**2.1 Pathogenesis of obesity-related adverse outcomes in pregnancy with a background of metabolic syndrome**

In recent years, visceral fat has been regarded as one of the endocrine organs [18]. Visceral fat plays an important role in the pathogenesis of local and systemic chronic inflammation in obese patients [19]. A large number of studies have demonstrated a relationship between obesity and the pathophysiology underlying metabolic syndrome, specifically involving dysfunction of adipocytes with reduced adiponectin and innate immune cells with subsequent production of inflammatory cytokines [16]. Inflammatory cytokines induce tissue factor (TF) and enhanced thrombin generation by up-regulation of TF expression on various types of cells (**Figure 3**). Enhanced thrombin generation consecutively leads to inflammation, thrombus formation, and vascular damage due to activation of the cell signaling system via protein-activated receptors (PARs) [20] with TF as a receptor [21]. The induction of cytokines and thrombin generation interacts with the crosstalk between coagulation and inflammation [22, 23].

Adipose tissue formed by adipocytes with fat accumulation increases the level of triglycerides and decreases the adiponectin level. The tissue also activates immunocompetent cells, such as macrophages and mast cells, which produce and release pro-inflammatory cytokines (TNF-α, IL-6, IFN-ϒ, and IL-1β) [24]. The induction of TF on the cell surface of adipocytes and macrophages accelerates the prothrombotic state accompanied by thrombin generation. With respect to the high estrogenic state in pregnancy, prothrombotic conditions are likely to be induced in obese women because of the additional effects of dietary, social, environmental, and genetic factors which increase the risk of pregnancy-related VTE, although the precise mechanisms are still uncertain.

The most recent hypothesis regarding the pathogenesis of HDP suggests that impaired trophoblastic invasion into the inner myometrial portion of the spiral arteries causes the vessels to retain musculoelastic properties, thereby inducing hypoperfusion and hypoxia [25]. The subsequent release of inflammatory cytokines [26] promotes the excess production of soluble fms-like tyrosine kinase 1 (sFLT1) [27], which binds to VEGF as a decoy instead of VEGFR. The cytokines may also enhance maternal inflammatory responses and systemic endothelial dysfunction, leading to maternal symptom [28]. The resulting inflammatory cytokines induce TF, which subsequently initiates the TF-dependent coagulation pathway as the receptor for coagulation factors VIIa/VII [29]. In a vicious cycle, activation of the coagulation system and thrombin formation in the placental intervillous space enhances the production of sFLT1s through G protein-coupled protease-activated receptors [30] and causes further ischemic damage to trophoblastic cells in a hypercoagulable state [31, 32], as shown in **Figure 4**.

As one of the current hypotheses of the pathogenesis in pregnancy-related VTE and HDP, these observations provide the probable relationship between the high estrogenic state of pregnancy and prothrombotic conditions caused by chronic

*New Insights into Metabolic Syndrome*

Thus, prepregnancy body weight and changes in weight gain during pregnancy may be indicators of maternal nutritional status, reflecting the balance between caloric intake and basal metabolism and exercise caloric expenditure [11].

Although hypertension and DM in obese patients with metabolic syndrome [12] are worrisome with respect to future health issues and increased mortality rate, pregnancy-related VTE has a greater and more direct impact on families among the childbearing population. Based on the annual report of the trends in maternal deaths and maternal mortality rates by cause of death from the Japan Ministry of Health, Labor, and Welfare in 2017 [13], the number of maternal deaths in Japan has decreased over time; however, 70% of maternal deaths are caused by hemorrhage, pulmonary embolism (including pulmonary thromboembolism and amniotic fluid embolism), and HDP. The percentage of maternal mortalities by cause of death has remained essentially unchanged over the past two decades, as shown in **Figure 1**. Increasing maternal age [14] due to changes in social lifestyle, advances in assisted reproductive medicine, and increased cesarean section rates may also be important factors in maternal deaths in Japan and developed countries worldwide [15]. Changes

*Pathogenesis of obesity-related adverse outcomes in pregnancy with a similar background to metabolic syndrome. Key words are pro-inflammatory state with insulin resistance and a prothrombotic state with a high* 

*Trends in maternal deaths and maternal mortality rates (per 100,000 total births) by causes of death in Japan.*

**138**

**Figure 2.**

**Figure 1.**

*estrogenic state in obese pregnant women.*

#### **Figure 3.**

*Enhanced thrombin generation by tissue factor (TF) with activation of protease-activated receptor (PAR). The increased coagulation factors and reduced sensitivity to activated protein C in pregnancy accelerate the enhanced thrombin generation on tissue factor (TF) induced by (pro)-inflammatory cytokines (TNF-α, IL-6, IFN-ϒ, and IL-1β). The formed thrombin induces (pro)-inflammatory cytokines via activation of the proteaseactivated receptor (PAR).*

inflammation due to the obesity with metabolic syndrome, although there is a lack of high-quality evidence (**Figure 5**).
