Oxidative Stress in Women Treated with Atosiban for Impending Preterm Birth

Mariusz Grzesiak, Zuzanna Gaj, Rafał Kocyłowski, Joanna Suliburska, Przemysław Oszukowski, Wojciech Horzelski, Constantin von Kaisenberg, Maciej Banach, Mariusz Grzesiak, Zuzanna Gaj, Rafał Kocyłowski, Joanna Suliburska, Przemysław Oszukowski, Wojciech Horzelski, Constantin von Kaisenberg, Maciej Banach

Abstract

Preterm birth is defined as delivery before 37 completed weeks of pregnancy, and it is the leading cause of neonatal morbidity and mortality. Oxidative stress is recognized as an important factor in the pathogenesis of premature labor. We conducted this analysis to investigate the safety of administration of the tocolytic drug Atosiban-a reversible, competitive antagonist of the oxytocin receptor in the treatment of preterm birth and its impact on the level of oxidative stress in pregnant women after 48 hours of tocolytic treatment. This prospective study was conducted between March 2016 and August 2017 at the Obstetric Clinic of the Polish Mother's Memorial Hospital Research Institute. Total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) values as well as 3-nitrotyrosine, carbonyl, and thiol group levels were measured using an ELISA test in serum and plasma of 56 pregnant women before and after 48 hours of continuous administration of Atosiban. We found that TAS levels decreased almost twice after the 48-hour drug administration (0.936 ± 0.360 mmol/L vs. 0.582 ± 0.305 mmol/L, P < 0.001) while TOS increased from 18.217 ± 16.093 μmol/L to 30.442 ± 30.578 μmol/L (P < 0.001). We also found a significant increase in OSI index-almost a threefold increase from 0.022 ± 0.022 to 0.075 ± 0.085, P < 0.001. In addition, statistically significant differences in the level of carbonyl groups were found. It increased from 65.358 ± 31.332 μmol/L to 97.982 ± 38.047 μmol/L (P < 0.001), which indicates increased oxidation of plasma proteins. Furthermore, patients who gave birth prematurely had higher levels of TOS after a 48-hour drug administration than the second group with labor after 37 weeks of pregnancy (42.803 ± 34.683 μmol/L vs. 25.792 ± 27.821 μmol/L, P < 0.031). The obtained results clearly indicate that pregnant women during tocolytic treatment with Atosiban are in a state of increased oxidative stress and occurrence of preterm birth can be associated with this phenomenon. This trial is registered with NCT03570294.

Figures

Figure 1
Figure 1
Analyses of total oxidative status (a), total antioxidant status (b), OSI index (c), and carbonyl group level (d) before and after a 48-hour treatment with Atosiban. The horizontal lines represent the mean values.

References

    1. Menon R., Boldogh I., Hawkins H. K., et al. Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro. The American Journal of Pathology. 2014;184(6):1740–1751. doi: 10.1016/j.ajpath.2014.02.011.
    1. Sultana Z., Maiti K., Aitken J., Morris J., Dedman L., Smith R. Oxidative stress, placental ageing-related pathologies and adverse pregnancy outcomes. American Journal of Reproductive Immunology. 2017;77(5, article e12653) doi: 10.1111/aji.12653.
    1. Menon R. Oxidative stress damage as a detrimental factor in preterm birth pathology. Frontiers in Immunology. 2014;5:p. 567. doi: 10.3389/fimmu.2014.00567.
    1. Turpin C. A., Sakyi S. A., Owiredu W. K. B. A., Ephraim R. K. D., Anto E. O. Association between adverse pregnancy outcome and imbalance in angiogenic regulators and oxidative stress biomarkers in gestational hypertension and preeclampsia. BMC Pregnancy and Childbirth. 2015;15(1):p. 189. doi: 10.1186/s12884-015-0624-y.
    1. Cinkaya A., Keskin H. L., Buyukkagnici U., et al. Maternal plasma total antioxidant status in preterm labor. Journal of Obstetrics and Gynaecology Research. 2010;36(6):1185–1188. doi: 10.1111/j.1447-0756.2010.01300.x.
    1. Mert I., Sargın Oruc A., Yuksel S., et al. Role of oxidative stress in preeclampsia and intrauterine growth restriction. Journal of Obstetrics and Gynaecology Research. 2012;38(4):658–664. doi: 10.1111/j.1447-0756.2011.01771.x.
    1. Toy H., Camuzcuoglu H., Arioz D. T., Kurt S., Celik H., Aksoy N. Serum prolidase activity and oxidative stress markers in pregnancies with intrauterine growth restricted infants. Journal of Obstetrics and Gynaecology Research. 2009;35(6):1047–1053. doi: 10.1111/j.1447-0756.2009.01063.x.
    1. Dutta E. H., Behnia F., Boldogh I., et al. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Molecular Human Reproduction. 2016;22(2):143–157. doi: 10.1093/molehr/gav074.
    1. Weber D., Stuetz W., Bernhard W., et al. Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome. European Journal of Clinical Nutrition. 2014;68(2):215–222. doi: 10.1038/ejcn.2013.263.
    1. Lawn J. E., Gravett M. G., Nunes T. M., Rubens C. E., Stanton C., the GAPPS Review Group Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data. BMC Pregnancy and Childbirth. 2010;10, article S1(Supplement 1) doi: 10.1186/1471-2393-10-S1-S1.
    1. Romero R., Dey S. K., Fisher S. J. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–765. doi: 10.1126/science.1251816.
    1. Haram K., Mortensen J. H. S., Morrison J. C. Tocolysis for acute preterm labor: does anything work. The Journal of Maternal-Fetal & Neonatal Medicine. 2015;28(4):371–378. doi: 10.3109/14767058.2014.918095.
    1. Roberts D., Brown J., Medley N., Dalziel S. R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews. 2017;(3, article CD004454) doi: 10.1002/14651858.CD004454.pub3.
    1. Pierzynski P. Oxytocin and vasopressin V1A receptors as new therapeutic targets in assisted reproduction. Reproductive Biomedicine Online. 2011;22(1):9–16. doi: 10.1016/j.rbmo.2010.09.015.
    1. Akerlund M., Bossmar T., Brouard R., et al. Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. BJOG: An International Journal of Obstetrics and Gynaecology. 1999;106(10):1047–1053. doi: 10.1111/j.1471-0528.1999.tb08112.x.
    1. Younger J. D., Reitman E., Gallos G. Tocolysis: present and future treatment options. Seminars in Perinatology. 2017;41(8):493–504. doi: 10.1053/j.semperi.2017.08.008.
    1. de Heus R., Mulder E. J. H., Derks J. B., Visser G. H. A. Acute tocolysis for uterine activity reduction in term labor: a review. Obstetrical & Gynecological Survey. 2008;63(6):383–388. doi: 10.1097/OGX.0b013e31816ff75b.
    1. Caritis S. Adverse effects of tocolytic therapy. BJOG: An International Journal of Obstetrics and Gynaecology. 2005;112(Supplement 1):74–78. doi: 10.1111/j.1471-0528.2005.00590.x.
    1. López Bernal A. The regulation of uterine relaxation. Seminars in Cell & Developmental Biology. 2007;18(3):340–347. doi: 10.1016/j.semcdb.2007.05.002.
    1. Simhan H. N., Caritis S. N. Prevention of preterm delivery. The New England Journal of Medicine. 2007;357(5):477–487. doi: 10.1056/NEJMra050435.
    1. Wex J., Abou-Setta A. M., Clerici G., di Renzo G. C. Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011;157(2):128–135. doi: 10.1016/j.ejogrb.2011.04.009.
    1. Kim S. H., MacIntyre D. A., Hanyaloglu A. C., et al. The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via Gαi signalling. Molecular and Cellular Endocrinology. 2016;420:11–23. doi: 10.1016/j.mce.2015.11.012.
    1. Simsek Y., Celik O., Karaer A., et al. Elevated cardiac oxidative stress in newborn rats from mothers treated with atosiban. Archives of Gynecology and Obstetrics. 2012;285(3):655–661. doi: 10.1007/s00404-011-2069-5.
    1. Kim S. H., Pohl O., Chollet A., et al. Differential effects of oxytocin receptor antagonists, Atosiban and Nolasiban, on oxytocin receptor–mediated signaling in human amnion and myometrium. Molecular Pharmacology. 2017;91(4):403–415. doi: 10.1124/mol.116.106013.
    1. Committee on Obstetric Practice. Committee Opinion No. 713: antenatal corticosteroid therapy for fetal maturation. Obstetrics & Gynecology. 2017;130(2):e102–e109. doi: 10.1097/AOG.0000000000002237.
    1. Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical Biochemistry. 2005;38(12):1103–1111. doi: 10.1016/j.clinbiochem.2005.08.008.
    1. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clinical Biochemistry. 2004;37(2):112–119. doi: 10.1016/j.clinbiochem.2003.10.014.
    1. Martin L. F., Moço N. P., de Lima M. D., et al. Histologic chorioamnionitis does not modulate the oxidative stress and antioxidant status in pregnancies complicated by spontaneous preterm delivery. BMC Pregnancy and Childbirth. 2017;17(1):p. 376. doi: 10.1186/s12884-017-1549-4.
    1. Wielgoś M., Bomba-Opoń D. A. Tocolysis in preterm labour – current recommendations. Ginekologia Polska. 2014;85(5):332–334. doi: 10.17772/gp/1732.
    1. Romero R., Sibai B. M., Sanchez-Ramos L., et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. American Journal of Obstetrics & Gynecology. 2000;182(5):1173–1183. doi: 10.1067/mob.2000.95834.
    1. Grzesiak M., Wilczynski J. Preliminary report of 48-hours Atosiban administration in spontaneous preterm labor - Doppler blood flow assessment of placental and fetal circulation. Neuro Endocrinology Letters. 2013;34(7):681–686.
    1. Grzesiak M., Ahmed R. B., Wilczynski J. Doppler evaluation of blood flow in fetal inferior vena cava during 48-hours Atosiban administration in spontaneous preterm labor. Neuro Endocrinology Letters. 2013;34(8):787–791.
    1. Valenzuela G. J., Craig J., Bernhardt M. D., Holland M. L. Placental passage of the oxytocin antagonist atosiban. American Journal of Obstetrics & Gynecology. 1995;172(4):1304–1306. doi: 10.1016/0002-9378(95)91497-8.
    1. Aycicek A., Varma M., Ahmet K., Abdurrahim K., Erel O. Maternal active or passive smoking causes oxidative stress in placental tissue. European Journal of Pediatrics. 2011;170(5):645–651. doi: 10.1007/s00431-010-1338-9.
    1. Marseglia L., D’Angelo G., Manti S., et al. Oxidative stress-mediated aging during the fetal and perinatal periods. Oxidative Medicine and Cellular Longevity. 2014;2014:8. doi: 10.1155/2014/358375.358375
    1. Argüelles S., Machado M. J., Ayala A., Machado A., Hervías B. Correlation between circulating biomarkers of oxidative stress of maternal and umbilical cord blood at birth. Free Radical Research. 2006;40(6):565–570. doi: 10.1080/10715760500519834.
    1. Martin A., Faes C., Debevec T., Rytz C., Millet G., Pialoux V. Preterm birth and oxidative stress: effects of acute physical exercise and hypoxia physiological responses. Redox Biology. 2018;17:315–322. doi: 10.1016/j.redox.2018.04.022.
    1. Chakravartya S., Sontakkeb A. A correlation of antioxidants and lipid peroxidation between maternal and cord blood in full term and preterm deliveries. Current Pediatric Research. 2012;16(2):167–174.
    1. Ferguson K. K., McElrath T. F., Chen Y.-H., Loch-Caruso R., Mukherjee B., Meeker J. D. Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. American Journal of Obstetrics & Gynecology. 2015;212(2):208.e1–208.e8. doi: 10.1016/j.ajog.2014.08.007.
    1. Hsieh T.’s.-T.’a., Chen S. F., Lo L. M., Li M. J., Yeh Y. L., Hung T. H. The association between maternal oxidative stress at mid-gestation and subsequent pregnancy complications. Reproductive Sciences. 2012;19(5):505–512. doi: 10.1177/1933719111426601.
    1. Murtha A. P., Menon R. Regulation of fetal membrane inflammation: a critical step in reducing adverse pregnancy outcome. American Journal of Obstetrics & Gynecology. 2015;213(4):447–448. doi: 10.1016/j.ajog.2015.07.008.
    1. Moore T. A., Ahmad I. M., Zimmerman M. C. Oxidative stress and preterm birth: an integrative review. Biological Research for Nursing. 2018;20(5):497–512. doi: 10.1177/1099800418791028.
    1. Agarwal A., Aponte-Mellado A., Premkumar B. J., Shaman A., Gupta S. The effects of oxidative stress on female reproduction: a review. Reproductive Biology and Endocrinology. 2012;10(1):p. 49. doi: 10.1186/1477-7827-10-49.

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