THE ROLE OF HORMONAL AND NON-HORMONAL MARKERS IN ASSESSING PERINATAL STRESS AND ITS CLINICAL IMPLICATIONS
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5224Keywords:
Perinatal Stress, Biomarkers, HPA Axis, Cortisol, Copeptin, Oxidative Stress, Preterm LaborAbstract
Background: Prenatal and perinatal stress activates the maternal and fetal HPA axis, releasing biomarkers that can cross the placenta. In high concentrations, these substances may lead to congenital malformations, preterm labor, or intrauterine growth restriction (IUGR). Despite their potential, endogenous biomarkers are not yet part of standard gynecological diagnostics.
Aim: This paper analyzes recent reports on hormonal and non-hormonal perinatal stress biomarkers to evaluate their application in assessing health risks for mothers and fetuses.
Material and Methods: This literature review examines clinical trials and observational studies from the late 20th and early 21st centuries. It focuses on laboratory techniques such as ELI-SA, HPLC, and radioimmunoassay used to measure stress markers in maternal serum, cord blood, amniotic fluid, and urine.
Results: Studies show that copeptin levels rise significantly during fetal hypoxia and IUGR, aiding ultrasonographic differentiation. Maternal cortisol levels correlate negatively with birth weight and increase the risk of infants being small for gestational age (SGA). ACTH and CRH serve as indicators of HPA axis maturity and predictors of preterm birth. Regarding non-hormonal markers, malondialdehyde and 8-isoprostane are sensitive indicators of oxidative stress linked to preeclampsia. Furthermore, elevated proinflammatory cytokines (IL-1, IL-6, IL-8, TNF-alpha) are closely associated with intrauterine infections and the onset of preterm labor.
Conclusions: Perinatal stress biomarkers offer significant prognostic value for identifying risks of preterm labor and developmental pathologies. While cortisol currently has the greatest clinical utility, copeptin and malondialdehyde are noted for their stability and potential for routine screening. Further clinical trials are necessary to integrate these markers into standard obstetric care.
References
Mulder, E. J. H., Robles de Medina, P. G., Huizink, A. C., Van den Bergh, B. R. H., Buitelaar, J. K., & Visser, G. H. A. (2002). Prenatal maternal stress: Effects on pregnancy and the (unborn) child. Early Human Development, 70(1–2), 3–14. https://doi.org/10.1016/S0378-3782(02)00075-0
Schlapbach, L. J., Frey, S., Bigler, S., Manh-Nhi, C., Aebi, C., Nelle, M., & Nuoffer, J.-M. (2011). Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia. BMC Pediatrics, 11, 38. https://doi.org/10.1186/1471-2431-11-38
Alizzi, F., & Bardan, R. (2018). Role of maternal serum copeptin in correlation with umbilical cord copeptin and umbilical artery Doppler indices in differentiating IUGR from constitutional small and appropriate for gestational age fetuses. Journal of Pharmaceutical Sciences and Research, 10(3), 597–600.
Fill Malfertheiner, S., Bataiosu-Zimmer, E., Michel, H., Fouzas, S., Bernasconi, L., Bührer, C., & Wellmann, S. (2021). Vasopressin but not oxytocin responds to birth stress in infants. Frontiers in Neuroscience, 15. https://doi.org/10.3389/fnins.2021.718056
Flahault, A., Bollée, G., El-Jalbout, R., Cloutier, A., Santos, R. A. S., Lapeyraque, A.-L., Luu, T. M., & Nuyt, A. M. (2022). Plasma copeptin is increased and associated with smaller kidney volume in young adults born very preterm. Clinical Kidney Journal, 15(4), 709–717. https://doi.org/10.1093/ckj/sfab226
Bhattarai, A., Shah, S., Baidya, S., Thapa, R., Bhandari, S., Tuladhar, E. T., Acharya, S. P., & Sah, R. (2024). Association of copeptin levels with patient prognosis and survival in sepsis syndromes: A meta-analysis. International Journal of Surgery, 110(4), 2355–2365. https://doi.org/10.1097/JS9.0000000000001069
Mancuso, R. A., Schetter, C. D., Rini, C. M., Roesch, S. C., & Hobel, C. J. (2004). Maternal prenatal anxiety and corticotropin-releasing hormone associated with timing of delivery. Psychosomatic Medicine, 66(5), 762–769. https://doi.org/10.1097/01.psy.0000138284.70670.d5
Bagnoli, F., Mori, A., Fommei, C., Coriolani, G., Badii, S., & Tomasini, B. (2013). ACTH and cortisol cord plasma concentrations in preterm and term infants. Journal of Perinatology, 33(7), 520–524. https://doi.org/10.1038/jp.2012.165
Economides, D. L., Nicolaides, K. H., Linton, E. A., Perry, L. A., & Chard, T. (1988). Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses. Fetal Diagnosis and Therapy, 3(3), 158–164. https://doi.org/10.1159/000263348
Fenster, T., Rao, M., Mamzhi, Y., & Tsou, H., Jr. (2020). Fetal neurobehavioral development: The role of maternal psychosocial, pathological, and pharmacological stress. Georgetown Medical Review, 4(1). https://doi.org/10.52504/001c.12642
Joseph, D., & Whirledge, S. (2017). Stress and the HPA axis: Balancing homeostasis and fertility. International Journal of Molecular Sciences, 18(10), 2224. https://doi.org/10.3390/ijms18102224
Giussani, D. A. (2010). The relation of S100beta and metabolic and endocrine responses to acute fetal hypoxemia. Frontiers in Bioscience (Elite Edition), 2(1), 66. https://doi.org/10.2741/e66
Cole, T. J., Blendy, J. A., Monaghan, A. P., Krieglstein, K., Schmid, W., Aguzzi, A., Fantuzzi, G., Hummler, E., Unsicker, K., & Schütz, G. (1995). Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes & Development, 9(13), 1608–1621. https://doi.org/10.1101/gad.9.13.1608
Goedhart, G., Vrijkotte, T. G. M., Roseboom, T. J., van der Wal, M. F., Cuijpers, P., & Bonsel, G. J. (2010). Maternal cortisol and offspring birthweight: Results from a large prospective cohort study. Psychoneuroendocrinology, 35(5), 644–652. https://doi.org/10.1016/j.psyneuen.2009.10.003
Buss, C., Davis, E. P., Shahbaba, B., Pruessner, J. C., Head, K., & Sandman, C. A. (2012). Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences, 109(20). https://doi.org/10.1073/pnas.1201295109
Beech, A., Edelman, A., Yatziv, T., Rutherford, H. J. V., Joormann, J., & Gadassi-Polack, R. (2023). Cortisol reactivity to a laboratory stressor predicts increases in depressive symptoms in perinatal and nulliparous women during population-level stress. Journal of Affective Disorders, 340, 33–41. https://doi.org/10.1016/j.jad.2023.07.093
Johansson, S., Norman, M., Legnevall, L., Dalmaz, Y., Lagercrantz, H., & Vanpée, M. (2007). Increased catecholamines and heart rate in children with low birth weight: Perinatal contributions to sympathoadrenal overactivity. Journal of Internal Medicine, 261(5), 480–487. https://doi.org/10.1111/j.1365-2796.2007.01776.x
Giorgetti, A., Bonasoni, M. P., Lacchè, E., Comitini, G., Migliavacca, C., Ferretti, A., Galeone, C., Polese, A., Stridi, G., Monari, F., Melis, B., & Pelotti, S. (2024). Biochemical analysis of catecholamine and cortisol for the evaluation of fetal distress in third trimester stillbirths. International Journal of Legal Medicine, 138(6), 2569–2581. https://doi.org/10.1007/s00414-024-03303-2
Chiba, T., Omori, A., Takahashi, K., Tanaka, K., Kudo, K., Manabe, M., Mariya, Y., & Kashiwakura, I. (2010). Correlations between the detection of stress-associated hormone/oxidative stress markers in umbilical cord blood and the physical condition of the mother and neonate. Journal of Obstetrics and Gynaecology Research, 36(5), 958–964. https://doi.org/10.1111/j.1447-0756.2010.01292.x
Krasomski, G., Oszukowski, P., Brocka, U., Pietrzak, Z., & Biesiada, L. (2007). Markers of oxidative stress in pregnancies complicated by pregnancy induced hypertension and intrahepatic cholestasis. Ginekologia Polska, 78(12). https://doi.org/10.5603/gpl.46780
Aydin Berktaş, Ö., & Tutar, S. O. (2022). Sağlıklı ve preeklamptik gebelerde oksidatif stres parametrelerinin ve nitrik oksitin değerlendirilmesi. European Journal of Science and Technology. https://doi.org/10.31590/ejosat.1092209
Quilantán-Cabrera, J. J., López-Ávalos, L. F., Huerta-Olvera, S. G., Gómez-Sandoval, J. R., Morales-Núñez, J. J., Graciano-Machuca, O., & Sifuentes-Franco, S. (2026). The role of oxidative stress and antioxidant approaches in preeclampsia: A narrative review. European Journal of Midwifery, 10. https://doi.org/10.18332/ejm/216377
Madazli, R., Benian, A., Aydin, S., Uzun, H., & Tolun, N. (2002). The plasma and placental levels of malondialdehyde, glutathione and superoxide dismutase in pre-eclampsia. Journal of Obstetrics and Gynaecology, 22(5), 477–480. https://doi.org/10.1080/0144361021000003573
Raghupathy, R. (2008). Cytokine imbalance in pregnancy complications and its modulation. Frontiers in Bioscience, 13(13), 985. https://doi.org/10.2741/2737
Keelan, J. A., Marvin, K. W., Sato, T. A., Coleman, M., McCowan, L. M. E., & Mitchell, M. D. (1999). Cytokine abundance in placental tissues: Evidence of inflammatory activation in gestational membranes with term and preterm parturition. American Journal of Obstetrics and Gynecology, 181(6), 1530–1536. https://doi.org/10.1016/S0002-9378(99)70400-X
Inglis, S. R., Jeremias, J., Kuno, K., Lescale, K., Peeper, Q., Chervenak, F. A., & Witkin, S. S. (1994). Detection of tumor necrosis factor-α, interleukin-6, and fetal fibronectin in the lower genital tract during pregnancy: Relation to outcome. American Journal of Obstetrics and Gynecology, 171(1), 5–10. https://doi.org/10.1016/S0002-9378(94)70069-9
Romero, R., Gomez, R., Ghezzi, F., Yoon, B. H., Mazor, M., Edwin, S. S., & Berry, S. M. (1998). A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. American Journal of Obstetrics and Gynecology, 179(1), 186–193. https://doi.org/10.1016/S0002-9378(98)70271-6
Arntzen, K. J., Kjøllesdal, A. M., Halgunset, J., Vatten, L., & Austgulen, R. (1998). TNF, IL-1, IL-6, IL-8 and soluble TNF receptors in relation to chorioamnionitis and premature labor. Journal of Perinatal Medicine, 26(1), 17–26. https://doi.org/10.1515/jpme.1998.26.1.17
Gradaščević Gubaljević, J., & Čaušević, A. (2013). Monitoring changes in serum 8-isoprostane concentration as a possible marker of oxidative stress in pregnancy. Journal of Health Sciences, 3(3), 227–231. https://doi.org/10.17532/jhsci.2013.112
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Daniel Chołuj, Wiktor Śliwiński, Jakub Marciniak, Jakub Mazur, Mateusz Kosowski, Weronika Pura, Karolina Zarówna, Dominika Matecka

This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.

