Preeclampsia, a multisystem pregnancy complication, affects about 2-8% of all pregnant women worldwide and is one of the leading causes of maternal and fetal morbidity and mortality (ACOG Practice Bulletins, 2020, Poon et al., 2019). If undetected and untreated, preeclampsia increases the risk of developing HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets) and eclampsia; both life-threatening conditions. Medical treatment of preeclampsia is only symptomatic, and preterm delivery is often necessary to avoid further complications in cases of severe preeclampsia. A timely diagnosis of preeclampsia can be a challenge in clinical settings. Maternal history and risk factors, such as first-time pregnancy, predict about 30% of cases of preeclampsia. The clinical utility of biochemical markers to support a preeclampsia diagnosis in late pregnancy remains controversial (Stamilio et al., 2000, ACOG Practice Bulletins, 2020).

The pathogenesis and etiology of preeclampsia are unclear due to the multifactorial origin of the disorder. Several studies report that a healthy pregnancy is dependent on a balanced maternal immune system. On one hand, activation of the maternal immune system is necessary to defeat invading pathogens, and on the other hand, tolerance of the semi-allogenic fetus requires maternal immune suppression. Well-regulated angiogenesis is another crucial factor in normal placentation, and thus a healthy pregnancy. Preeclampsia is subclassified as, among others, early- and late-onset, based on the time of diagnosis and delivery (Poon et al., 2019). While studies have associated the origin of late-onset preclampsia with predisposing metabolic and cardiovascular risks for endothelial dysfunction (Egbor et al., 2006, Steegers et al., 2010), current hypotheses suggest that the pathophysiology of early-onset preeclampsia involves at least two stages (Steegers et al., 2010, Egbor et al., 2006). The first stage is a shallow invasion of extravillous trophoblasts into the decidua, which causes suboptimal colonization and remodeling of spiral arteries (Steegers et al., 2010, Rana et al., 2019). The latter may be caused by suboptimal interactions between human leukocyte antigen (HLA) class Ib molecules expressed on trophoblast cells and maternal immune cells (Nilsson and Hviid, 2022). The following ischemia increases the shedding of cytokines and syncytiotrophoblast microparticles (STBMs) by the syncytiotrophoblasts that make up the feto-maternal interface (Moodley, Moodley and Naicker, 2020). The second stage unfolds as the STBMs and cytokines exacerbate the amount and activation of both peripheral and placental neutrophils and monocytes, which contribute to maternal systemic inflammation (Regal et al., 2015, Nadkarni et al., 2016, Faas and de Vos, 2017). Neutrophils and monocytes also release the highly reactive molecules, oxygen free radicals, that cause endothelial damage (Aneman et al., 2020). Studies have reported ambiguous data on the association between peripheral lymphocyte count and preeclampsia. Nevertheless, there is a consensus that regulatory T cell levels, involved in the immune tolerance of the semi-allogenic fetus, are reduced in the peripheral blood of preeclamptic women compared with healthy pregnant women (Djurisic and Hviid, 2014, Cornelius, 2018, Jørgensen et al., 2019). Neutrophils, short-lived phagocytotic granulocytes, are the most abundant leukocytes in human blood circulation, and a main component of the innate immune system, as they provide first-line defense during acute inflammation (Aneman et al., 2020). Monocytes are present in peripheral blood for a few days and constitute around 5-10% of peripheral leukocytes. They migrate into the tissues becoming phagocytotic macrophages and antigen-presenting dendritic cells, where they live for months to years (Faas and de Vos, 2017). Like neutrophils, monocytes are also a part of innate immunity (Vishnyakova et al., 2019, Aneman et al., 2020). Lymphocytes make up around 20-40% of peripheral leukocytes and are important immune cells of the adaptive immune system. Compared with non-pregnant women, neutrophil and monocyte levels seem to increase in peripheral blood during a healthy pregnancy, whereas lymphocyte levels decrease (Klajnbard et al., 2010, Dockree et al., 2021). These observations brought interest to explore the use of their ratios, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), as markers of systemic inflammation and thus preeclampsia. We hypothesized that maternal systemic inflammation in preeclampsia is reflected in the maternal blood levels of certain inflammation markers and that differences in these levels could distinguish pregnancies complicated by preeclampsia in late pregnancy from healthy pregnancies. The aim of the current study was to investigate differential cell counts and specific acute phase reactants as biochemical markers that support a preeclampsia diagnosis in late pregnancy, also in relation to pregnancy term, gravidity and the severity of hypertension among pregnancies with preeclampsia.