Predictive value of NLR and PLR in missed miscarriage

Abstract Background The aim of the study was to investigate the predictive value of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in missed miscarriage. Methods In this retrospective cohort study, a total of 400 women (involving 200 with missed early miscarriage and 200 with normal pregnancy but terminate by artificial abortion) were included. General clinical data and complete blood count (CBC) such as white blood cells (WBC), red blood cells (RBC), platelet (PLT), red blood cell distribution width‐standard deviation (RDW‐SD), platelet distribution width (PDW), mean platelet volume (MPV), neutrophil count, and lymphocyte count were collected, and the NLR and PLR were calculated for both groups. Receiver operating characteristic curve (ROC) was used to calculate the predictive value. Results There was no significant difference in the WBC, RBC, PLT, RDW‐SD, PDW, neutrophil, lymphocyte, NLR, and PLR between the two groups (p > 0.05).But MPV was lower in the missed early miscarriage group than in the control group (p < 0.05), and the area under the working curve (AUC) of ROC was 0.58, specificity and sensitivity was 69% and 47%, respectively. Conclusion NLR and PLR were not the suitable indictor for missed miscarriage, but MPV should be a concern in the first trimester.


| Sample collection
Age, gestational week, gravida, parity, body weight, and height were obtained by examining the medical records of patients. The gestational week was determined by sonographic measurement. CBC parameters including white blood cells (WBC), red blood cells (RBC), platelet (PLT), red blood cell distribution width-standard deviation (RDW-SD), platelet distribution width (PDW), mean platelet volume (MPV), neutrophil count, and lymphocyte count were determined.
Neutrophil to lymphocyte ratio (NLR) was defined by dividing the neutrophil count by lymphocyte count, and platelet to lymphocyte ratio (PLR) was defined as platelet count divided by lymphocyte count. Preoperative CBC parameters were compared between the missed miscarriage and control groups.

| Statistical analysis
Statistical analyses were performed using SPSS windows version 20.0 software (SPSS Inc.

| RE SULTS
A total of 200 patients with missed miscarriage was compared with 200 participants in the control group who had normal pregnancies.
The two groups were similar in terms of maternal age, gestational age, BMI, gravidity, and parity (p > 0.05). (Table 1).
Further analysis showed that the MPV value showed that the AUC of ROC was 0.58, the cutoff value is 10.45, and the specificity and sensitivity was 69% and 47%, respectively. (Figure 1).

| DISCUSS ION
In this study, we found that WBC, RBC, PLT, RDW-SD, PDW, neutrophil, lymphocyte, NLR, and PLR were similar in missed miscarriage group and the control group (p > 0.05). Interestingly, MPV was found to be lower in the missed miscarriage group than in the controls (p < 0.05). Further analysis showed that the best predicted values for missed miscarriage based on the AUC was MPV with the optimal cutoff value of 10.45, but the AUC was 0.58, the specificity and sensitivity was 69% and 47%, respectively.
Inflammation is essential for successful female reproduction. 6,26 At different stages of pregnancy, the maternal immune system presents different inflammatory states. 27 In the beginning, a moderate inflammatory environment is conducive to embryo implantation.
Then, the local decidua needs to establish an anti-inflammatory and immune-tolerant microenvironment to ensure the survival and growth of the embryo. At the time of delivery, the microenvironment of the decidua shifts toward the proinflammatory direction again.
An excessive inflammatory reaction has been associated with miscarriage or other pregnancy complications such as pre-eclampsia or premature labor. 28 In recent years, as systemic markers of inflammation, with advantages of convenience, simplicity, sensitivity, versatility and speed, and CBC parameters have attracted more and more attention in miscarriage. NLR and PLR were the most commonly used inflammation markers among CBC parameters. However, the relationship between NLR, PLR and miscarriage are confusing. Oglak et al. 29 found that NLR and PLR values were significantly higher in the early pregnancy loss group than the control group who had given birth at term, while Yakıştıran et al. 30  To our surprise, we observed that MPV was lower in the missed miscarriage group than in the control. As far as we know, the only research Biyik et al. 35 has similar results with ours. These may be the cause of inflammation. According to our searches, increased MPV levels are observed in low-grade inflammatory diseases, while decreased MPV levels are observed in high-grade inflammatory diseases. 37,38 Increased MPV was observed in cardiovascular diseases, cerebral stroke, respiratory diseases, chronic renal failure, intestine diseases, rheumatoid diseases, diabetes, and various cancers, decreased MPV was noted in tuberculosis during disease exacerbation, ulcerative colitis, SLE in adult, and different neoplastic diseases. 39 There are many studies have reported the relationship between miscarriage and MPV, but findings are also still confusing. Study show that MPV was significantly lower in miscarriage than the women given birth at term without complication and healthy control patients. 32 However, there are also studies found that MPV levels was higher or no difference in the miscarriage group vs the control group.
Confounding factors can be a probable reason for the different findings observed among the studies, and the pathophysiology between miscarriage and missed miscarriage is different, more researches are needed to illustrate the problem.
The limitations of this study include the fact that, firstly, the embryos of the control group were alive at the time of termination of pregnancy, but the subsequent pregnancy was unknown, which may cause bias in the data. Secondly, the missed miscarriage CBC parameters was detected when women confirm a missed early miscarriage, and we do not know whether CBC parameters abnormalities will only occur after the missed miscarriage, it still needs a systematic and detailed follow-up of the CBC parameters in missed early miscarriage. Third, this study only included a single center of data.

| CON CLUS ION
In our study, we found that NLR and PLR values do not have any determining effect on the presence of missed miscarriage. MPV was found to be lower in the missed miscarriage group than in the controls, although it was not powerful enough to predict of missed miscarriage, but reminds clinicians to pay attention to the rapid and simple parameters in early pregnancy patients. In a word, further large-sample, multicenter and systematic prospective studies are needed.

This work was supported by The Medical Research Project of Foshan
Health Bureau, China (20220099).

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.