Ashley Gillen

Background: According to the American College of Obstetrics and Gynecology, “obesity is the most common medical condition in women of reproductive age”, with 50% of American women being classified as overweight or obese prior to pregnancy^1-3. Maternal obesity increases the risk of neurodevelopmental disorders including Autism Spectrum Disorder (ASD), schizophrenia, epilepsy, depression, Cerebral Palsy (CP), and cognitive impairment in offspring^1,2. Currently, very little recommendations exist regarding neuroprotective therapies for obese pregnancies^2,6. Treatment development requires identifying the mechanism by which maternal obesity affects fetal neurodevelopment. One proposed mechanism is fetal immune system activation via maternal proinflammatory substances. Obesity causes low-level, chronic, systemic inflammation involving an increase in proinflammatory cytokines, some of which may cross the placental barrier and induce immune activation in the fetus^1,4,5. Interleukin-6 (IL-6), a proinflammatory cytokine elevated during obesity and capable of crossing the placenta is of particular interest as recent animal and human studies have demonstrated a correlation between elevated maternal IL-6 and incidence of neurodevelopmental disorders in offspring.

Objective: In this review, we discuss the findings of recent experiments which correlate elevated IL-6 exposure during development to increased incidence of neurodevelopmental differences in offspring.

Search Methods: We performed a search of the PubMed database between 2017-2023 using the following keywords: “maternal obesity”, “interleukin-6”, “fetal neurodevelopment”, “neurodevelopmental disorders”.

Results: Exposure of cultured human cortical pyramidal neurons to elevated IL-6 during differentiation resulted in a significant decrease in gene expression associated with the extracellular matrix, the actin cytoskeleton, and TBF-β signaling and an increase in gene expression related to chemokine signaling and binding pathways⁷. These cells also demonstrated decreased mitochondrial respiration, and increased oxidative stress, metabolic needs, and oxygen consumption⁷. Interestingly, mitochondrial dysfunction is linked to psychiatric disorders including schizophrenia and bipolar disorder⁷. In the female offspring of mice, maternal obesity and exposure to IL-6 separately resulted in disinhibition of the Lepr gene in hippocampal neurons⁸. In human observation studies, elevated maternal IL-6 averaged over pregnancy was correlated with marked neuroanatomical and functional differences in offspring^9-11. Functional MRI of infants indicated that elevated maternal IL-6 during pregnancy is associated with alterations in amygdala connectivity in the newborn human brain⁹. Increased maternal IL-6 was correlated with increased right amygdala volume, increased pars triangularis volume, globally decreased gray matter volume, and decreased development of the left and right uncinate fasciculi^9-11. Contrastingly, elevated IL-6 exposure in utero was also correlated to accelerated white matter growth in both uncinate fasciculi during the first year of life, a phenomenon like that seen in the brains of children diagnosed with ASD¹⁰. These studies also correlated elevated maternal IL-6 to decreased impulse control, lower cognitive development, and decreased fluid intelligence in the first 1-2 years of postnatal life^9-11. These behavioral and cognitive changes have been characterized in several neuropsychiatric disorders^9-10.

Conclusions: Recent studies have demonstrated an association between elevated IL-6 and biochemical, neuroanatomical, neurofunctional, behavioral, and cognitive changes in the offspring that resemble those alterations observed in neuropsychiatric disorders. Exploration into the mechanism by IL-6 alters neurodevelopment may lead to neuroprotective therapies for obese pregnancies.

Works Cited:

1. Paredes C, Hsu RC, Tong A, Johnson JR. Obesity and Pregnancy. Neoreviews. 2021;22(2):e78-e87. doi:10.1542/neo.22-2-e78
2. Tong L, Kalish BT. The impact of maternal obesity on childhood neurodevelopment. J Perinatol. 2021;41(5):928-939. doi:10.1038/s41372-020-00871-0
3. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Obesity in Pregnancy: ACOG Practice Bulletin, Number 230. Obstet Gynecol. 2021;137(6):e128-e144. doi:10.1097/AOG.0000000000004395
4. Davis J, Mire E. Maternal obesity and developmental programming of neuropsychiatric disorders: An inflammatory hypothesis. Brain Neurosci Adv. 2021;5:23982128211003484. Published 2021 Apr 8. doi:10.1177/23982128211003484
5. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. 2021;320(3):C375-C391. doi:10.1152/ajpcell.00379.2020
6. Giouleka S, Tsakiridis I, Koutsouki G, et al. Obesity in Pregnancy: A Comprehensive Review of Influential Guidelines. Obstet Gynecol Surv. 2023;78(1):50-68. doi:10.1097/OGX.0000000000001091
7. Kathuria A, Lopez-Lengowski K, Roffman JL, Karmacharya R. Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons. Brain Behav Immun. 2022;103:97-108. doi:10.1016/j.bbi.2022.04.007
8. Glendining KA, Higgins MBA, Fisher LC, Jasoni CL. Maternal obesity modulates sexually dimorphic epigenetic regulation and expression of leptin receptor in offspring hippocampus. Brain Behav Immun. 2020;88:151-160. doi:10.1016/j.bbi.2020.03.006
9. Graham AM, Rasmussen JM, Rudolph MD, et al. Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age. Biol Psychiatry. 2018;83(2):109-119. doi:10.1016/j.biopsych.2017.05.027
10. Rasmussen JM, Graham AM, Entringer S, et al. Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life. Neuroimage. 2019;185:825-835. doi:10.1016/j.neuroimage.2018.04.020
11. Rasmussen JM, Graham AM, Gyllenhammer LE, et al. Neuroanatomical Correlates Underlying the Association Between Maternal Interleukin 6 Concentration During Pregnancy and Offspring Fluid Reasoning Performance in Early Childhood. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022;7(1):24-33. doi:10.1016/j.bpsc.2021.03.007