Maternal Obesity: Shaping Future Generations' Well-being: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Susana P. Pereira.

Maternal obesity (MO) results in short- and long-term adverse outcomes for the offspring, including an increased risk for cardiovascular disease (CVD) development. Maternal obesity can have profound implications for metabolic regulation during pregnancy due to changes in glucose metabolism to support fetal growth.

  • cardiovascular disease
  • fetal programming
  • maternal obesity
  • maternal physical exercise

1. Introduction

Obesity is defined as abnormal or excessive fat accumulation in the body, affecting one’s health. The increasing incidence of obesity among women of childbearing age (18–39 years) has made it one of the most common and severe obstetric conditions. Between 2013 and 2014, 37% of women of reproductive age were obese in the United States [1]. Maternal obesity (MO) results in short- and long-term adverse outcomes for the offspring, including an increased risk for cardiovascular disease (CVD) development [2,3][2][3]. CVD is the number one cause of mortality worldwide. In 2019, 17.9 million people died from CVD. This represents a massive 32% of the global population. By 2030, it is estimated that more than 23.6 million people will die of CVD [4].
Increasing evidence suggests that MO is a key determinant of offspring’s health not only in the womb but throughout the entire lifetime. Neonates born to obese mothers have an increased predisposition to overgrow, resulting in macrosomia (birth weight, BW > 4000 g) [5]. Moreover, MO offspring have a higher risk of developing congenital anomalies, such as heart defects [6] and neural tube defects [7], increasing the risk of injury during birth, stillbirth, and perinatal death. Later in life, offspring from obese mothers are more prone to develop childhood obesity and chronic diseases [8]. Studies have shown stronger associations between maternal weight gain status, obesity, and increased offspring cardiometabolic risk [9]. A cohort showed increased systolic blood pressure in 6-year-old children of overweight or obese mothers, a primer for higher cardiometabolic risk, emphasizing the link between MO and offspring’s early CVD development [10]. In an Australian cohort, abnormal gestational weight gain was associated with higher systolic blood pressure in 21-year-old offspring [11]. A meta-analysis revealed that human fetuses born to obese mothers exhibited traces of reduced systolic blood pressure and that children (1–12 years old) presented thicker intraventricular septum [12]. These observations strengthen the association between MO and offspring’s cardiovascular health impairment, enhancing the risk of developing CVD in later life [13,14][13][14] and challenging the concept that cardiovascular risk is uniquely determined by genetic predisposition and postnatal lifestyle [15]. Despite better healthcare systems, CVD-related events have increased by approximately 50% in children and young adults in recent decades [16]. Although several epidemiological studies explore the relationship between low birth weight and increased risk for CVD development, it is recognized that CVD incidence occurs at both ends of the birth weight spectrum, in a U-shaped curve behavior [17]. In light of the developmental origins of the health and disease (DOHaD) paradigm, the increased number of registered premature deaths caused by CVD could be related to the abrupt rise in MO and malnutrition in the womb.

2. The Impact of Maternal Obesity on Maternal Health

Maternal obesity has become a significant public health concern worldwide, with its prevalence steadily increasing in recent years. The World Health Organization (WHO) estimates that approximately 20% of pregnant women globally are affected by obesity. This alarming trend is a cause for concern due to the potential adverse effects on both maternal and fetal health. In the context of pregnancy, MO poses specific challenges that can impact not only the well-being of the mother but also the developing fetus. Pregnancy is a period of physiological adaptations for every maternal organ. Women’s bodies are challenged by pregnancy at metabolic, hemodynamic, hematological, and vascular levels [22][18]. Therefore, in women with an already compromised physiology, such as obesity, pregnancy may constitute a more drastic challenge and lead to pregnancy-associated diseases, such as gestational diabetes mellitus (GDM), preeclampsia, deterioration of maternal cardiovascular health, and complications during labor and delivery, which can impair maternal and fetal health [21][19]. Maternal obesity can have profound implications for metabolic regulation during pregnancy due to changes in glucose metabolism to support fetal growth. Due to the increase in fetal glucose usage, higher peripheral consumption, and blood volume expansion, the fasting glucose levels tend to decrease throughout pregnancy [23][20]. In obese women, maternal blood glucose concentration is higher than in nonobese women [24][21]. The reduced peripheral insulin sensitivity and insulin rise from the second trimester onwards is physiologic in a lean pregnancy. This effect is mainly driven by the release of hormones with diabetogenic effects, such as cortisol, prolactin, growth hormone, and progesterone [25][22]. This effect is even more drastic in MO since obese mothers present higher insulin and cortisol blood concentrations at late gestation [26][23]. The inability of pregnant women to compensate for these metabolic adaptations may result in the development of GDM [27][24]. Obese pregnant women present lower metabolic flexibility to adapt from fasting to a postprandial state and more postprandial inflammatory markers [28][25]. Consequently, obese women during pregnancy show a higher risk of developing GDM [29][26]. Two different phases of lipid metabolism occur during pregnancy: during the first half of the pregnancy, triglycerides are synthesized and stored as energy reserves in maternal adipose tissue; during the second half, lipids are mobilized to the peripheral tissues preparing for lactation [30][27]. Consequently, circulating triglycerides and cholesterol levels increase during pregnancy in the form of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), while circulating free fatty acids (FA) decrease with pregnancy progression when compared with preconception levels, resulting in a hyperlipidemic environment in the mother—fetus interface [30][27]. Pregnant obese women show net lipolysis throughout pregnancy in contrast with lean pregnant women who demonstrate anabolic lipogenesis in early gestation and lipolysis in late gestation [31][28]. Increased maternal circulating triglyceride and fatty acids have been found in MO [32][29]. Compared with lean women, obese pregnant women show higher monounsaturated and saturated FAs and lower polyunsaturated FAs, higher branched-chain and aromatic amino acids, and increased GlycA levels, a marker of inflammation associated with metabolic dysfunctions, including type 2 diabetes and CVD [33,34,35,36][30][31][32][33]. Higher levels of branched-chain amino acids have been associated with reduced activity of branched-chain amino acids catabolism enzymes and reduced utilization in liver and adipose tissue causally related to insulin resistance [37][34]. The entire cardiovascular system, composed of the heart and the closed system of vessels, undergoes physiologic adaptations during pregnancy. Heart rate rises 15–25% via catecholamine release during pregnancy, resulting in 20–30% increased stroke volume and 30–50% increased cardiac output for the first and second trimesters [38,39,40][35][36][37]. Increased myocardial contractility is associated with higher left ventricular (LV) mass, wall thickness, and left atrial diameter compared to nonpregnant women [39,41][36][38]. Pregnancy is also a hypercoagulable state, which can predispose the pregnant woman to thromboembolic events [42,43][39][40]. Erythropoiesis is stimulated but is not able to compensate for the increase in blood volume, which can lead to anemia [44,45][41][42]. Maternal systemic vascular resistance decreases by 10–30% in early pregnancy resulting in lower mean arterial pressure. Consequent peripheral vasodilatation is achieved through the decreased response to vasoconstrictive molecules (e.g., angiotensin II) and the rise of circulating levels of vascular relaxing agents (e.g., nitric oxide, NO) [22,40,46,47][18][37][43][44]. In overweight and obese women, NO levels are increased in maternal blood at late gestation [48][45]. Circulating blood leptin and concentration of low-grade inflammatory markers (i.e., C-reactive protein (CRP) and interleukin-6 (IL-6)) are increased in the maternal blood of obese women [49,50][46][47]. Together with excessive VLDL, it can lead to endothelial and placental dysfunction, establishing a link between MO, hyperlipidemia, and the development of preeclampsia [51][48]. Highlighting the role of hyperlipidemia in preeclampsia development, studies in humans have found that mothers who develop preeclampsia present increased peripheral triglyceride levels either before, during, or shortly after pregnancy [52,53][49][50]. The highest reported triglyceride concentration was associated with a 4-fold increased risk for preeclampsia development in a case-control study [53][50]. Consistently, a higher risk of preeclampsia was found in obese women compared with women of normal weight [54][51]. Subsequent to the lower vascular resistance, the renin–angiotensin–aldosterone system is activated, resulting in water and sodium retention and increased blood volume, which can reach up to 45% before term [55,56][52][53]. When the fall in systemic vascular resistance reverses, a low-resistance uteroplacental circulation is created, which helps increase the blood flow to the placenta to support fetal growth requirements [22][18]. Abnormal placentation is observed in the first weeks of pregnancy and mostly results from the remodeling of the uterine spiral arteries leading to low vascular resistance and provoking systemic endothelial dysfunction [57,58][54][55]. The suboptimal occurrence of these processes provokes high-resistance uteroplacental circulation and may result in preeclampsia [59,60][56][57]. The mother—fetus interface is critical to the proper fetal development and maternal health; thus, it is critical to understand the impact of MO on the fetoplacental unit to better comprehend its adverse effects on fetal and maternal health.

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