Rebecca L. Wilson

Fetal growth restriction (FGR) resulting from maternal undernutrition is commonly attributed to insufficient nutrient substrate delivery to the fetus. However, the contribution of maternal physiological stress responses to this outcome remains poorly characterized. Using the well-established guinea pig maternal nutrient restriction (MNR) model, we conducted a comprehensive retrospective analysis to interrogate the hypothesis that maternal stress physiology actively mediates fetal growth outcomes beyond simple substrate limitation. Maternal salivary and serum cortisol were significantly elevated in MNR dams throughout pregnancy despite no baseline differences at conception, indicating that hypothalamic-pituitary-adrenal (HPA) axis activation was specifically triggered by the combined physiological demands of pregnancy and nutritional constraint. The sustained cortisol elevation was accompanied by acute metabolic perturbations at mid-pregnancy, including hypoglycemia and depleted circulating lipids. While most acute metabolic disturbances resolved by near-term, cortisol remained elevated, and MNR fetuses exhibited parallel cortisol elevation alongside sustained growth restriction. Maternal weight divergence emerged only in late gestation and was driven primarily by reduced conceptus weight. Maternal organ analysis revealed selective hepatic enlargement with apparent lipid accumulation in MNR dams near-term. Overall, these findings help to reframe nutrition-related FGR as a condition in which maternal adaptive stress responses, reduced nutritional components and placental insufficiency are mechanistically intertwined, with important implications for the design of effective interventions beyond simply nutrient supplementation. New and Noteworthy: This study demonstrates that maternal physiological stress, not substrate limitation alone, is a driver of impaired fetal growth in a guinea pig model of undernutrition in pregnancy. We show that maternal hypothalamic-pituitary-adrenal axis activation produces sustained cortisol elevation throughout pregnancy independent of nutritional recovery. This stress-related response was accompanied by selective hepatic and metabolic adaptations.

Background: Periodontitis has been epidemiologically associated with adverse pregnancy outcomes, but causality remains difficult to establish in humans due to confounding factors. This study uses a controlled murine model to examine the effects of experimentally induced periodontitis on the composition of the gut microbiota and gastrointestinal inflammation during pregnancy. Methods: Periodontitis was induced in pregnant BALB/c mice via oral inoculation with Porphyromonas gingivalis and Fusobacterium nucleatum before conception ( n = 20 per group). Pregnancy outcomes, gut histology, systemic inflammatory markers, and microbiome composition, assessed by 16S rRNA sequencing, were evaluated at gestational Day 18. Results: Periodontitis was confirmed by significant alveolar bone loss. While fetal and placental weights were modestly increased in periodontitis‐positive mice, there were no changes in implantation rates or placental efficiency. Systemic inflammatory markers, including C‐reactive protein and interleukin‐33, were reduced, suggesting pregnancy‐specific immunomodulation. Histological analysis revealed significant inflammation in the jejunum and colon of periodontitis‐exposed mice. Despite this, alpha and beta diversity metrics of the gut microbiota remained essentially unchanged. Taxonomic shifts were observed at the genus level, with reductions in protective taxa, such as Akkermansia muciniphila and increases in potentially pro‐inflammatory genera, like Desulfovibrio . Conclusions: Periodontitis during pregnancy alters gut microbial composition and increases gastrointestinal inflammation without overtly impairing pregnancy outcomes in mice. These findings suggest an association between oral inflammation, intestinal inflammatory changes, and systemic inflammatory modulation during pregnancy. Further studies are warranted to explore long‐term maternal and offspring consequences and their relevance to human pregnancy. Plain language summary: This study explored how periodontitis during pregnancy can influence the gut and immune system. Periodontitis is already associated with poor pregnancy outcomes, but establishing cause and effect in humans is difficult. To investigate this, the researchers used a controlled mouse model. We induced periodontitis in pregnant mice and examined its impact on the gut microbiome, intestinal health, and immune responses. The results revealed that periodontitis does not stay confined to the mouth; it disrupts gut bacterial balance, causes gut inflammation, and modifies immune pathways. Notably, these effects occurred during pregnancy, a time when the immune system is already adapting. The findings suggest that oral infections during pregnancy can have widespread effects, impacting gut health and immune regulation. This may help explain the link between periodontitis and human pregnancy complications. Overall, the study underscores the importance of oral health during pregnancy and supports the idea that treating periodontitis might also safeguard gut and immune health, leading to better outcomes for both mothers and their babies.

Increased maternal stress during pregnancy has been linked to numerous adverse pregnancy outcomes, including preterm birth and impaired fetal development. While clinical studies have established strong associations between maternal stress and adverse pregnancy outcomes, understanding the biological mechanisms is crucial for developing effective preventive intervention. Rodent models have provided valuable insights, however physiological differences from humans limit translational relevance. This systematic review evaluated and synthesized experimental models of increased maternal stress during pregnancy in guinea pigs. Guinea pigs share key pregnancy characteristics with humans, including relevant placental structure, maternal hormonal recognition of pregnancy and precocial offspring development. We identified 43 studies using various experimental approaches categorized into three main types: behavioral models, drug/substance exposure models, and physiological challenge models. These studies demonstrated significant fetal and offspring effects, particularly sex-specific neurodevelopmental outcomes. However, maternal physiological adaptations were often superficially characterized, focusing primarily on weight gain and occasional stress hormone measurements. Most studies began interventions during established pregnancy, potentially missing critical pre-pregnancy and early pregnancy periods. Overall, this review highlights the need for future studies to consider pre-conception interventions to better model human conditions and more comprehensively examine maternal adaptations.

Fetal growth restriction (FGR) is most commonly due to placental insufficiency. There are currently no treatments for placental insufficiency or FGR, and the only intervention is iatrogenic pre-term delivery. We have previously shown efficacy of repeated placental nanoparticle-mediated insulin-like 1 growth factor ( IGF1 ) treatment in improving placental efficiency (increased fetal-placental weight ratio) and correcting fetal growth in a maternal nutrient restriction (MNR) guinea pig model of FGR. Here we investigate the structural remodeling of the placenta following 3 repeated intraplacental injections of nanoparticle-mediated hIGF1 that may underpin the published improvements in placental efficiency and fetal growth. We hypothesize placenta structural changes (reduced exchange area, altered vascular structure) that we and others have previously shown in the FGR/MNR placenta which lead to deficits in placental function are mitigated by our repeated nanoparticle-mediated hIGF1 treatment. Sham-treated MNR placentas displayed disorganized microvasculature labyrinthine exchange areas with a reduction in placental capillary number and maternal blood space areas, and an increase in the volume of the placenta macrovasculature. Repeated nanoparticle-mediated hIGF1 treatment, however, resulted in an improved exchange area with normalized placental capillary number and maternal blood space area, and macrovasculature volume. This data demonstrates repeated nanoparticle-mediated hIGF1 delivery corrects aberrant placenta structure likely leading to improved gas exchange and transfer of nutrients to the fetus restoring fetal growth.

Appropriate fetal growth during pregnancy requires multi-directional communication from the maternal, placental and fetal systems. Disruption in any of these signaling arms can have deleterious consequences for fetal growth and initiate developmental adaptations within fetal tissues and organs that are associated with both short- and long-term morbidities. In this proof-of-concept translational, human cell model study we aimed to identify the impacts of altered trophoblast stress response mechanisms and human insulin-like 1 growth factor ( hIGF1 ) nanoparticle gene therapy on gene and protein expression in fetal liver hepatocytes and fetal kidney epithelial cells. We utilized human cell lines: BeWo choriocarcinoma cells (trophoblast), Human Placental Micro-Vascular Endothelial Cells, and WRL68 (hepatocytes) or HEK293T/17 (kidney epithelium), in a co-culture model designed to mimic cytotrophoblast-villous endothelium-fetal organ communication. Trophoblast stress response mechanisms were increased by culturing BeWo cells in growth media without FBS. Stressed BeWo cells were also treated with a hIGF1 nanoparticle gene therapy known to mitigate cellular stress mechanisms. Stressed BeWo cells had increased expression of cellular stress mechanisms but not when IGF1 was over-expressed with a transient hIGF1 nanoparticle gene therapy. Stressed and Stressed+ hIGF1 BeWo cells had increased expression of gluconeogenesis and glycolysis rate-limiting enzymes. Gene and protein expression in fetal liver and kidney cells was not impacted by increased trophoblast stress or hIGF1 nanoparticle gene therapy. In conclusion, our data demonstrated that cytotrophoblast under stress turn on mechanisms involved in glucose production. Whether this is reflected in vivo remains uninvestigated but may represent a placental compensation mechanism in complicated pregnancies.

Fetal development in an adverse in utero environment significantly increases the risk of hypertension and cardiovascular disease. The kidneys play a pivotal role in the regulation of blood pressure and cardiovascular function, and perturbations in kidney structure and molecular profile are often demonstrated in offspring born fetal growth restricted (FGR). The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate FGR-associated dysregulation of fetal kidney development. Using the guinea pig maternal nutrient restriction (MNR) model, we improved placenta efficiency and fetal weight following three placental administrations of a non-viral polymer-based nanoparticle gene therapy from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 ( hIGF1 ) in placenta trophoblast. Fetal kidney tissue was collected near-term at gestational day 60. Differences in kidney structure, glomeruli size and gene expression of extracellular matrix (ECM) remodeling and blood pressure regulation-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. We speculate that mitigating the FGR-associated changes in kidney architecture and molecular profiles might confer protection against increased susceptibility to aberrant kidney physiology in later-life. Overall, this work opens avenues for future research to assess the long-term impact of the placental hIGF1 nanoparticle gene therapy on cardiovascular function in offspring.

A placenta-specific nonviral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later life. This knowledge may have implications toward removing predispositions that increase the risk of metabolic diseases, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease in later life.

Roughly 10% of all pregnancies are affected by fetal growth restriction (FGR). The primary etiology of FGR is placental insufficiency: the placenta not providing the appropriate amount of nutrients and oxygen to the fetus. There is currently no treatment for FGR or placental insufficiency. Because of the placentas pivotal role in FGR and supplying nutrients to the fetus, it offers an excellent target for therapeutic intervention. Using a guinea pig maternal nutrient restriction model and a repeated placental nanoparticle-mediated IGF1 treatment, placental IGF1 signaling and nutrient transport pathways were characterized to understand changes with FGR and treatment. This study elucidates the signaling mechanisms in which repeated placental nanoparticle-mediated IGF1 treatment leads to correct fetal growth. Overall, this study resulted in sex-specific kinase signaling and nutrient transporter changes within the placenta in both FGR and treatment groups. Combined with our previous studies using this treatment, we demonstrate the basic molecular signaling of this treatment and recapitulate the plausibility of this therapy for future human translation.