Inflamaţia în obezitatea maternă – mecanisme patologice şi impactul asupra rezultatelor naşterii şi a sănătăţii fătului

Introduction

The prevalence of obesity is increasing in women of reproductive age, and currently it is estimated that between 20% and 50% of pregnancies occur in either overweight (BMI: 25-29.9 kg/m²) or obese (BMI≥30 kg/m²) women^(1,2). Through its wide pathological mechanisms and influences, maternal obesity has been demonstrated to have major negative health effects and to be associated with the development and progression of various pathologies. One of the most studied mechanisms of these pathologies is the chronic low-grade inflammation induced by obesity.

Obesity has a direct impact on the quality of life, as obese patients frequently express negative psychological effects, such as low self-esteem due to negative body image, depression and social stigma, which has a detrimental impact on their social interactions and couple relationships⁽³⁾. Pre-gravid obesity has significant health risks to both the mother and the baby, with an increased risk of miscarriage, preeclampsia, gestational diabetes, stillbirth, caesarean delivery, fetal overgrowth, altered body composition and neural tube defects^(4,5). Infants born to overweight or obese mothers are more likely to be large for gestational age, macrosomic, and insulin resistant⁽⁶⁾. Maternal obesity could also have long-term consequences in offspring, such as an increased risk to develop cardiovascular disease, metabolic syndrome, diabetes, cancer and psychiatric disorders^(7-9).

From the pathogenesis perspective, cells such as placental macrophages and natural killer (NK) cells have been implicated in spontaneous miscarriage, preeclampsia, preterm birth, perinatal neuroinflammation and other postnatal conditions. Differing levels of placental cytokines and molecular inflammatory mediators have also well-known associations with preeclampsia and developmental outcomes.

High Body Mass Index (BMI) before the onset of pregnancy and excessive gestational weight gain are important predictors of short-term postpartum morbidity and higher postpartum weight retention, with the latter being linked with increased risks during future pregnancies and of lifelong obesity for women.

Pathological mechanisms

Maternal obesity is related with maternal, placental and fetal metabolic dysfunction with increased inflammation. “Metaflammation” is the proposed term for the chronic, low-grade inflammatory state associated with obesity, which differs from acute inflammatory responses induced by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs)⁽¹⁰⁾. Metaflammation is triggered by metabolites and nutrients and may lead to systemic insulin resistance due to inflammatory mechanisms associated with obesity^(11,12). Early inflammation affects the developing immunophenotypes of fetal immune cells, which likely relate to obesity effects on epigenetics and the microbiome^(13,14).

In this context, women entering pregnancy obese have more pronounced insulin resistance, higher circulating plasma insulin, leptin, insulin-like growth factors (IGFs), lipids and proinflammatory cytokines and lower plasma adiponectin, as compared with pregnant women with normal BMI⁽¹⁵⁾. Recent studies have shown increased macrophage accumulation and increased expression of proinflammatory molecules in adipose tissue, as well as decreased expression of insulin-sensitizing molecules. Obesity is characterized by adipocyte hypertrophy, followed by increased angiogenesis. There is a chronic state of low-grade inflammation with progressive immune cell infiltration and extracellular matrix overproduction into obese adipose tissue. The metabolic complications in obesity derive partly from the abnormal production of proinflammatory molecules called “adipokines” in the adipose tissue⁽¹⁶⁾.

Leptin is an adipokine that has been intensely studied in the past years. It is an adipocyte-derived peptide hormone with central and peripheral effects on energy balance. Its production and secretion from adipose tissue are positively correlated with increased adipocyte size and number⁽¹⁷⁾. Leptin shows a positive correlation with maternal insulin levels and BMI during the first and third trimesters, as well as with BMI at the time of delivery^(18,19). Additionally, there is a positive correlation between maternal leptin levels and fetal circulating leptin concentrations. Elevated cord leptin levels have been associated with insulin resistance in the fetus^(20,21).

Another intensely studied adipokine is adiponectin, a molecule which exerts antiproliferative effects. Throughout pregnancy, obese women have reduced plasma adiponectin levels compared to women with a normal BMI⁽²²⁾. Maternal adiponectin is negatively correlated with maternal fat mass, insulin resistance, glucose production and fetal growth, suggesting that adiponectin plays a significant role in modulating maternal metabolism, placental function and fetal development⁽¹⁵⁾. Low maternal adiponectin, as observed in maternal obesity, is expected to promote placental nutrient transport, as suggested by studies in which knockdown of the maternal adiponectin gene causing lower circulating levels resulted in increased fetal growth^(23,24).

Compared with adipose tissue of normoponderal individuals, adipose tissue of obese patients expresses increased amounts of proinflammatory factors such as TNF-a, C-reactive protein (CRP)⁽²⁵⁾, IL-6⁽²⁶⁾, TGF-b1, soluble ICAM, monocyte chemotactic protein-1 (MCP-1)⁽²⁷⁾, and procoagulant proteins such as plasminogen activator inhibitor type-1 (PAI-1), tissue factor and factor VII⁽²⁸⁾. In obese mothers, elevated levels of IGF-1 and reduced levels of IGFBPs (insulin-like-growth factor binding proteins), indicating a higher maternal IGF-1 bioavailability, might enhance the placental uptake and transfer of nutrients to the fetus⁽¹⁵⁾. Concerning the proinflammatory cytokines, IL-6 and TNF-a have been intensely studied, as they influence critical placental processes, such as the transport of lipids and amino acids, along with placental metabolism. Radaelli and colleagues showed a positive correlation between maternal IL-6 and neonatal fat mass⁽²⁹⁾. Furthermore, TNF-a from macrophages induces adipocyte apoptosis, impairs insulin signaling, and locally induces insulin resistance in adipocytes⁽³⁰⁾. Additionally, some evidence suggests that TNF-a inhibits the signaling associated with IGF-I/insulin hybrid receptors, providing a potential mechanisms by which TNF-a may inhibit insulin actions on the trophoblast⁽³¹⁾. Interestingly, in cases of maternal obesity, placental TNF-a levels were found to be higher in female placentas compared to male ones, indicating that there may be gender-specific differences in how the placenta responds to inflammation related to obesity⁽³²⁾.

Impact of maternal obesity on pregnancy outcomes

Intrapartum, women with maternal obesity have an increased risk of failed trial of labor, caesarean delivery and endometritis⁽³³⁾. The risk of anesthetic complications – such as epidural failure, hypotension and prolonged fetal heart rate decelerations, impaired respiratory function, difficult endotracheal intubation and increased prevalence of obstructive sleep apnea – is also increased in women with maternal obesity⁽¹²⁾. Also, it is considered a risk factor for venous and pulmonary thromboembolism during the postpartum period (adjusted odds ratio 14.9; 3 to 74.8)⁽³⁴⁾.

Maternal obesity also influences the neonatal weight, as these babies are at an increased risk of overgrowth, macrosomia and/or large for gestational age (LGA). Macrosomia is defined as birth weight greater than 4000 to 4500 grams, without consideration for gestational age⁽³⁵⁾, being further associated with an increased risk of several complications, particularly maternal and/or fetal trauma during birth and neonatal hypoglycemia and respiratory problems. Large for gestational age is defined as birth weight greater than the 90^th percentile for gestational age.

Newborns born to obese mothers exhibit higher levels of umbilical cord leptin and IL-6 compared to those born to lean mothers. Additionally, infants of obese mothers display higher insulin resistance compared to those of their lean counterparts. A significant correlation exists between insulin resistance in obese infants, maternal insulin resistance, and neonatal body fat⁽²⁰⁾. Obesity-induced metabolic dysfunction and pregnancy complications share a number of features and characteristics. Particularly, proinflammatory factors such as HMGB1⁽³⁶⁾, TNF-a^(37,38) and IL-1b^(39,40) play critical roles in the inflammation underlying both obesity and preeclampsia.

Placental stress has been noted via placental expression of soluble fms-like tyrosine kinase-1 (sFlt-1) and triglycerides in maternal serum⁽⁴¹⁾, being usually associated with maternal hypertension and proteinuria, which is induced by sFlt-1 (sVEGFR1). sFlt-1 is an anti-angiogenic protein, as it interferes with vascular endothelial growth factor (VEGF), which triggers angiogenesis. VEGF has also been suggested to recruit macrophages and aid shift toward type-2 macrophages, which enhances immune tolerance and tissue remodeling⁽⁴²⁾. The endothelial dysfunction in the placenta increases the likelihood of preeclampsia, along with an immunophenotype skewing more toward Th1 cells producing proinflammatory cytokines⁽⁴³⁾.

Long-term effect of maternal obesity on offspring health

Maternal obesity could negatively impact fetal growth, leading to long-term effects on the child, such as a higher susceptibility to obesity and diabetes⁽⁴⁴⁾, but the exact processes by which mother’s obesity contributes to a higher risk of obesity and related metabolic disorders in their children are not clearly understood.

The association of maternal obesity with obesity and cardiometabolic risk factors in the offspring has been extensively studied and is well known. Being LGA at birth heightens the likelihood of obesity during teenage years and adulthood and doubles the risk of developing insulin resistance⁽⁴⁵⁾.

Inflammatory mediators might begin their influence in utero, predisposing fetal adipose tissue, liver and skeletal muscle to develop insulin resistance in later stages of life⁽⁴⁶⁾. In various animal models, maternal obesity has been associated with adipogenesis, increased adiposity and insulin resistance in fetal tissues⁽⁴⁷⁾.

Even though the effects of inflammation on fetal tissues in utero need further studies, emerging evidence suggests that maternal obesity and its associated inflammation have detrimental effects on the development of various fetal tissues.

For example, the development of fetal muscle and skeleton could be influenced by maternal obesity through various mechanisms orchestrated by inflammation. Recent research concludes that chronic inflammation downregulates myogenesis and enhances adipogenesis in fetal skeletal muscle⁽⁴⁸⁾. It affects the mesenchymal stem cells in fetal muscle through several possible mechanisms, as identified by Du and colleagues: inflammation downregulates wingless and int-1 (WNT) signaling, which attenuates myogenesis, it inhibits AMP-activated protein kinase, which promotes adipogenesis, and it may induce epigenetic modification through polycomb group protein⁽⁴⁴⁾.

The specific mechanisms that link maternal inflammation to a high risk of neurodevelopmental disorders are not clearly defined, but various studies have recently focused on the various pathways in which neurogenesis could be influenced by maternal obesity. There is a growing consensus that obese pregnant women frequently exhibit disruptions in one-carbon metabolism and an imbalance in gut microbiota due to the consumption of nutritionally deficient foods and to a persistent state of systemic inflammation, leading to adverse pregnancy outcomes and potential long-term offspring metabolic and neurologic disorders⁽⁴⁹⁾. Recent studies found that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta, with an increased placental output of serotonin to the fetal brain⁽⁵⁰⁾. Serotonin is a neurotransmitter that plays a fundamental role in various physiological processes, including mood regulation, appetite and sleep. The increased placental output of his neurotransmitter to the fetal brain can have several potential consequences such as altered neurogenesis, neuronal migration and differentiation, leading to changes in brain architecture or function. Furthermore, there is growing evidence to suggest that disruptions in the fetal serotonergic system might be linked to neurodevelopmental disorders such as autism spectrum disorder⁽⁵¹⁾. Imbalances in serotonin levels have been implicated in various mood disorders such as depression. Although the foundational mechanisms are still under investigation, changes in early-life serotonin exposure could potentially predispose an individual to mood disturbances later in life^(52,53). A recent systematic review that included 32 meta-analyses and 26 additional individual studies showed that maternal obesity is associated with autism spectrum disorder and attention deficit hyperactivity disorder in offspring, supporting the idea that inflammation in maternal obesity contributes to the pathological mechanisms of a variety of neuropathologies, including neuronal dysfunction, microglial activation, and a consequent spectrum of neurobehavioral phenotypes in children⁽⁵⁴⁾.

The association between maternal obesity and an increased offspring cardiometabolic risk has also been studied. Some research reveals associations between maternal obesity and the development of high systolic blood pressure in 6-year-old children⁽⁵⁵⁾ and in 21-year-old offspring⁽⁵⁶⁾, proving an association between maternal obesity and offspring’s cardiovascular health, with an increased risk of developing cardiovascular disease.

The implications of maternal obesity on the kidney health of offspring include renal lipid accumulation and activation of renal fibrosis, leading to renal structural change and dysfunction in offspring⁽⁵⁷⁾. Furthermore, maternal obesity leads to increasing renal inflammation in offspring via the programmed recruitment of macrophages into the kidneys of the offspring, along with increased levels of proinflammatory cytokines. As the consequential oxidative stress promotes DNA damage in the offspring’s kidneys, maternal obesity is considered to be a promotor of chronic kidney disease in the later life of the offspring⁽⁵⁷⁾.

Conclusions

Lifestyle changes, emphasizing better nutrition and enhanced physical activity during pregnancy, have shown modest effectiveness in reducing excessive gestational weight gain in women with maternal obesity. However, these interventions have not mitigated the risks associated with maternal metabolic abnormalities and excessive fetal growth, as the metabolic disfunctions in obese women influence the reproductive functions even before conception. Excess of fat mass, particularly visceral and ectopic fat, is considered the primary driver of this type of inflammation. In obese pregnant women, the fetoplacental unit develops under conditions of inflammation and excess of nutrients, with serious implications for morbidity and mortality both for the mother and the baby.

Further epidemiological and clinical studies are necessary in order to develop strategies that could ameliorate, revert, or even prevent deleterious effects of maternal obesity on the pregnancy and offspring’s development. It is imperative to take appropriate measures before conception in order to alleviate the burden of metabolic alterations on the health and quality of life of the offspring. 


 

Conflict of interest: none declared  
Financial support: none declared
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