**2.2 Epidemiologic aspects of obesity-related adverse outcomes in pregnancy**

Prepregnancy body mass index (BMI), weight changes during pregnancy, and perinatal prognosis are the epidemiologic aspects of obesity-related adverse outcomes in pregnancy.

Although various academic societies have recommended guidelines for optimal weight gain and nutrition during pregnancy, the basic concept for the management of maternal nutrition has changed over time based on epidemiologic data. From the view of adverse maternal outcomes in North America in the first half of the twentieth century, a weight gain of 9.1 kg throughout pregnancy was recommended to prevent HDP and operative deliveries, such as cesarean section and forceps deliveries, because of macrosomic fetuses.

By the 1970s, at least 11.4 kg of weight gain during pregnancy was recommended to prevent spontaneous preterm births, fetal growth restriction, and adverse neonatal outcomes [33]. In the 1990s, the BMI classification was introduced as a means to establish optimal weight gain based on body weight and surface area. A weight gain of 11.5–16 kg was recommended in pregnant women with a normal prepregnancy BMI (19.8–26 kg/m<sup>2</sup> ) [17].

During pregnancy, it is preferable to increase caloric intake by approximately 390 kcal per day with small variations in addition to the daily caloric intake during non-pregnancy [34]. Insufficient calorie intake leads to increased proteolysis and the lack of nutrition for fetal growth. Strict limitation of weight gain during pregnancy may increase the risk of preterm birth and fetal growth restriction [33], which is why an 11–16 kg weight gain is recommended for women with a normal prepregnancy BMI in North America [35]. Maternal weight gain with excessive calorie intake increases the risk of dystocia with macrosomic fetuses. Recent research has also suggested that maternal obesity increases the risk of childhood obesity [36] and the risk of autism spectrum [37].

**141**

**Figure 5.**

**Figure 4.**

before pregnancy (25–29.9 kg/m2

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

*Pathogenesis of hypertensive disorders of pregnancy (HDP). The important role of thrombin generation in* 

*factor, ET: endothelin, AT: angiotensin, sFLT1: soluble FLT1, PlGF: placental growth factor, VEGF: vascular endothelial growth factor, AT: antithrombin, TAT: thrombin-antithrombin complex, SFMC: soluble fibrin-*

*: hypoxia-induced* 

*the "two-stage disorder" theory for the pathogenesis of HDP. sEng: soluble endoglin, HIF-1<sup>α</sup>*

*monomer complex, PIC: plasmin-α 2-plasmin inhibitor complex.*

The Institute of Medicine (IOM) guidelines in 2009 recommended that weight

) and 0.18 kg/week for women who are obese

gain during pregnancy should be 0.3 kg/week for women who are overweight

*Pathogenesis of obesity-related adverse outcomes in pregnancy. The critical role of the induction of proinflammatory cytokines by dysfunction of adipocytes with fat accumulation initiates the thrombin generation of tissue factor (TF) in various cells. The prothrombotic state with estrogen-induced hypercoagulability plays a* 

*role in the pathogenesis of venous thrombosis and hypertensive disorders of pregnancy.*

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

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

#### **Figure 4.**

*New Insights into Metabolic Syndrome*

of high-quality evidence (**Figure 5**).

ies, because of macrosomic fetuses.

) [17].

obesity [36] and the risk of autism spectrum [37].

comes in pregnancy.

*activated receptor (PAR).*

**Figure 3.**

BMI (19.8–26 kg/m<sup>2</sup>

inflammation due to the obesity with metabolic syndrome, although there is a lack

*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 protease-*

**2.2 Epidemiologic aspects of obesity-related adverse outcomes in pregnancy**

Prepregnancy body mass index (BMI), weight changes during pregnancy, and perinatal prognosis are the epidemiologic aspects of obesity-related adverse out-

Although various academic societies have recommended guidelines for optimal weight gain and nutrition during pregnancy, the basic concept for the management of maternal nutrition has changed over time based on epidemiologic data. From the view of adverse maternal outcomes in North America in the first half of the twentieth century, a weight gain of 9.1 kg throughout pregnancy was recommended to prevent HDP and operative deliveries, such as cesarean section and forceps deliver-

By the 1970s, at least 11.4 kg of weight gain during pregnancy was recommended to prevent spontaneous preterm births, fetal growth restriction, and adverse neonatal outcomes [33]. In the 1990s, the BMI classification was introduced as a means to establish optimal weight gain based on body weight and surface area. A weight gain of 11.5–16 kg was recommended in pregnant women with a normal prepregnancy

During pregnancy, it is preferable to increase caloric intake by approximately 390 kcal per day with small variations in addition to the daily caloric intake during non-pregnancy [34]. Insufficient calorie intake leads to increased proteolysis and the lack of nutrition for fetal growth. Strict limitation of weight gain during pregnancy may increase the risk of preterm birth and fetal growth restriction [33], which is why an 11–16 kg weight gain is recommended for women with a normal prepregnancy BMI in North America [35]. Maternal weight gain with excessive calorie intake increases the risk of dystocia with macrosomic fetuses. Recent research has also suggested that maternal obesity increases the risk of childhood

**140**

*Pathogenesis of hypertensive disorders of pregnancy (HDP). The important role of thrombin generation in the "two-stage disorder" theory for the pathogenesis of HDP. sEng: soluble endoglin, HIF-1<sup>α</sup> : hypoxia-induced factor, ET: endothelin, AT: angiotensin, sFLT1: soluble FLT1, PlGF: placental growth factor, VEGF: vascular endothelial growth factor, AT: antithrombin, TAT: thrombin-antithrombin complex, SFMC: soluble fibrinmonomer complex, PIC: plasmin-α 2-plasmin inhibitor complex.*

#### **Figure 5.**

*Pathogenesis of obesity-related adverse outcomes in pregnancy. The critical role of the induction of proinflammatory cytokines by dysfunction of adipocytes with fat accumulation initiates the thrombin generation of tissue factor (TF) in various cells. The prothrombotic state with estrogen-induced hypercoagulability plays a role in the pathogenesis of venous thrombosis and hypertensive disorders of pregnancy.*

The Institute of Medicine (IOM) guidelines in 2009 recommended that weight gain during pregnancy should be 0.3 kg/week for women who are overweight before pregnancy (25–29.9 kg/m2 ) and 0.18 kg/week for women who are obese

(>30 kg/m2 ) after the second trimester [38]. In addition, the IOM recommended an 11.3–15.8 kg weight gain during pregnancy for women with a normal prepregnancy BMI (18.5–24.9 kg/m<sup>2</sup> ), 6.8–11.3 kg for women who are overweight before pregnancy, and 4.9–9.0 kg for women who are obese before pregnancy. In 2015, the American College of Obstetricians and Gynecologists (ACOG) recommended a similar proposal in an ACOG Practice Bulletin [10]; however, it has been shown that women who are overweight and obese before pregnancy with inappropriate weight gain and loss during pregnancy are at increased risk for fetal growth restriction [39] due to pathologic placental changes [40].

In recent years, although underweight pregnant women with a prepregnancy BMI ≤18.5 kg/m<sup>2</sup> have a reduced risk of HDP compared with obese pregnant women, a decrease in newborn birth weight in underweight pregnant women is associated with future health problems [41]. With respect to fetal programming, future health issues in adulthood should focus on the relationship between an increased risk for essential hypertension and DM [42] and low birthweight infants. Barker's hypothesis in the 1980s [43] was based on epidemiologic observations of malnutrition during pregnancy in World War II and underweight children with an increased risk for hypertension (ischemic heart disease) and DM in adulthood.

Malnutrition is a significant problem in the developing countries. There is a relatively high prevalence of women of childbearing age who are obese worldwide [44]. During pregnancy, obesity with metabolic syndrome shares an underlying pathogenesis of cardio-thrombo-metabolic dysfunction and further worsens the health status. Specifically, pregnancy-related VTE and sudden maternal death have a greater impact [45] on the family and society compared with HDP and GDM.

## **2.3 Pregnancy-related VTE in the UK and North America**

In Europe, especially in the United Kingdom, with a background of heritable thrombotic predisposition, medical journals have reported clinical cases of maternal deaths due to VTE since the 1860s [46, 47]. National policy in the UK has provided guidance to reduce maternal mortality from pregnancy-related VTE [45, 48]. Epidemiologic and clinical studies have focused on pregnancy-related VTE [49] and showed the relationship between VTE and prepregnant obesity in pregnant women [50]. Multivariate analysis of prepregnant obese patients compared with non-obese patients as controls demonstrated that the adjusted odds ratio (aOR) is 1.93 (95% CI, 1.10–3.39) for VTE in the moderately obese group and 4.32 (95% CI, 1.26–14.84) for VTE in the highly obese group, as shown in 2008 [49].

Studies focusing on prepregnancy BMI and immobilization in the hospital showed a further increased risk of VTE during pregnancy and postpartum [49]. The aOR for VTE in pregnant women with a prepregnancy BMI >25 kg/m<sup>2</sup> is 1.8 (95% CI, 1.3–2.4). During immobilization with bed rest, the aOR for VTE increases to 62.3 (95% CI, 11.5–337.6) in patients with a BMI >25 kg/m2 [49]. The aOR for VTE in patients with a prepregnancy BMI >25 kg/m2 is 2.4 (95% CI, 1.7–3.3) during the postpartum period. The aOR is 40.1 (95% CI, 8.0–201.5) in a similar condition [49]. These epidemiologic data have supported the guidelines for the prevention and reduction in the risk of pregnancy-related VTE in the UK [51, 52] and North America [53].

The Royal College of Obstetricians and Gynecologists published data in 2015 that indicated 60% of women who died of pulmonary thromboembolism (PE) between 2003 and 2008 were obese with a BMI ≥30 kg/m<sup>2</sup> . The prevalence of obesity with a similar BMI at 16–44 years of age in the population was 20% in the UK [52]. Pregnancy is a risk factor for VTE, and the risk increases in proportion to the degree of obesity. Obese pregnant women had a higher aOR for PE

**143**

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

pregnant women who had a prepregnancy BMI of 25–29.9 kg/m<sup>2</sup>

mon, affecting nearly 50% in the childbearing population [52].

(aOR, 14.9; 95% CI, 3.0–74.8) than for deep vein thrombosis (DVT) (aOR, 4.4; 95% CI, 1.6–11.9). The risk for pregnancy-related VTE is minimal in overweight

guidance in the UK states that VTE risk in overweight women is extremely com-

VTE according to the guidelines [52]. However, pregnant women with a BMI of

with other risk factors in women undergoing emergency cesarean section [53]. Epidemiologic observations have suggested that obesity and pregnancy are related to the prothrombotic state. The pathophysiology of metabolic syndrome may, in part, provide insight into understanding the increased hypercoagulable

status with obese women in pregnancy with a high estrogenic state.

additional risk factors, including elective cesarean section, prolonged labor (>24 h), and operative delivery. These risk factors are more likely encountered in daily clini-

The American College of Chest Physicians has also proposed similar guidelines to prevent pregnancy-associated VTE in obese pregnant women based on epidemiologic risk [51, 53]. Specifically, the American College of Chest Physicians showed that the occurrence of VTE is 3% among all women in the puerperium and the OR increases to >6 compared with women with a normal prepregnancy BMI if obese

Estrogens are a type of sex steroid hormone. The endogenous estrogens are classified into estrone (E1), estradiol (E2), estriol (E3), and esterol (E4) [54]. Estrogens were initially thought to be female hormones; however, it has recently been shown that estrogens are involved not only in female physiologic functions but also in male reproductive physiologic functions. Recent studies have explored the bioactivity of estrogen in the neuroendocrine [55], vascular [56], musculoskeletal [57], and immune systems. Estrogen is associated with the pathogenesis of infertility, obesity [58], osteoporosis, endometriosis [59], and various types of cancers [60]. Estrogen crosses the cell membrane and binds to estrogen receptor (ER) α and ERβ in the cell as a ligand and estrogen receptors (mERs) on the cell membrane as ligands. Then, estrogen regulates the expression of gene products by binding to a specific DNA

In pregnancy, the placenta and fetal adrenal cortex are the main estrogen production sites. E3 is produced through the maternal liver, placenta, and fetal adrenal gland, although E2 is mainly produced by ovarian granulosa and capsular cells in women of reproductive age. By contrast, estrogen is produced in testicular stromal Sertoli cells in men [62]. The physiologic hormonal bioactivity is the highest in E2

Epidemiologic observations have shown that obesity increases the risk of

As described above, apoptotic cell death of adipocytes in adipose tissue by overstored fat in obese patients induces the migration of macrophages to the tissues [19, 65]. Consequently, chronic inflammation caused by pro-inflammatory cytokines, such as TNFα and IL-8, leads to activation of the NF-κB signaling system and increased aromatase activity in various cells, including adipocytes, thus resulting in estrogen production [66]. Although the abnormal regulation of aromatase activity in adipose stromal cells in response to various inflammatory mediators involves a complex signaling pathway, visceral fat, which contributes to obesity,

are classified as having an intermediate risk if they have two or more

; however, the

alone is classified as a lower risk category for

are combined with those

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

Obesity with a BMI of 3040 kg/m<sup>2</sup>

cal situations compared with a history of VTE.

sequence, the hormone response element [61].

and then decreases in the order of E1 and E3.

estrogen-dependent breast [63] and endometrial cancer [64].

pregnant women with a prepregnancy BMI ≥30 kg/m<sup>2</sup>

30–40 kg/m<sup>2</sup>

**2.4 Obesity and estrogen**

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

(aOR, 14.9; 95% CI, 3.0–74.8) than for deep vein thrombosis (DVT) (aOR, 4.4; 95% CI, 1.6–11.9). The risk for pregnancy-related VTE is minimal in overweight pregnant women who had a prepregnancy BMI of 25–29.9 kg/m<sup>2</sup> ; however, the guidance in the UK states that VTE risk in overweight women is extremely common, affecting nearly 50% in the childbearing population [52].

Obesity with a BMI of 3040 kg/m<sup>2</sup> alone is classified as a lower risk category for VTE according to the guidelines [52]. However, pregnant women with a BMI of 30–40 kg/m<sup>2</sup> are classified as having an intermediate risk if they have two or more additional risk factors, including elective cesarean section, prolonged labor (>24 h), and operative delivery. These risk factors are more likely encountered in daily clinical situations compared with a history of VTE.

The American College of Chest Physicians has also proposed similar guidelines to prevent pregnancy-associated VTE in obese pregnant women based on epidemiologic risk [51, 53]. Specifically, the American College of Chest Physicians showed that the occurrence of VTE is 3% among all women in the puerperium and the OR increases to >6 compared with women with a normal prepregnancy BMI if obese pregnant women with a prepregnancy BMI ≥30 kg/m<sup>2</sup> are combined with those with other risk factors in women undergoing emergency cesarean section [53].

Epidemiologic observations have suggested that obesity and pregnancy are related to the prothrombotic state. The pathophysiology of metabolic syndrome may, in part, provide insight into understanding the increased hypercoagulable status with obese women in pregnancy with a high estrogenic state.

## **2.4 Obesity and estrogen**

*New Insights into Metabolic Syndrome*

nancy BMI (18.5–24.9 kg/m<sup>2</sup>

due to pathologic placental changes [40].

) after the second trimester [38]. In addition, the IOM recommended

), 6.8–11.3 kg for women who are overweight before

an 11.3–15.8 kg weight gain during pregnancy for women with a normal prepreg-

pregnancy, and 4.9–9.0 kg for women who are obese before pregnancy. In 2015, the American College of Obstetricians and Gynecologists (ACOG) recommended a similar proposal in an ACOG Practice Bulletin [10]; however, it has been shown that women who are overweight and obese before pregnancy with inappropriate weight gain and loss during pregnancy are at increased risk for fetal growth restriction [39]

In recent years, although underweight pregnant women with a prepregnancy

In Europe, especially in the United Kingdom, with a background of heritable thrombotic predisposition, medical journals have reported clinical cases of maternal deaths due to VTE since the 1860s [46, 47]. National policy in the UK has provided guidance to reduce maternal mortality from pregnancy-related VTE [45, 48]. Epidemiologic and clinical studies have focused on pregnancy-related VTE [49] and showed the relationship between VTE and prepregnant obesity in pregnant women [50]. Multivariate analysis of prepregnant obese patients compared with non-obese patients as controls demonstrated that the adjusted odds ratio (aOR) is 1.93 (95% CI, 1.10–3.39) for VTE in the moderately obese group and 4.32 (95% CI, 1.26–14.84)

Studies focusing on prepregnancy BMI and immobilization in the hospital showed a further increased risk of VTE during pregnancy and postpartum [49]. The aOR for VTE in pregnant women with a prepregnancy BMI >25 kg/m<sup>2</sup>

(95% CI, 1.3–2.4). During immobilization with bed rest, the aOR for VTE increases

the postpartum period. The aOR is 40.1 (95% CI, 8.0–201.5) in a similar condition [49]. These epidemiologic data have supported the guidelines for the prevention and reduction in the risk of pregnancy-related VTE in the UK [51, 52] and North

The Royal College of Obstetricians and Gynecologists published data in 2015 that indicated 60% of women who died of pulmonary thromboembolism (PE)

obesity with a similar BMI at 16–44 years of age in the population was 20% in the UK [52]. Pregnancy is a risk factor for VTE, and the risk increases in proportion to the degree of obesity. Obese pregnant women had a higher aOR for PE

is 1.8

[49]. The aOR for

. The prevalence of

is 2.4 (95% CI, 1.7–3.3) during

women, a decrease in newborn birth weight in underweight pregnant women is associated with future health problems [41]. With respect to fetal programming, future health issues in adulthood should focus on the relationship between an increased risk for essential hypertension and DM [42] and low birthweight infants. Barker's hypothesis in the 1980s [43] was based on epidemiologic observations of malnutrition during pregnancy in World War II and underweight children with an increased risk for hypertension (ischemic heart disease) and DM in adulthood. Malnutrition is a significant problem in the developing countries. There is a relatively high prevalence of women of childbearing age who are obese worldwide [44]. During pregnancy, obesity with metabolic syndrome shares an underlying pathogenesis of cardio-thrombo-metabolic dysfunction and further worsens the health status. Specifically, pregnancy-related VTE and sudden maternal death have a greater impact [45] on the family and society compared with HDP and GDM.

**2.3 Pregnancy-related VTE in the UK and North America**

for VTE in the highly obese group, as shown in 2008 [49].

to 62.3 (95% CI, 11.5–337.6) in patients with a BMI >25 kg/m2

between 2003 and 2008 were obese with a BMI ≥30 kg/m<sup>2</sup>

VTE in patients with a prepregnancy BMI >25 kg/m2

have a reduced risk of HDP compared with obese pregnant

(>30 kg/m2

BMI ≤18.5 kg/m<sup>2</sup>

**142**

America [53].

Estrogens are a type of sex steroid hormone. The endogenous estrogens are classified into estrone (E1), estradiol (E2), estriol (E3), and esterol (E4) [54]. Estrogens were initially thought to be female hormones; however, it has recently been shown that estrogens are involved not only in female physiologic functions but also in male reproductive physiologic functions. Recent studies have explored the bioactivity of estrogen in the neuroendocrine [55], vascular [56], musculoskeletal [57], and immune systems. Estrogen is associated with the pathogenesis of infertility, obesity [58], osteoporosis, endometriosis [59], and various types of cancers [60]. Estrogen crosses the cell membrane and binds to estrogen receptor (ER) α and ERβ in the cell as a ligand and estrogen receptors (mERs) on the cell membrane as ligands. Then, estrogen regulates the expression of gene products by binding to a specific DNA sequence, the hormone response element [61].

In pregnancy, the placenta and fetal adrenal cortex are the main estrogen production sites. E3 is produced through the maternal liver, placenta, and fetal adrenal gland, although E2 is mainly produced by ovarian granulosa and capsular cells in women of reproductive age. By contrast, estrogen is produced in testicular stromal Sertoli cells in men [62]. The physiologic hormonal bioactivity is the highest in E2 and then decreases in the order of E1 and E3.

Epidemiologic observations have shown that obesity increases the risk of estrogen-dependent breast [63] and endometrial cancer [64].

As described above, apoptotic cell death of adipocytes in adipose tissue by overstored fat in obese patients induces the migration of macrophages to the tissues [19, 65]. Consequently, chronic inflammation caused by pro-inflammatory cytokines, such as TNFα and IL-8, leads to activation of the NF-κB signaling system and increased aromatase activity in various cells, including adipocytes, thus resulting in estrogen production [66]. Although the abnormal regulation of aromatase activity in adipose stromal cells in response to various inflammatory mediators involves a complex signaling pathway, visceral fat, which contributes to obesity,

plays an important role in the local and systematic production of estrogen [67]. The enhanced production of estrogen can be associated with the upregulated production of coagulation factors that may lead to the induction of a prothrombotic state.
