The Use of Uterotonic Agents and Oxytocin Receptor Desensitization
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Published:
Feb 3, 2021
Keywords:
Cesarean delivery, Uterine atony, Uterotonic agents, Oxytocin receptor desensitization
Main Article Content
Abstract
The administration of uterotonic agents after delivery of the fetus are recommended to prevent and treatment postpartum uterine atony during caesarean section. However, most clinical trials are performed in healthy parturients undergoing elective cesarean delivery, which have low risk of postpartum hemorrhage. Prolonged exposure to oxytocin for labor augmentation can result in desensitization and down-regulation of its receptor. The aim of this article is to review recent data on the use of oxytocin, carbetocin and second-line uterotonics to obtain adequate uterine tone in women at increased risk of postpartum hemorrhage.
Article Details
Section
Review articles
References
1. Robinson C, Schumann R, Zhang P, Young RC. Oxytocininduced
desensitization of the oxytocin receptor. Am J
Obstet Gynecol 2003;188:497-502.
2. Phaneuf S, Asbóth G, Carrasco MP, et al. The desensitization
of oxytocin receptors in human myometrial cells is
accompanied by down-regulation of oxytocin receptor
messenger RNA. J Endocrinol 1997;154:7-18.
3. Magalhaes JK, Carvalho JC, Parkes RK, Kingdom J, Li Y,
Balki M. Oxytocin pretreatment decreases oxytocin-induced
myometrial contractions in pregnant rats in a concentrationdependent
but not time-dependent manner. Reprod Sci
2009;16:501-8.
4. Balki M, Cristian AL, Kingdom J, Carvalho JC. Oxytocin
pretreatment of pregnant rat myometrium reduces the
efficacy of oxytocin but not of ergonovine maleate or
prostaglandin F2α. Reprod Sci 2010;17:269-77.
5. Balki M, Erik-Soussi M, Kingdom J, Carvalho JC. Oxytocin
pretreatment attenuates oxytocin-induced contractions in
human myometrium in vitro. Anesthesiology 2013;119:552-61.
6. Balki M, Ramachandran N, Lee S, Talati C. The recovery time
of myometrial responsiveness after oxytocin-induced
desensitization in human myometrium in vitro. Anesth Analg
2016;122:1508-15.
7. Balki M, Erik-Soussi M, Ramachandran N, Kingdom J,
Carvalho JC. The contractile effects of oxytocin, ergonovine,
and carboprost and their combinations: an in vitro study on
human myometrial strips. Anesth Analg 2015;120:1074-84.
8. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose
requirement after cesarean delivery for labor arrest. Obstet
Gynecol 2006;107:45-50.
9. Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin
requirements at elective cesarean delivery: a dose-finding
study. Obstet Gynecol 2004;104:1005-10.
10. Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B.
Minimum effective bolus dose of oxytocin during elective
Caesarean delivery. Br J Anaesth 2010;104:338-43.
11. Lavoie A, McCarthy RJ, Wong CA. The ED90 of prophylactic
oxytocin infusion after delivery of the placenta during
cesarean delivery in laboring compared with nonlaboring
women: an up-down sequential allocation dose-response
study. Anesth Analg 2015;121:159-64.
12. Foley A, Gunter A, Nunes KJ, Shahul S, Scavone BM. Patients
undergoing cesarean delivery after exposure to oxytocin
during labor require higher postpartum oxytocin doses.
Anesth Analg 2018;126:920-4.
13. Drife J, Lewis G. Why mothers die, 1997-1999: The Fifth
Report of the Confidential Enquiries into Maternal Deaths in
the United Kingdom. London: Royal College of Obstetricians
and Gynecologists Press; 2001.
14. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects
of ephedrine, phenylephrine, and the coadministration of
phenylephrine with oxytocin during spinal anesthesia for
elective cesarean delivery. Anesthesiology 2009;111:753-65.
15. Rumboll CK, Dyer RA, Lombard CJ. The use of phenylephrine
to obtund oxytocin-induced hypotension and tachycardia during
caesarean section. Int J Obstet Anesth 2015;24:297-302.
16. Farber MK, Schultz R, Lugo L, Liu X, Huang C, Tsen LC. The
effect of co-administration of intravenous calcium chloride
and oxytocin on maternal hemodynamics and uterine tone
following cesarean delivery: a double-blinded, randomized,
placebo-controlled trial. Int J Obstet Anesth 2015;24:217-24.
17. Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of
oxytocin given as i.v. bolus or infusion on women undergoing
caesarean section. Br J Anaesth 2007;98:116-9.
18. Jonsson M, Hanson U, Lidell C, Nordén-Lindeberg S. ST
depression at caesarean section and the relation to oxytocin
dose. A randomised controlled trial. Br J Obstet Gynaecol
2010;117:76-83.
19. Moran C, Ni Bhuinneain M, Geary M, Cunningham S,
McKenna P, Gardiner J. Myocardial ischaemia in normal
patients undergoing elective caesarean section: a peripartum
assessment. Anaesthesia 2001;56:1051-8.
20. Bergum D, Lonnée H, Hakli TF. Oxytocin infusion: acute
hyponatraemia, seizures and coma. Acta Anaesthesiol
Scand 2009;53:826-7.
21. Sartain JB, Barry JJ, Howat PW, McCormack DI, Bryant M.
Intravenous oxytocin bolus of 2 units is superior to 5 units
during elective caesarean section. Br J Anaesth 2008;101:
822-6.
22. Cole NM, Carvalho JC, Erik-Soussi M, Ramachandran N,
Balki M. In vitro comparative effect of carbetocin and
oxytocin in pregnant human myometrium with and without
oxytocin pretreatment. Anesthesiology 2016;124:378-86.
23. Su LL, Chong YS, Samuel M. Carbetocin for preventing
postpartum haemorrhage. Cochrane Database Syst Rev.
2012;2:CD005457.
24. Nguyen-Lu N, Carvalho JC, Farine D, Seaward G, Ye XY,
Balki M. Carbetocin at cesarean delivery for labour arrest:
a sequential allocation trial to determine the effective dose.
Can J Anaesth 2015;62:866-74.
25. Cordovani D, Balki M, Farine D, Seaward G, Carvalho JC.
Carbetocin at elective cesarean delivery: a randomized
controlled trial to determine the effective dose. Can J Anaesth
2012;59:751-7.
26. Khan M, Balki M, Ahmed I, Farine D, Seaward G, Carvalho
JC. Carbetocin at elective cesarean delivery: a sequential
allocation trial to determine the minimum effective dose. Can
J Anaesth 2014;61:242-8.
27. Anandakrishnan S, Balki M, Farine D, Seaward G, Carvalho
JC. Carbetocin at elective cesarean delivery: a randomized
controlled trial to determine the effective dose, part 2. Can
J Anaesth 2013;60:1054-60.
28. 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
2019;74:190-6.
29. Rosseland LA, Hauge TH, Grindheim G, Stubhaug A,
Langesæter E. Changes in blood pressure and cardiac
output during cesarean delivery: the effects of oxytocin and
carbetocin compared with placebo. Anesthesiology 2013;
119:541-51.
30. Moertl MG, Friedrich S, Kraschl J, Wadsack C, Lang U,
Schlembach D. Haemodynamic effects of carbetocin and
oxytocin given as intravenous bolus on women undergoing
caesarean delivery: a randomised trial. Br J Obstet Gynaecol
2011;118:1349-56.
31. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology
of postpartum hemorrhage in a large, nationwide sample of
deliveries. Anesth Analg 2010;110:1368-73.
32. Butwick AJ, Carvalho B, Blumenfeld YJ, El-Sayed YY, Nelson
LM, Bateman BT. Second-line uterotonics and the risk of
hemorrhage-related morbidity. Am J Obstet Gynecol
2015;212:642.e1-642.e6427.
33. Amant F, Spitz B, Timmerman D, Corremans A, Van Assche
FA. Misoprostol compared with methylergometrine for the
prevention of postpartum haemorrhage: a double-blind
randomised trial. Br J Obstet Gynaecol 1999;106:1066-70.
34. World Health Organization. WHO recommendations for the
prevention and treatment of postpartum haemorrhage.
Geneva: World Health Organization, 2018.
35. Bateman BT, Huybrechts KF, Hernandez-Diaz S, Liu J,
Ecker JL, Avorn J. Methylergonovine maleate and the risk of
myocardial ischemia and infarction. Am J Obstet Gynecol
2013;209:459.e1-459.e13.
36. Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic
Z. Treatment for primary postpartum haemorrhage. Cochrane
Database Syst Rev. 2014;2014:CD003249.
37. Blum J, Winikoff B, Raghavan S, et al. Treatment of post-partum
haemorrhage with sublingual misoprostol versus oxytocin in
women receiving prophylactic oxytocin: a double-blind,
randomised, non-inferiority trial. Lancet 2010;375:217-23.
38. Bilgin Z, Kömürcü N. Comparison of the effects and side
effects of misoprostol and oxytocin in the postpartum period:
a systematic review. Taiwan J Obstet Gynecol 2019;58:748-56.
39. Schmitz T, Tararbit K, Dupont C, et al. Prostaglandin E2
analogue sulprostone for treatment of atonic postpartum
hemorrhage. Obstet Gynecol 2011;118:257-65.
40. Zdanowicz JA, Utz AC, Bernasconi I, Geier S, Corti R, Beinder
E. «Broken heart» after cesarean delivery, case report and
review of literature. Arch Gynecol Obstet 2011;283:687-94.
desensitization of the oxytocin receptor. Am J
Obstet Gynecol 2003;188:497-502.
2. Phaneuf S, Asbóth G, Carrasco MP, et al. The desensitization
of oxytocin receptors in human myometrial cells is
accompanied by down-regulation of oxytocin receptor
messenger RNA. J Endocrinol 1997;154:7-18.
3. Magalhaes JK, Carvalho JC, Parkes RK, Kingdom J, Li Y,
Balki M. Oxytocin pretreatment decreases oxytocin-induced
myometrial contractions in pregnant rats in a concentrationdependent
but not time-dependent manner. Reprod Sci
2009;16:501-8.
4. Balki M, Cristian AL, Kingdom J, Carvalho JC. Oxytocin
pretreatment of pregnant rat myometrium reduces the
efficacy of oxytocin but not of ergonovine maleate or
prostaglandin F2α. Reprod Sci 2010;17:269-77.
5. Balki M, Erik-Soussi M, Kingdom J, Carvalho JC. Oxytocin
pretreatment attenuates oxytocin-induced contractions in
human myometrium in vitro. Anesthesiology 2013;119:552-61.
6. Balki M, Ramachandran N, Lee S, Talati C. The recovery time
of myometrial responsiveness after oxytocin-induced
desensitization in human myometrium in vitro. Anesth Analg
2016;122:1508-15.
7. Balki M, Erik-Soussi M, Ramachandran N, Kingdom J,
Carvalho JC. The contractile effects of oxytocin, ergonovine,
and carboprost and their combinations: an in vitro study on
human myometrial strips. Anesth Analg 2015;120:1074-84.
8. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose
requirement after cesarean delivery for labor arrest. Obstet
Gynecol 2006;107:45-50.
9. Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin
requirements at elective cesarean delivery: a dose-finding
study. Obstet Gynecol 2004;104:1005-10.
10. Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B.
Minimum effective bolus dose of oxytocin during elective
Caesarean delivery. Br J Anaesth 2010;104:338-43.
11. Lavoie A, McCarthy RJ, Wong CA. The ED90 of prophylactic
oxytocin infusion after delivery of the placenta during
cesarean delivery in laboring compared with nonlaboring
women: an up-down sequential allocation dose-response
study. Anesth Analg 2015;121:159-64.
12. Foley A, Gunter A, Nunes KJ, Shahul S, Scavone BM. Patients
undergoing cesarean delivery after exposure to oxytocin
during labor require higher postpartum oxytocin doses.
Anesth Analg 2018;126:920-4.
13. Drife J, Lewis G. Why mothers die, 1997-1999: The Fifth
Report of the Confidential Enquiries into Maternal Deaths in
the United Kingdom. London: Royal College of Obstetricians
and Gynecologists Press; 2001.
14. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects
of ephedrine, phenylephrine, and the coadministration of
phenylephrine with oxytocin during spinal anesthesia for
elective cesarean delivery. Anesthesiology 2009;111:753-65.
15. Rumboll CK, Dyer RA, Lombard CJ. The use of phenylephrine
to obtund oxytocin-induced hypotension and tachycardia during
caesarean section. Int J Obstet Anesth 2015;24:297-302.
16. Farber MK, Schultz R, Lugo L, Liu X, Huang C, Tsen LC. The
effect of co-administration of intravenous calcium chloride
and oxytocin on maternal hemodynamics and uterine tone
following cesarean delivery: a double-blinded, randomized,
placebo-controlled trial. Int J Obstet Anesth 2015;24:217-24.
17. Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of
oxytocin given as i.v. bolus or infusion on women undergoing
caesarean section. Br J Anaesth 2007;98:116-9.
18. Jonsson M, Hanson U, Lidell C, Nordén-Lindeberg S. ST
depression at caesarean section and the relation to oxytocin
dose. A randomised controlled trial. Br J Obstet Gynaecol
2010;117:76-83.
19. Moran C, Ni Bhuinneain M, Geary M, Cunningham S,
McKenna P, Gardiner J. Myocardial ischaemia in normal
patients undergoing elective caesarean section: a peripartum
assessment. Anaesthesia 2001;56:1051-8.
20. Bergum D, Lonnée H, Hakli TF. Oxytocin infusion: acute
hyponatraemia, seizures and coma. Acta Anaesthesiol
Scand 2009;53:826-7.
21. Sartain JB, Barry JJ, Howat PW, McCormack DI, Bryant M.
Intravenous oxytocin bolus of 2 units is superior to 5 units
during elective caesarean section. Br J Anaesth 2008;101:
822-6.
22. Cole NM, Carvalho JC, Erik-Soussi M, Ramachandran N,
Balki M. In vitro comparative effect of carbetocin and
oxytocin in pregnant human myometrium with and without
oxytocin pretreatment. Anesthesiology 2016;124:378-86.
23. Su LL, Chong YS, Samuel M. Carbetocin for preventing
postpartum haemorrhage. Cochrane Database Syst Rev.
2012;2:CD005457.
24. Nguyen-Lu N, Carvalho JC, Farine D, Seaward G, Ye XY,
Balki M. Carbetocin at cesarean delivery for labour arrest:
a sequential allocation trial to determine the effective dose.
Can J Anaesth 2015;62:866-74.
25. Cordovani D, Balki M, Farine D, Seaward G, Carvalho JC.
Carbetocin at elective cesarean delivery: a randomized
controlled trial to determine the effective dose. Can J Anaesth
2012;59:751-7.
26. Khan M, Balki M, Ahmed I, Farine D, Seaward G, Carvalho
JC. Carbetocin at elective cesarean delivery: a sequential
allocation trial to determine the minimum effective dose. Can
J Anaesth 2014;61:242-8.
27. Anandakrishnan S, Balki M, Farine D, Seaward G, Carvalho
JC. Carbetocin at elective cesarean delivery: a randomized
controlled trial to determine the effective dose, part 2. Can
J Anaesth 2013;60:1054-60.
28. 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
2019;74:190-6.
29. Rosseland LA, Hauge TH, Grindheim G, Stubhaug A,
Langesæter E. Changes in blood pressure and cardiac
output during cesarean delivery: the effects of oxytocin and
carbetocin compared with placebo. Anesthesiology 2013;
119:541-51.
30. Moertl MG, Friedrich S, Kraschl J, Wadsack C, Lang U,
Schlembach D. Haemodynamic effects of carbetocin and
oxytocin given as intravenous bolus on women undergoing
caesarean delivery: a randomised trial. Br J Obstet Gynaecol
2011;118:1349-56.
31. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology
of postpartum hemorrhage in a large, nationwide sample of
deliveries. Anesth Analg 2010;110:1368-73.
32. Butwick AJ, Carvalho B, Blumenfeld YJ, El-Sayed YY, Nelson
LM, Bateman BT. Second-line uterotonics and the risk of
hemorrhage-related morbidity. Am J Obstet Gynecol
2015;212:642.e1-642.e6427.
33. Amant F, Spitz B, Timmerman D, Corremans A, Van Assche
FA. Misoprostol compared with methylergometrine for the
prevention of postpartum haemorrhage: a double-blind
randomised trial. Br J Obstet Gynaecol 1999;106:1066-70.
34. World Health Organization. WHO recommendations for the
prevention and treatment of postpartum haemorrhage.
Geneva: World Health Organization, 2018.
35. Bateman BT, Huybrechts KF, Hernandez-Diaz S, Liu J,
Ecker JL, Avorn J. Methylergonovine maleate and the risk of
myocardial ischemia and infarction. Am J Obstet Gynecol
2013;209:459.e1-459.e13.
36. Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic
Z. Treatment for primary postpartum haemorrhage. Cochrane
Database Syst Rev. 2014;2014:CD003249.
37. Blum J, Winikoff B, Raghavan S, et al. Treatment of post-partum
haemorrhage with sublingual misoprostol versus oxytocin in
women receiving prophylactic oxytocin: a double-blind,
randomised, non-inferiority trial. Lancet 2010;375:217-23.
38. Bilgin Z, Kömürcü N. Comparison of the effects and side
effects of misoprostol and oxytocin in the postpartum period:
a systematic review. Taiwan J Obstet Gynecol 2019;58:748-56.
39. Schmitz T, Tararbit K, Dupont C, et al. Prostaglandin E2
analogue sulprostone for treatment of atonic postpartum
hemorrhage. Obstet Gynecol 2011;118:257-65.
40. Zdanowicz JA, Utz AC, Bernasconi I, Geier S, Corti R, Beinder
E. «Broken heart» after cesarean delivery, case report and
review of literature. Arch Gynecol Obstet 2011;283:687-94.