Maternal Excess Adiposity and Decidual Dyshomeostasis—A New Temporal Target for Intervention

The mechanisms linking maternal metabolic health to adverse pregnancy outcomes are important to understand. The December issue of Acta Physiologica contains an excellent study with an insightful analysis that changes prevailing hypotheses [1]. Bellissimo and colleagues question the long-standing paradigm that structural failure of spiral artery remodeling is the initial pathology that links maternal metabolic dysfunction to adverse outcomes like preeclampsia [2]. Bellissimo and colleagues found that diet-induced obesity in prepregnant mice induces profound decidual immune and vascular dyshomeostasis at gestational Day 10.5, which is the end of decidualization in the mouse. Yet, the process of spiral artery remodeling was not impaired [1]. The study offers a powerful and nuanced perspective on this critical maternal-fetal interface, and their findings are illuminating when contrasted with the bulk of research on placental insufficiency. Preeclampsia models, for instance, often focus on the ultimate failure of trophoblast-mediated spiral artery remodeling as the central pathology, a structural defect that prevents adequate blood flow and nutrient delivery to the placenta. While prior work has established that maternal obesity influences the overall uterine immune environment and compromises endometrial stromal cell decidualization [3], this study delineates the defect in detail. The demonstration that maternal obesity induces significant decidual immune and vascular dyshomeostasis at GD 10.5 before any impairment in spiral artery remodeling provides a vital temporal shift [1]. This refinement redirects attention from late-stage structural failure and supports the contention that an early inflammatory-metabolic imbalance in decidual development is the key initiating event in maternal obesity-driven placental dysfunction. By focusing on the decidua, the interface where maternal and fetal tissues first interact, the authors pinpoint a state of early immunological imbalance. While some research observed a net decrease in total decidual immune cells under maternal obesity [4], Bellissimo et al. demonstrate that the key pathology lies in the quality and proportion of the populations. They first observed an increase in total decidual immune cell populations in the High Fat High Sucrose treated mothers compared to controls, which allowed them to control for and recognize the critical increase in Natural Killer (NK) cells of both tissue resident NK and conventional like NK phenotypes and MHCII+ macrophages essential for immune tolerance and vascular support. The concurrent demonstration of decidual and vascular dyshomeostasis including elevated inflammation, activation, coagulation markers, and angiogenic growth factor levels, distinct from structural remodeling failure, suggests that even subtle shifts in the decidual milieu can compromise the delicate balance of decidual angiogenesis required for successful gestation [1]. In summary, the study suggests that the adverse effects of maternal adiposity may not lie in an initial failure of maternal vascular conversion, but rather in a chronic, low-grade inflammatory state in the early decidua that compromises later placental function. They provide conclusive molecular and histological proof that placental development is unaffected by maternal diet at d10.5 [1]. Their findings significantly refine our understanding of how maternal metabolic health impacts pregnancy success and provide a renewed urgency and focus for the development of early preventative strategies in clinical practice targeted on the dynamic interplay of all decidual cell types during the decidualization process. One such potential treatment is the use of daily low dose aspirin (LDA). The American College of Obstetricians and Gynecologists recommend LDA should be considered for women with any risk factors for preeclampsia (PE), including obesity, chronic hypertension, and a previous preeclamptic pregnancy [5]. However, at present, the literature on the evidence of aspirin's effectiveness in preventing PE in obese women is unclear due to reports of reduced effectiveness of standard doses of LDA (81 or 100 mg) in preventing platelet aggregation [6]. The Royal College of Obstetricians and Gynecologists' guidelines specifically recommend a higher dose of 150 mg/day for obese women with more than one moderate risk factor for PE [7]. The recent ASPREO (Aspirin for High-risk Obese Individuals: A Comparative Effectiveness Open Label) Randomized Trial of 162 mg versus 81 mg in the prevention of PE in obese pregnancies found that in high-risk obese individuals, there was a 78% probability of benefit that 162 mg aspirin compared with 81 mg will decrease the rate of preeclampsia with severe features. These authors recommended a further multicenter trial to confirm these findings [8]. In PE, circulating urine and placental prostacyclin (PGI2) levels drop sharply resulting in an imbalance in the PGI2/Thromboxane A2 (TXA2) ratio, leading to vasoconstriction. The main mechanism of action for low-dose aspirin to prevent PE is thought to be the restoration of the disproportionate PGI2/TXA2 ratio via its inhibitory effect on the production of TXA2 [9]. However, a recent study has further shown that LDA given from early in pregnancy to the third trimester to women at high risk of developing PE resulted in an increase in CD4 and CD8 cells, naïve Treg cells, a decline in activated inflammatory Th17 cells and a shift from cytotoxic to tolerogenic NK cells in the peripheral blood [10]. The effect of LDA on decidual immune and vascular homeostasis are yet unknown (Figure 1). The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.