Maternal Obesity Causes Elevated Maternal Interleukin 6 Concentrations Which is Associated With a Range of Neurodevelopmental Disorders in Offspring
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 pregnancy1-3. Maternal obesity increases the risk of neurodevelopmental disorders including Autism Spectrum Disorder (ASD), schizophrenia, epilepsy, depression, Cerebral Palsy (CP), and cognitive impairment in offspring1,2. Currently, very little recommendations exist regarding neuroprotective therapies for obese pregnancies2,6. 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 fetus1,4,5. 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 offspring9-11. 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 fasciculi9-11. 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 life9-11. These behavioral and cognitive changes have been characterized in several neuropsychiatric disorders9-10.
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.
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- 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
- 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
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- 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
- 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
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- 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
- 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
- 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