Preeclampsia is a specific condition of pregnancy and is one of main cause of maternal organ damage and intra-uterine growth retardation[15, 16]. In the present retrospective case-control study, we investigated the association between preeclampsia and NLR in whole blood during the third trimester. Our results showed NLR in whole blood and MPO expression in the placental tissues were significantly elevated in pregnancies with preeclampsia compared with healthy controls.
In normal pregnancy, T cells shift toward the anti-inflammatory Th2 phenotype, which can synthesize IL-4, IL-5, IL-6, IL-10, IL-13, and antibody. These factors can neutralize inflammation, inhibit oxidative stress, and reduce cell damage. In preeclampsia, T cells shift toward the Th1 phenotype, which can synthesize IL-12, IL-18, IFN, and TNF[18, 19]. These proinflammatory cytokines can stimulate systemic inflammatory response, leading to apoptosis and reduced trophoblast invasion. As a systemic inflammatory response syndrome, preeclampsia can increase the expression of white blood cells. Neutrophils, the most abundant type of white blood cell in the human circulation system, are the principal cells during inflammatory reactions. Scholars found that in maternal circulation, all classes of leukocytes are activated in women with preeclampsia, but only neutrophils penetrate into the systemic vasculature . Our research also confirmed that neutrophil count in preeclampsia groups was significantly higher than that in the healthy control group (P < 0.05). Neutrophils can lead to the generation of NETs, which are fibrous extracellular lattices containing DNA[23, 24]. In preeclampsia, a large number of NETs are observed in maternal circulation in vivo in the intervillous space, especially within the areas of tissue damage[25–29]. When extracellular trapping nets are not cleared by the body, they lead to damages to endothelial injury and cause preeclampsia. In addition, the level of NETs was positively correlated with the severity of the disease[26, 30]. These NETs serve as a source of elevated levels of cell-free maternal DNA, leading to endothelial damage and enhancing the severity of preeclampsia[27–29]. In the present study, the level of NLR was prominently higher in patients with severe preeclampsia compared with those with mild preeclampsia (p = 0.0006 < 0.05).
The etiology and pathogenesis of preeclampsia are complex. Pregnancy-related immunological changes, in addition to extensive maternal vascular damage, are more important fetal placental changes. This disease is believed to arise owing to defective placentation and eventually resolves when the placenta is removed[31–33]. Thus, preeclampsia is also called ‘placental diseases’. The trophoblast invasion and insufficient remodeling of uterine spiral arteries is considered the main cause of defective placentation[34–36]. Inadequate spiral arteriolar lead to narrow maternal vessels, which will form low flow, low volume capacitance, high-resistance vessels. Placental ischemia and hypoxia can cause intermittent hypoxia and reoxygenation, resulting in oxidative stress of the placenta. Some scholars believe that oxidative stress is the central component of placental and endothelial dysfunction and considered the main cause of preeclampsia. Under oxidative stress, hypoxia/reperfusion with high ROS production provokes the release of sFlt-1 and soluble endoglin via NF-κB [38–40]. NF-κB, a nuclear factor, enters the cell nucleus and promotes the transcription of several proinflammatory mediators. The secretion of proinflammatory cytokines activate the systemic inflammatory response. MPO, an inflammatory marker, is a heme protein produced and released by activated neutrophils. In the present study, the MPO expression in the placental tissues was significantly elevated in pregnancies with preeclampsia compared with that in healthy controls. In addition, the neutrophil counts of pregnant women with preeclampsia were significantly higher than those in the healthy controls. These activated neutrophils in the intervillous space of the placenta of pregnant women with preeclampsia can result in excessive amounts of oxidized lipids. These lipids in turn activate neutrophil, leading to expression of cyclooxygenase (COX) . COX-2 promotes the secretion of thromboxane prostaglandin E2 TNFa and superoxide, which induce oxidative stress and dysfunction in endothelial cells . These explanations are feasible for our results.
A number of reports have shown that white blood cell is associated with atherosclerosis. Various scholars believe that neutrophil count is an objective marker of forecasting cardiovascular events. The mechanism of vascular endothelial injury in preeclampsia, a disease of systemic excessive inflammatory response, has been widely recognized. In the present study, preeclampsia is associated with an increase in neutrophil count, which is higher than that in the healthy control group. In addition, the lymphocyte counts in women with preeclampsia did not differ. Increase in neutrophil count and basically unchanged lymphocyte counts could result in increased NLR in the preeclampsia group. In our study, NLR was more meaningful and correlated in this study.
Our study has several limitations. The first limitation is the retrospective nature of the study and the inability to calculate population-based rates. Second, all of the pregnant women in the study are from China; as such, whether this research can be generalized to other ethnic groups should be further investigated.
In conclusion, elevated NLR was positively related to the severity of preeclampsia. Hence, NLR could predict the severity of preeclampsia. Our study and previous works have added value to the use of maternal NLR level in determination of the severity of preeclampsia. We believe that pregnancy outcomes can be improved with optimal antenatal preparation. Nevertheless, scholars should further study the association between NLR level and preeclampsia.