Madison Arthur

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic inflammation, endothelial dysfunction, and abnormal placental development that contributes significantly to maternal and fetal morbidity and mortality worldwide.¹ Defective placentation occurs when extravillous trophoblasts (EVTs) fail to adequately invade the maternal decidua and remodel spiral arteries into low-resistance vessels, leading to placental hypoxia, oxidative stress, and inflammatory signaling.² Increasing evidence suggests that placental cytokines and immune-cell signaling regulate trophoblast differentiation, invasion, and vascular remodeling.³ Maternal exercise has consistently been associated with improved metabolic health and reduced risk of adverse pregnancy outcomes; however, the molecular mechanisms linking exercise to placental development remain incompletely understood.⁴ This review examines whether exercise-induced cytokine and immune modulation may influence trophoblast invasion and placental vascular remodeling in pathways associated with preeclampsia pathogenesis.

Objective: To evaluate the potential mechanistic relationship between maternal exercise, placental cytokine signaling, trophoblast invasion, and preeclampsia risk.

Search Methods: A literature review was conducted using PubMed and other scholar databases. Search terms included “preeclampsia,” “placental cytokines,” “exercise during pregnancy,” “G-CSF,” “IL-6,” “TNF-alpha,” “uterine natural killer cells,” “trophoblast invasion,” “spiral artery remodeling,” and “TPBG.” Primary literature published between 2021 and 2025 was emphasized, with additional foundational review articles included for background context.

Results: A randomized controlled trial involving 76 pregnant women demonstrated that supervised moderate-to-vigorous exercise during pregnancy increased placental granulocyte colony-stimulating factor (G-CSF) and reduced pro-inflammatory cytokines, including TNF-alpha and IL-6, suggesting a shift toward a less inflammatory placental environment.⁴ Additional mechanistic studies demonstrated that macrophage-derived G-CSF promotes trophoblast epithelial-to-mesenchymal transition, migration, and invasion through PI3K/Akt and Erk1/2 signaling pathways activation.⁵ Studies of uterine natural killer (uNK) cels further demonstrated that cytokine signaling at the maternal-fetal interface regulates EVT differentiation and transcriptional programs involved in vascular remodeling and placental development.³  A separate exercise intervention study demonstrated reduced NK-cell activating receptor expression and decreased interferon-gamma production following moderate-intensity aerobic exercise, supporting the concept that exercise modulates inflammatory immune signaling relevant to placentation.⁶ Finally, studies investigating trophoblast glycoprotein (TPBG) showed that its overexpression impairs trophoblast migration and invasion, disrupting spiral artery remodeling and producing preeclampsia-like features in animal models.⁷ Elevated maternal plasma TPBG levels were also associated with pregnancies that later developed preeclampsia.⁷

Conclusions: Current evidence supports a mechanistic model for maternal exercise altering placental cytokine and immune signaling, promoting trophoblast invasion and spiral artery remodeling while reducing inflammatory signaling associated with preeclampsia pathogenesis. Increased G-CSF and reduced IL-6, TNF-alpha, and inflammatory NK-cell signaling may contribute to a placental microenvironment more permissive for normal vascular remodeling and uteroplacental perfusion. These findings support the concept that the placenta is an immune-regulated organ responsive to maternal physiologic factors, such as exercise. Further investigation is needed to determine causality, identify optimal exercise intervention, take potential confounding variables into account, and evaluate whether modulation of placental inflammatory signaling may provide future therapeutic or preventative strategies for preeclampsia.

 Works Cited:

1. Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;76(14):1690-1702. doi:10.1016/j.jacc.2020.08.014
2. Horvat Mercnik M, Schliefsteiner C, Sanchez-Duffhues G, Wadsack C. TGFβ signaling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy. Hum Reprod Update. 2024;30(4):442-471.doi:10.1093/humupd/dmae007
3. Li Q, Sharkey A, Sheridan M, et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell. 2024;31(2):181-195.e9. doi:10.1016/j.stem.2023.12.013
4. Acosta-Manzano P , Flor-Alemany M, Martínez-González LJ, et al. The effects of a supervised exercise training program during pregnancy on placental cytokines, and the potential role of fetal sex and maternal weight status. J Sport Health Sci. Published online September 8, 2025. doi:10.1016/j.jshs.2025.101082
5. Ding J, Yang C, Zhang Y, et al. M2 macrophage‐derived G‐CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy. Journal of cellular and molecular medicine. 2021;25(4):2136-2147. Accessed February 19, 2026. https://research.ebsco.com/linkprocessor/plink?id=9c6d676b-8713-3873-8272-0cc310c931ff
6. Gurbanova A, Lombardi AEM, Habets DHJ, Al-Nasiry S, Spaanderman MEA, de Jonge MI, Meuleman T, Wieten L, van der Molen RG. Impact of a moderate-intensity aerobic exercise intervention on systemic and uterine natural killer cells in women with unexplained recurrent pregnancy loss. Front Immunol. 2025;16:1602939. doi:10.3389/fimmu.2025.1602939.
7. Sun L, Shi M, Wang J, et al. Overexpressed trophoblast glycoprotein contributes to preeclampsia development by inducing abnormal trophoblast migration and invasion toward the uterine spiral artery. 2024;81(7):1524-1536. doi:10.1161/HYPERTENSIONAHA.124.22923
8. Pahlavani HA, Laher I, Weiss K, Knechtle B, Zouhal H. Physical exercise for a healthy pregnancy: the role of placentokines and exerkines. J Physiol Sci. 2023;73(1):30. Published 2023 Nov 14. doi:10.1186/s12576-023-00885-1
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