**1. Introduction**

Epidemiologic studies in North America and Europe have shown that obesity increases the risk of venous thromboembolism (VTE) during pregnancy and the puerperium [1, 2], as well as postpartum hemorrhage [3]. Furthermore, women with prepregnancy obesity are also at increased risk of hypertensive disorders of pregnancy (HDP) [4, 5], including preeclampsia [6]. HDP is associated with placental abruption, which may lead to severe obstetric complications with disseminated intravascular coagulation (DIC) [7].

Recent research has shown that HDP and gestational diabetes mellitus (GDM) increase the risk of hypertension and diabetes mellitus (DM) later in life [8]. Conversely, maternal malnutrition during pregnancy because of inadequate dietary intake increases the risk of fetal growth restriction and low-birth-weight infants; it is increasingly evident that offspring are at increased risk of developing hypertension and DM as well [9]. Indeed, addressing nutrition and weight gain before pregnancy are an important part of perinatal care [10].

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

**Figure 1.**

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

#### **Figure 2.**

*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 estrogenic state in obese pregnant women.*

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*Metabolic Syndrome and Pathogenesis of Obesity-Related Adverse Outcomes in Pregnancy*

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

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

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

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 hyper-

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

in dietary habits and a sedentary modern lifestyle are partly responsible for prepregnancy obesity, which is followed by obesity-related adverse outcomes in pregnancy. A growing number of epidemiologic observations on obesity in pregnancy have linked basic research findings [16] with the pathogenesis of obesity-related adverse outcomes in pregnancy with a similar background to metabolic syndrome [12, 17],

*DOI: http://dx.doi.org/10.5772/intechopen.93144*

**2. Obesity-related adverse outcomes in pregnancy**

**background of metabolic syndrome**

between coagulation and inflammation [22, 23].

precise mechanisms are still uncertain.

coagulable state [31, 32], as shown in **Figure 4**.

as shown in **Figure 2**.

#### *Metabolic Syndrome and Pathogenesis of Obesity-Related Adverse Outcomes in Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.93144*

in dietary habits and a sedentary modern lifestyle are partly responsible for prepregnancy obesity, which is followed by obesity-related adverse outcomes in pregnancy.

A growing number of epidemiologic observations on obesity in pregnancy have linked basic research findings [16] with the pathogenesis of obesity-related adverse outcomes in pregnancy with a similar background to metabolic syndrome [12, 17], as shown in **Figure 2**.
