Elsevier

Placenta

Volume 36, Issue 7, July 2015, Pages 709-715
Placenta

Current topic
Inflammation in maternal obesity and gestational diabetes mellitus

https://doi.org/10.1016/j.placenta.2015.04.006Get rights and content

Highlights

  • Inflammation occurs in maternal obesity and gestational diabetes mellitus (GDM).

  • The placenta plays a key role in inflammation in obesity and GDM.

  • Maternal inflammation may not equate to fetal inflammation.

Abstract

Background

The prevalence of maternal obesity is rising rapidly worldwide and constitutes a major obstetric problem, increasing mortality and morbidity in both mother and offspring. Obese women are predisposed to pregnancy complications such as gestational diabetes mellitus (GDM), and children of obese mothers are more likely to develop cardiovascular and metabolic disease in later life. Maternal obesity and GDM may be associated with a state of chronic, low-grade inflammation termed “metainflammation”, as opposed to an acute inflammatory response. This inflammatory environment may be one mechanism by which offspring of obese women are programmed to develop adult disorders.

Methods

Herein we review the evidence that maternal obesity and GDM are associated with changes in the maternal, fetal and placental inflammatory profile.

Results

Maternal inflammation in obesity and GDM may not always be associated with fetal inflammation.

Conclusion

We propose that the placenta ‘senses’ and adapts to the maternal inflammatory environment, and plays a central role as both a target and producer of inflammatory mediators. In this manner, maternal obesity and GDM may indirectly program the fetus for later disease by influencing placental function.

Introduction

Obesity in pregnancy is rapidly becoming more common worldwide and constitutes a major medical problem. In the United States, 35% of women of reproductive age are obese (body mass index, BMI > 30 kgm/m2) [1]. Maternal obesity has a significant economic impact, estimated to cost $106.8 million annually in the US alone [2]. Obesity during pregnancy is associated with increased mortality and morbidity for both mother and offspring. Obese women are at greater risk for developing pregnancy complications such as preeclampsia, thromboembolism, and gestational diabetes mellitus (GDM), as well as cardiovascular and metabolic disorders in later life [3], [4]. The risk of developing GDM is increased 1.3–3.8 times in obese women compared to women of normal BMI [5], and ∼70% of women with GDM may go on to develop type 2 diabetes up to 28 years post-partum [6].

Infants of obese mothers have a higher incidence of congenital abnormalities and are more likely to be large for gestational age (LGA) at birth [4], [7], [8]. Children of obese mothers, in particular if they are born LGA, are prone to develop metabolic disease [9], [10], [11], [12]. The hypothesis that the fetal environment may influence the development of disease in adulthood, now termed the ‘developmental origins of adult disease’, was proposed by Barker and based on the observation that low birthweight correlated positively with the development of cardiovascular disease in later life [13]. Considerable epidemiological evidence has accumulated demonstrating that maternal obesity is predictive for the development of obesity [14], cardiovascular disease [15], and type 2 diabetes in offspring [10]. Children of obese women with GDM are more likely to have increased adiposity and be insulin resistant, propagating the vicious cycle of metabolic disorders into the next generation [16]. There are currently limited options for early prevention of the metabolic syndrome in children born to obese women. Improving the metabolic environment of the obese pregnant mother to break this vicious cycle may be an attractive approach to decrease the future economical, societal, and personal burden of obesity. However, to make progress in this area, better understanding of the mechanisms linking obesity in pregnancy to adverse outcomes in the infant is necessary.

In recent years, there has been increased interest in the role of inflammation as a mediator of programming of metabolic disorders following exposure to the adverse intrauterine environment in maternal obesity. In the non-pregnant state, obesity is associated with a chronic, low-grade inflammatory state, termed ‘metainflammation’, or metabolically induced inflammation [17]. Metainflammation is distinct from an acute pro-inflammatory response and is triggered primarily by metabolites and nutrients, leading to systemic insulin resistance [17].

Placental inflammation has been observed in pregnancies complicated by obesity [18] and GDM [19], and may play a central role in determining the fetal environment in these pregnancies. Normal pregnancy is associated with a highly regulated inflammatory response that is vital to the process of placentation, from implantation through to labor at term [20]. Maternal obesity and GDM have been associated with changes in placental nutrient transporter expression and activity [21], [22]. These changes in placental function may be caused by altered inflammatory profiles in the mother, placenta and fetus in obesity and GDM, leading to the co-morbidities observed in these pregnancies [23], [24]. This article summarizes the literature reporting inflammatory profiles in the maternal, placental and fetal compartments in association to maternal obesity and GDM. Unless otherwise stated, we have focused specifically on studies documenting inflammation in women. While vascular and endothelial changes, oxidative stress, and tissue damage do occur in response to inflammation, we have focused on primary changes in inflammatory mediators and immune cells and pathways in obese pregnancies and GDM. A better understanding of how maternal obesity and metainflammation relates to the fetal intrauterine environment may lead to the development of better therapeutic interventions to prevent the development of metabolic disorders in later life.

Section snippets

Metainflammation, obesity and insulin resistance in the non-pregnant state

The acute inflammatory response induced by infection or trauma is typically a rapid response, characterized by vasodilation, infiltration of tissue by neutrophils, accumulation of macrophages and lymphocytes, and resolution. Acute inflammation is also characterized by an increased basal metabolic rate due to the focused and rapid response to the insult. Once the insult is neutralized, inflammation subsides. Inflammation induced by obesity in non-pregnant individuals is distinct from the

Maternal inflammation

Pregnancy itself is characterized by an altered inflammatory profile compared to the non-pregnant state. A tightly regulated balance between pro- and anti-inflammatory cytokines may be necessary for normal implantation, trophoblast invasion and placentation. A pro-inflammatory response localized to the uterine site of implantation may be necessary for this process [32]. In contrast, the post-implantation period is associated with an ‘immunosuppressive’ bias towards producing Th2 cytokines,

The placenta as an inflammatory organ: not just a silent observer

It is well established that placental cytokine production is critical for the maintenance of pregnancy. Cytotrophoblasts, syncytiotrophoblast and Hofbauer cells are known to secrete cytokines necessary at various stages of pregnancy from implantation to delivery [20]. It has been suggested that the placenta plays an active role in mediating inflammation in women with obesity and GDM. Placental structure and function may be altered in an adaptive response to obesity, and the placenta may act as

Inflammation and developmental programming

Inflammatory mediators may act in utero to program fetal adipose tissue, liver and skeletal muscle for insulin resistance later in life. Because it is not possible to examine fetal and neonatal tissues in humans, animal models have been utilized to investigate inflammation in specific tissues in offspring of obese dams. Maternal obesity is associated with adipogenesis, increased adiposity and insulin resistance in fetal tissues in several animal models [71]. In one study, activation of the

Conclusions and future directions

In conclusion, metainflammation, or chronic, low-grade metabolically induced inflammation may play a role in maternal obesity and GDM, leading to developmental programming in utero. The maternal inflammatory profile associated with GDM may be more pronounced than in obese women pregnant women without GDM. Studies investigating inflammatory mediators in the maternal, placental and fetal compartments in obesity and GDM are not always concordant. There is insufficient evidence that maternal

Conflict of interest

None.

Acknowledgements

This work was funded by NIH grant DK89989 to TLP.

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