Neutrophil to lymphocyte ratio (NLR), which can be easily calculated from complete blood count and leukocyte differential count, is an inexpensive parameter with multiple clinical applications. For example, accumulated evidences have indicated that NLR is a prognostic factor for heart failure (1), adult subarachnoid hemorrhage (2) and gastric cancer (3). One of the possible mechanisms underlying the multiple applications of NLR is inflammation response, which increases circulating neutrophils and decreased lymphocytes (4,5).
Pregnancy related complications (PRCs), such as preeclampsia (PE) and gestational diabetes mellitus (GDM), are potent contributors to mortality and morbidity in pregnant women. Early diagnosis and prediction of PRCs are crucial to improve its outcomes. Interestingly, inflammation response is involved in the pathogenesis of nearly all types of these complications (6-8). Therefore, inflammation indicators, such as C-reactive protein (CRP) and interleukin 6 (IL-6), are associated with the occurrence of PRCs (9-11).
Because NLR is a simple and inexpensive inflammatory indicator, accumulated studies have investigated the clinical utility of NLR during pregnancy. Therefore, we summarized and commented the currently available evidence regarding NLR and PRCs. In this review, we categorized the available studies into the cross-sectional, case-control and cohort studies. This information was not extracted from the original reports, but justified by the author. Cross-sectional design was defined as any studies that measure exposure factors and outcomes simultaneously. Case-control design was defined as any studies in which outcomes are firstly obtained and exposure factors before the occurrence of outcomes are retrospectively obtained. Cohort design was defined as any studies in which exposure factors are firstly obtained and subjects are followed until the occurrence of outcome.
PE is a major cause of mortality and morbidity for both mother and fetus around the world (12). It is characterized by hypertension and proteinuria after 20 weeks of pregnancy (12). The prevalence of PE is around 1% to 8% (13-15). Although the pathogenesis of PE is largely unknown, animal and clinical studies indicate that inflammation response is critically involved in the occurrence and development of PE (6,16,17). Because NLR is simple indicator of inflammation response, some studies have investigated the clinical utility of NLR in PE.
Two cross-sectional studies published in 2014 (18,19) investigated the relationship between NLR and PE, but the results are inconsistent. One study found that NLR in PE patients was higher than that in normal pregnant woman, and increased NLR was independently associated with PE after adjusting for cofounding factors (19). The other study determined the NLR level before the caesarean delivery but failed to find the increased NLR in PE (18). Subsequently, several cross-sectional studies have investigated the relationship between PE and NLR, and the results varied (20-28). Some studies found that NLR was higher in PE than in normal pregnant women (20-25,28), while one study failed to demonstrate a significant difference (27). In addition, some of the studies indicated that NLR was associated with severity (22-24), outcome (21), and proteinuria (24) of PE.
Currently, four case-control studies investigated the relationship between NLR and PE (20,29-31). Two of these four studies indicated that increased NLR in first (30) and second trimester (31) was a risk factor for PE. But in one study with large sample size (118 PE patients and 1,495 normal pregnant women), the authors failed to found NLR before the twentieth pregnancy week was increased in PE patients (20).
Taken together, the current evidence regarding NLR and PE is not consistent, and majority of the current evidence is cross-sectional or case-control design. Therefore, prospective cohort studies and meta-analyses are needed to provide robust evidence regarding the clinical utility of NLR in PE.
Hemolysis, elevated liver enzymes, low-platelet count (HELLP) syndrome
HELPP syndrome is characterized by hemolysis, liver injury, and decreased platelet count in the third trimester of pregnancy (32,33). To present, two studies from the one group have investigated the clinical utility of NLR in HELLP syndrome (34,35). In a case-control study, the author enrolled 14 HELLP syndrome patients and 14 age-matched normal pregnant women and found that NLR in third trimester was significantly increased in HELPP syndrome patients (35). Contrarily in a cross-sectional study the authors failed to prove that NLR in the third trimester was increased in PE (34). Considering that the sample sizes in these two studies are small and cofounding factors were not fully considered, further studies are needed to investigate the utility of NLR in HELLP syndrome management.
GDM is defined as glucose metabolism disorder that occurs for the first time during pregnancy, and inflammation is believed to be involved in the pathogenesis of GDM (36). In 2014, a cross-sectional study with 42 GDM and 68 non-GDM indicated that NLR was increased in GDM patients, and NLR was independently associated with GDM in a multivariable logistic regression model (37). However, a subsequent study with large sample size failed to found the increased NLR in GMD (38). The possible reasons for the inconsistency are largely unknown. In a recently published work, the researcher included 114 GDM and 114 well-matched non-GDM and found that NLR was increased in GDM patients (39). Furthermore, NLR was independently associated with HbA1c in a multivariable liner regression model (39). Taken together, current evidence regarding GDM and NLR is controversial, and further studies, especially prospective cohort studies, are needed to illustrate the clinical utility of NLR in GDM.
Ectopic pregnancy (EP)
EP is a complication of pregnancy which is defined as the implantation of the embryo outside the uterine cavity (40). Currently, methotrexate (MTX) and surgery are usually used for EP treatment in clinical practice. MTX is a noninvasive treatment approach and thus much preferred by obstetricians. However, the benefit and hazard of MTX should be balanced when deciding the treatment approach. Generally, MTX is usually used in patients with stable hemodynamics, smaller pregnancy mass size, lower beta-subunit human chorionic gonadotropin (β-hCG), while surgery is used in the remaining. However, the board line between MTX and surgery is not always clear in clinical practice. For some patients, treatment approach selection is really a challenge for obstetricians.
In a study published in 2017, the researchers compared the clinical and laboratory characteristic of EP patients received MTX (n=93) and surgery (n=60) (41). They found that NLR was significantly increased in patients received surgery, indicating that NLR was helpful in the choice of the EP treatment. This finding was validated by a subsequent study (42). In a study published recently, the researcher found that EP patients with tubal rupture had higher NLR than these without (43), also supports that NLR can assist obstetricians choosing treatment approach. Further, in one study with 78 MTX treatment successful and 37 MTX treatment failure patients, higher NLR was observed in MTX treatment successful patients (44), indicating that NLR is a predictor of MTX treatment efficiency.
Hyperemesis gravidarum (HG)
HG is a serious complication characterized by nausea and vomiting in first trimester of pregnancy. It can lead to dehydration, ketonuria, fluid and electrolyte imbalance, and weight loss (45). Some studies have compared the NLR level between normal pregnant women and HG patients (46-51) and all of them found that NLR was increased in HG patients. One study found that NLR increased as the advance of HG severity (47), indicating that NLR is a useful indicator in estimating the severity of HG. However, this finding was not validated in other two studies (48,51). Notably, all of these studies are cross-sectional and the therefore causality cannot be established. Further prospective cohort studies are needed to verify whether NLR is a risk factor for HG.
Preterm delivery (PD)
PD, defined as birth before 37 weeks’ gestation, is the major cause of perinatal morbidity and mortality worldwide. Some pregnant women may present with threatened preterm labor (TPL) on admission, but delivery does not occur after a tocolytics treatment. It is of great value to identify TPL women who will give birth preterm. Some studies have investigated the value of NLR in predicting PD (52-57). In three retrospective cohort studies (52,55,56), NLR was reported to be a risk factor for PD. However, in two case-control studies (54,57), the authors reported that NLR was not a risk factor for PD. In another study, the authors reported that NLR was higher in the patients with preterm premature rupture of membranes and it was a predictor of neonatal sepsis (53).
To date, accumulated studies have investigated the clinical utility of NLR in PRCs (Table 1). However, the results were not always consistent. This may be due to the small sample sizes and low statistical power in some studies. Therefore, meta-analysis may be needed to pool the results of available results in future. Notably, majority of evidences is case-control or cross-sectional design and multivariable analysis is not performed in large portion of available studies. Therefore, prospective cohort studies with large sample sizes and fully-adjusted analyses are needed to rigorously evaluate the clinical utility of NLR in PRCs.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Hai L, Hu ZD. The clinical utility of neutrophil to lymphocyte ratio in pregnancy related complications: a mini-review. J Lab Precis Med 2020;5:1.