DOI: https://doi.org/10.18370/2309-4117.2020.52.8-17

Modern uterotonics: vitally required and dangerous... Literature review

Е. Н. Носенко

Abstract


Uterotonics are widely used in obstetrics for pre-induction and induction of labor, for prevention and treatment of postpartum hemorrhages. Oxytocin, carbetocin and misoprostol are used as uterotonic agents for prevention of postpartum hemorrhages. Oxytocin, ergometrine, syntomethrin and misoprostol are used for treatment of postpartum hemorrhages. Subject to the principle of active management of the third stage of labor, prophylactic use of uterotonics reduces the postpartum hypotonic bleeding risk by 60%.

This review provides current data on the pharmacokinetics, doses, modes of use and possible complications of oxytocin drugs, prostaglandin E1 and E2 analogues, ergot alkaloids in obstetric practice. International consensus statement on the use of uterotonic agents during caesarean section (2019) are presented, taking into account the differences between their dose for planned and urgent Caesarean section.

In addition to the uterotonic effect of oxytocin it has parasympathetic neuromodulation, vasodilation, negative inotropic and chronotropic effects, lowers blood pressure, and in large doses and fast administration can have a negative effect on the fetus. The author emphasizes that uterotonics of the second row should be considered as early as possible if the oxytocin/carbetocin does not give a good uterine tone, but remember that the combined use of oxytocin with ergometrine increases the risks of cardiac complications.

Methylergometrine can lead to an increase in central venous pressure, as well as an increase in blood pressure, in some cases it can provoke ischemia and necrosis of the heart muscle.

Misoprostol is used for labor pre-induction, induction and for prevention and off-label treatment of postpartum bleeding. Misoprostol increases the risk of uterine hyperstimulation and increased heart rate in fetus, and the mother's body temperature rises. Therefore the key to the effectiveness and safety of uterotonics is the correct use of the method, dose, route and administration speed, taking into account indications and contraindications, careful monitoring of the condition of pregnant woman, fetus, woman in childbirth, compliance with the recommended storage conditions for drugs.


Keywords


uterotonics; labor pre-induction; labor induction; oxytocin; carbetocin; ergot alkaloids; methylergometrine; prostaglandins; misoprostol; postpartum hemorrhage; uterine atony

References


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Akour, A., Kasabri, V., Bulatova, N., et al. “Association of Oxytocin with Glucose Intolerance and Inflammation Biomarkers in Metabolic Syndrome Patients with and without Prediabetes.” Rev Diabet Stud 14.4 (2018): 364–71. DOI: 10.1900/RDS.2017.14.364.83

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Birch, S., Lu, C. “Ergometrine-induced atrial fibrillation at caesarean section.” BMJ Case Rep 12.2 (2019). DOI: 10.1136/bcr-2018-226747

Butwick, A.J., Carvalho, B., Blumenfeld, Y.J., et al. “Second-line uterotonics and the risk of hemorrhage-related morbidity.” Am J Obstet Gynecol 212.5 (2015): 642.e1–7. DOI: 10.1016/j.ajog.2015.01.008

Cole, N.M., Carvalho, J.C., Erik-Soussi, M., et al. “In vitro comparative effect of carbetocin and oxytocin in pregnant human myometrium with and without oxytocin pretreatment.” Anesth 124.2 (2016): 378–86.

D’Ovidio, C., Sablone, S., Carnevale, A. “Spontaneous coronary artery dissection: case report and literature review.” J Forensic Sci 60. 3 (2015): 801–6.

The International Federation of Gynecology and Obstetrics. Misoprostol Reccommended Dosages (2012). FIGO Guideline. Available from: [https://www.figo.org/sites/default/files/uploads/project-publications/iso/Misoprostol_Recommended%20 Dosages%202012.pdf].

Gallos, I., Williams, H., Price, M., et al. “Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis.” Health Technol Assess 23.9 (2019): 1–356. DOI: 10.3310/hta23090

Gottlieb, M.M. “A Mathematical Model Relating Pitocin Use during Labor with Offspring Autism Development in terms of Oxytocin Receptor Desensitization in the Fetal Brain.” Comput Math Methods Med 2019 (2019): 8276715. DOI: 10.1155/2019/8276715

Gutkowska, J., Jankowski, M., Antunes-Rodrigues, J. “The role of oxytocin in cardiovascular regulation.” Braz J Med Biol Res 47.3 (2014): 206–14.

Heesen, M., Carvalho, B., Carvalho, J.C.A., et al. “International consensus statement on the use of uterotonic agents during caesarean section.” Anaesthesia 74.10 (2019): 1305–19. DOI: 10.1111/anae.14757

Hidalgo-Lopezosa, P., Hidalgo-Maestre, M., Rodríguez-Borrego, M.A. “Labor stimulation with oxytocin: effects on obstetrical and neonatal outcomes.” Rev Lat Am Enfermagem 24 (2016): e2744. DOI: 10.1590/1518-8345.0765.2744

Hofmeyr, G.J., Gülmezoglu, A.M., Pileggi, C. “Vaginal misoprostol for cervical ripening and induction of labour.” Cochrane Database Syst Rev 10 (2010): CD000941.

James, A.H., Cooper, D.L., Paidas, M.J. “Hemostatic assessment, treatment strategies, and hematology consultation in massive postpartum hemorrhage: results of a quantitative survey of obstetrician-gynecologists.” Int J Womens Hlth 7 (2015): 873–81. DOI: 10.2147/IJWH.S89573

Stoof, S.C., van Steenbergen, H.W., Zwagemaker, A., et al. “Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey.” Haemophilia 21.4 (2015): 505–12. DOI: 10.1111/hae.12635

Jin, B., Du, Y., Zhang, F., et al. “Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials.” J Matern Fetal Neonat Med 29.3 (2016): 400–7.

Jonsson, M., Hanson, U., Lidell, C., Norden-Lindeberg, S. “ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial.” Br J Obstet Gynaecol 117 (2010): 76–83.

Kenyon, S., Tokumasu, H., Dowswell, T., et al. “High-dose versus low-dose oxytocin for augmentation of delayed labour.” Cochrane Database Syst Rev 7 (2013): CD007201.

Kjaer, B.N., Kroigaard, M., Garvey, L.H. “Oxytocin use during Caesarean sections in Denmark – are we getting the dose right?” Acta Anaesthesiol Scand 60 (2016): 18–25.

Kovacheva, F.P., Soens, M.A., Tsen, L.C. “A randomized, double-blinded trial of a ‘rule of threes’ algorithm versus continuous infusion of oxytocin during elective cesarean delivery.” Anesthesiology 123.1 (2015): 92–9.

Martínez-Quintana, E., Rodríguez-Gonzílez, F. “Pregnancy and coronary artery dissection.” Clin Invest Arterioscler 27.4 (2015): 215–9.

Nyflot, L.T., Babill Stray-Pedersen, I.S., Pettersen, S., et al. “Risk factors for severe postpartum hemorrhage: a case-control study.” BMC Pregnancy Childbirth 17 (2017): 17. DOI: 10.1186/s12884-016-1217-0

Onwochei, D.N., Van Ross, J., Singh, P.M., et al. “Carbetocin reduces the need for additional uterotonics in elective caesarean delivery: a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.” Int J Obstet Anesth 40 (2019): 14–23. DOI: 10.1016/j.ijoa.2019.06.007

Phillips, R.J., Fortier, M.A., Bernal, A.L. “Prostaglandin pathway gene expression in human placenta, amnion and choriodecidua is differentially affected by preterm and term labour and by uterine inflammation.” BMC Pregnancy Childbirth 14 (2014): 241. DOI: 10.1186/1471-2393-14-241

Pierce, S., Bakker, R., Myers, D.A., Edwards, R.K. “Clinical Insights for Cervical Ripening and Labor Induction. Using Prostaglandins.” AJP Rep 8.4 (2018): e307–e314.

Pismenskiy, S.V., Pyregov, A.V., Golubeva, O.A. “Myocardial infarction after operation of caesarean section in spinal anesthesia during treatment metilergometrina and oxytocin (clinical observation).” Tol’yattinskiy meditsinskiy konsilium 1–2 (2016): 99–102.

Prevost, M., Zelkowitz, P., Tulandi, T., et al. “Oxytocin in pregnancy and the postpartum: relations to labor and its management.” Front Public Health 2 (2014): 1. DOI: 10.3389/fpubh.2014.00001

Rabow, S., Olofsson, P. “Pulse wave analysis by digital photoplethysmography to record maternal hemodynamic effects of spinal anesthesia, delivery of the baby, and intravenous oxytocin during cesarean section.” J Matern Fetal Neonat Med 26 (2016): 1–8.

Salati, J.A., Leathersich, S.J., Williams, M.J., et al. “Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage.” Cochrane Database Syst Rev 4 (2019): CD001808. DOI: 10.1002/14651858. CD001808.pub3

Savirón-Cornudella, R., Esteban, L.M., Laborda-Gotor, R., et al. “Maternal morbidity after implementation of a postpartum hemorrhage protocol including use of misoprostol.” Int J Gynaecol Obstet 140.2 (2018): 198–204. DOI: 10.1002/ijgo.12361

Say, L., Chou, D., Gemmill, A., et al. “Global Causes of Maternal Death: A WHO Systematic Analysis.” Lancet Global Health 2.6 (2014): e323–e333. DOI: 10.1016/S2214-109X(14)70227-X

Su, L.L., Chong, Y.S., Samuel, M. “Carbetocin for preventing postpartum haemorrhage.” Cochrane Database Syst Rev 4 (2012): CD005457.

Tabl, S., Balki, M., Downey, K., et al. “Uterotonics in elective caesarean delivery: a randomised non-inferiority study comparing carbetocin 20 μg and 100 μg.” Anaesthesia 74.2 (2019): 190–6. DOI: 10.1111/anae.14480

Tang, J., Kapp, N., Dragoman, M., de Souza, J.P. “WHO recommendations for misoprostol use for obstetric and gynecologic indications.” Int J Gynaecol Obstet 121.2 (2013): 186–9. DOI: 10.1016/j.ijgo.2012.12.009

van der Nelson, H.A., Draycott, T., Siassakos, D., et al. “Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An economic impact analysis.” Eur J Obstet Gynecol Reprod Biol 210 (2017): 286–91. DOI: 10.1016/j.ejogrb.2017.01.004

Vrachnis, N., Malamas, F.M., Sifakis, S., et al. “The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents.” Int J Endocrinol 2011 (2011): 350546. DOI: 10.1155/2011/350546

World Health Organization. WHO Model list of essential medicines. Geneva. WHO (2015).

World Health Organization. WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. Geneva. WHO (2017).

World Health Organization. WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. Geneva. WHO (2012).

Widmer, M., Piaggio, G., Nguyen, T.M.H., et al.; WHO CHAMPION Trial Group. “Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth.” N Engl J Med 379.8 (2018): 743–52. DOI: 10.1056/NEJMoa1805489


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18.          Hofmeyr, G.J., Gülmezoglu, A.M., Pileggi, C. “Vaginal misoprostol for cervical ripening and induction of labour.” Cochrane Database Syst Rev 10 (2010): CD000941.

19.          James, A.H., Cooper, D.L., Paidas, M.J. “Hemostatic assessment, treatment strategies, and hematology consultation in massive postpartum hemorrhage: results of a quantitative survey of obstetrician-gynecologists.” Int J Womens Hlth 7 (2015): 873–81. DOI: 10.2147/IJWH.S89573

20.          Stoof, S.C., van Steenbergen, H.W., Zwagemaker, A., et al. “Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey.” Haemophilia 21.4 (2015): 505–12. DOI: 10.1111/hae.12635

21.          Jin, B., Du, Y., Zhang, F., et al. “Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials.” J Matern Fetal Neonat Med 29.3 (2016): 400–7.

22.          Jonsson, M., Hanson, U., Lidell, C., Norden-Lindeberg, S. “ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial.” Br J Obstet Gynaecol 117 (2010): 76–83.

23.          Kenyon, S., Tokumasu, H., Dowswell, T., et al. “High-dose versus low-dose oxytocin for augmentation of delayed labour.” Cochrane Database Syst Rev 7 (2013): CD007201.

24.          Kjaer, B.N., Kroigaard, M., Garvey, L.H. “Oxytocin use during Caesarean sections in Denmark – are we getting the dose right?” Acta Anaesthesiol Scand 60 (2016): 18–25.

25.          Kovacheva, F.P., Soens, M.A., Tsen, L.C. “A randomized, double-blinded trial of a ‘rule of threes’ algorithm versus continuous infusion of oxytocin during elective cesarean delivery.” Anesthesiology 123.1 (2015): 92–9.

26.          Martínez-Quintana, E., Rodríguez-Gonzílez, F. “Pregnancy and coronary artery dissection.” Clin Invest Arterioscler 27.4 (2015): 215–9.

27.          Nyflot, L.T., Babill Stray-Pedersen, I.S., Pettersen, S., et al. “Risk factors for severe postpartum hemorrhage: a case-control study.” BMC Pregnancy Childbirth 17 (2017): 17. DOI: 10.1186/s12884-016-1217-0

28.          Onwochei, D.N., Van Ross, J., Singh, P.M., et al. “Carbetocin reduces the need for additional uterotonics in elective caesarean delivery: a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.” Int J Obstet Anesth 40 (2019): 14–23. DOI: 10.1016/j.ijoa.2019.06.007

29.          Phillips, R.J., Fortier, M.A., Bernal, A.L. “Prostaglandin pathway gene expression in human placenta, amnion and choriodecidua is differentially affected by preterm and term labour and by uterine inflammation.” BMC Pregnancy Childbirth 14 (2014): 241. DOI: 10.1186/1471-2393-14-241

30.          Pierce, S., Bakker, R., Myers, D.A., Edwards, R.K. “Clinical Insights for Cervical Ripening and Labor Induction. Using Prostaglandins.” AJP Rep 8.4 (2018): e307–e314.

31.          Pismenskiy, S.V., Pyregov, A.V., Golubeva, O.A. “Myocardial infarction after operation of caesarean section in spinal anesthesia during treatment metilergometrina and oxytocin (clinical observation).” Tol’yattinskiy meditsinskiy konsilium 1–2 (2016): 99–102.

32.          Prevost, M., Zelkowitz, P., Tulandi, T., et al. “Oxytocin in pregnancy and the postpartum: relations to labor and its management.” Front Public Health 2 (2014): 1. DOI: 10.3389/fpubh.2014.00001

33.          Rabow, S., Olofsson, P. “Pulse wave analysis by digital photoplethysmography to record maternal hemodynamic effects of spinal anesthesia, delivery of the baby, and intravenous oxytocin during cesarean section.” J Matern Fetal Neonat Med 26 (2016): 1–8.

34.          Salati, J.A., Leathersich, S.J., Williams, M.J., et al. “Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage.” Cochrane Database Syst Rev 4 (2019): CD001808. DOI: 10.1002/14651858. CD001808.pub3

35.          Savirón-Cornudella, R., Esteban, L.M., Laborda-Gotor, R., et al. “Maternal morbidity after implementation of a postpartum hemorrhage protocol including use of misoprostol.” Int J Gynaecol Obstet 140.2 (2018): 198–204. DOI: 10.1002/ijgo.12361

36.          Say, L., Chou, D., Gemmill, A., et al. “Global Causes of Maternal Death: A WHO Systematic Analysis.” Lancet Global Health 2.6 (2014): e323–e333. DOI: 10.1016/S2214-109X(14)70227-X

37.          Su, L.L., Chong, Y.S., Samuel, M. “Carbetocin for preventing postpartum haemorrhage.” Cochrane Database Syst Rev 4 (2012): CD005457.

38.          Tabl, S., Balki, M., Downey, K., et al. “Uterotonics in elective caesarean delivery: a randomised non-inferiority study comparing carbetocin 20 μg and 100 μg.” Anaesthesia 74.2 (2019): 190–6. DOI: 10.1111/anae.14480

39.          Tang, J., Kapp, N., Dragoman, M., de Souza, J.P. “WHO recommendations for misoprostol use for obstetric and gynecologic indications.” Int J Gynaecol Obstet 121.2 (2013): 186–9. DOI: 10.1016/j.ijgo.2012.12.009

40.          van der Nelson, H.A., Draycott, T., Siassakos, D., et al. “Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An economic impact analysis.” Eur J Obstet Gynecol Reprod Biol 210 (2017): 286–91. DOI: 10.1016/j.ejogrb.2017.01.004

41.          Vrachnis, N., Malamas, F.M., Sifakis, S., et al. “The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents.” Int J Endocrinol 2011 (2011): 350546. DOI: 10.1155/2011/350546

42.          World Health Organization. WHO Model list of essential medicines. Geneva. WHO (2015).

43.          World Health Organization. WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. Geneva. WHO (2017).

44.          World Health Organization. WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. Geneva. WHO (2012).

45.          Widmer, M., Piaggio, G., Nguyen, T.M.H., et al.; WHO CHAMPION Trial Group. “Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth.” N Engl J Med 379.8 (2018): 743–52. DOI: 10.1056/NEJMoa1805489





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