, 95% CI: 0.13 to 0.84, P=0.007). Meanwhile, no discrepancy existed in serum LMR levels between patients with spontaneous preterm labor and controls (0.35, 95% CI: -0.18 to 0.88, P=0.199). This finding implies that PLR is strongly associated with spontaneous preterm delivery, whereas LMR is not. The detection of PLR has a certain guiding significance in diagnosing spontaneous preterm births and selecting therapeutic targets.As seen in the funnel plot of publication bias evaluation of the literature, both sides of the funnel plot were symmetrical, indicating a low possibility of publication bias. In terms of literary quality, the NOS score suggested a relatively high overall quality of the included studies, and the conclusions of this study had high reliability and authenticity. However, the heterogeneity of this paper was high according to the results of the heterogeneity analysis. Based on the available information, regional differences in population, sample size, timing of testing of complete blood counts, and type of study design related to the predictive accuracy of spontaneous preterm birth were considered in different studies. In this case, subgroup analysis should be included. This study further used subgroup and sensitivity analyses to look for sources of heterogeneity.There were a number of limitations to the meta-analysis. For instance, data were collected from the published full text, and some studies without positive results may have been missed. In addition, significant heterogeneity existed in the included studies, which implies a possible selective bias. Finally, confounding factors were not excluded, which compromised the reliability of the results. Future study designs need to take these factors into account.


## 5. Conclusion

In conclusion, this meta-analysis showed that serum PLR levels in patients with spontaneous preterm labor surpassed those in the full-term controls. It cannot yet be assumed that there is a difference in serum LMR levels between the spontaneous preterm labor and control groups, suggesting the need for more clinical studies on spontaneous preterm labor and serum PLR and LMR levels to investigate in depth the diagnostic and prognostic value of serum PLR and LMR in spontaneous preterm labor. Therefore, PLR may be a potential biomarker for early clinical diagnosis and treatment of spontaneous preterm births. In the future, PLR may be used to prevent and treat spontaneous preterm birth. We will further study the causes of elevated PLR in the serum of patients with spontaneous preterm birth and other biological targets of preterm birth to reduce morbidity and mortality and ensure the health of both patients and newborns.



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