Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring

Abstract

The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring's health in numerous disease contexts, including offspring's risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells.

Keywords: developmental programming of adult diseases; long-term health of offspring in obese mothers; maternal inflammation during pregnancy; maternal obesity; offspring of mothers with obesity.

Figure 1

Schematic diagram of major changes in immune cells and inflammatory markers/cytokines during different stages of a normal pregnancy. First trimester is characterized by an initial pro-inflammatory stage necessary for implantation and placentation. dNK cells secrete high levels of pro-inflammatory factors including IL-1, IL-6, IL-8, IL-15, CXCL10, CXCL11, TNF, MMPs. Predominance of M1-type (pro-inflammatory) macrophages contribute to the inflammatory state observed in first trimester. At second trimester, Th2-type immune response and immunomodulatory cytokines secreted by Th2 cells (e.g., IL-4, IL-10, IL-13) lead to an anti-inflammatory stage that is crucial for fetal growth. M2-type (anti-inflammatory) macrophages and increased expression of inhibitory receptors on dNK cells such as killer cell immunoglobulin-like receptor (KIR) play a significant role in maintaining immune tolerance in maternal-fetal interface. Finally, third trimester is defined as a second pro-inflammatory stage and Th1-type immune state is thought to initiate labor and delivery. Other T helper cells including Th17, Th22, Treg and Tfh cells are also essential for healthy pregnancy. TH17 and Th22 cells offer immunity against extracellular pathogens at the maternal-fetal interface. Treg cells increase immune tolerance to fetus by repressing uncontrolled Th1 and Th17 immunity. Tfh cells provide humoral immunity by priming B cells to initiate extrafollicular and germinal center antibody responses in third trimester. Created with BioRender.com.

Figure 2

Proposed model of the effects of maternal obesity on placental adaptation and fetal reprogramming that led to end organ changes and adverse health outcomes in children. Placenta shows adaptation to environmental stressors including maternal obesity-associated inflammatory state. Changes in placenta predisposes the fetus to reprogramming that is associated with a higher risk of childhood obesity, neuropsychiatric disorders, altered HSPC function, atopic diseases, dysregulated pulmonary development, and/or cancer. Altered HSPC function and the immune cells that originate from the HSPCs may further predispose children to adverse health outcomes associated with maternal obesity. Created with BioRender.com.