Postpartum hemorrhage is the leading cause of maternal death worldwide.1 Oxytocin is the primary agent used for both prophylaxis and treatment of uterine–atony-associated hemorrhage during the third stage of labor and immediate postpartum period in the United States.2 Although the benefits provided by oxytocin immediately after delivery of the fetus are obvious, its side effects can be serious and include tachycardia, hypotension, myocardial ischemia, and, on rare occasions, even death.3–7 Many of these adverse effects follow dose-response kinetics.8,9
Researchers have investigated the dose-response curves of oxytocin in the third stage of labor.10–12 George et al12 determined the effective dose in 90% of patients (ED90) of oxytocin infusion after cesarean delivery without labor to be 17.4 (95% confidence interval [CI], 9.0–25.8) IU/h or 0.29 (95% CI, 0.15–0.43) IU/min. A more recent dose-response study, while confirming this approximate dose range for nonlaboring low-risk patients, demonstrated an increased ED90 of 44.2 (95% CI, 33.8–55.6) IU/h or 0.74 (95% CI, 0.56–0.93) IU/min for those patients who were exposed to oxytocin during labor and then progressed to cesarean delivery,13 a group known to be at increased risk of uterine atony and hemorrhage.2
The University of Chicago Family Birth Center protocol for oxytocin administration in the third stage of labor called for administration of 18 IU/h (0.3 IU/min) of oxytocin, and in cases where the response to this was deemed inadequate, the protocol recommended doubling the infusion rate to 36 IU/h (0.6 IU/min), an amount somewhat above the 95% CI in George’s study. In those cases where response remained inadequate, the protocol called for the administration of uterotonic agents other than oxytocin. We have previously reported that adoption of this protocol at these administration rates did not increase estimated blood loss (EBL), hemorrhage rates, or have any other adverse consequences.14 Our objective in the present retrospective study was to determine the clinical relevance of the apparent increased dosing requirements for third-stage oxytocin among those patients who were exposed to oxytocin before cesarean delivery versus those who were not. Specifically, we sought to determine if patients exposed to oxytocin before cesarean delivery more often required the higher infusion rate of oxytocin called for in our protocol (36 IU/h or 0.6 IU/min) than those patients unexposed.
This retrospective study was approved by the Institutional Review Board at the University of Chicago. Using the University of Chicago perinatal database, all cases of women who underwent cesarean delivery at the university between January 1 and September 30, of 2015, were identified, and their medical records were reviewed. Patients who received neuraxial anesthetics for cesarean delivery were included, and those receiving a general anesthetic were excluded, as were patients with placenta accreta. Investigators noted whether the patient received oxytocin for induction or augmentation of labor prior to cesarean, and if so, the maximum dose and the duration of administration. Demographic data extraction included gravidity, parity, and estimated gestational age (EGA) in completed weeks. Individual obstetric comorbidities known to affect uterine atony and hemorrhage including hypertensive diseases of pregnancy: diabetes, multiple gestation, premature/preterm/prolonged rupture of membranes, placenta previa, placental abruption, chorioamnionitis, large for gestational age infants (weight >4000 g), and polyhydramnios (amniotic fluid index >24) were noted. Medications administered during the third stage of labor, including maximum oxytocin infusion rate during the third stage of labor (ie, 18 vs 36 IU/h) and administration of any other uterotonic medication (methylergonovine, carboprost, and/or misoprostol), as called for in the Family Birth Center protocol when response to initial dosage rate of oxytocin appears inadequate, were recorded. Data on EBL, hemorrhage (≥1 L EBL), use of procedures to decrease bleeding (Bakri balloon insertion, B-Lynch suture, and hysterectomy), and red blood cell transfusion, as well as predelivery and postdelivery hemoglobin concentrations, were recorded.
Patients exposed to oxytocin prior to cesarean delivery (OXY+ group) were compared to those who were not (OXY− group). Nominal data were expressed as n (%) and compared with χ2 or Fisher exact test, as appropriate (proportions nulliparous, proportions with various obstetric comorbidities or neonatal macrosomia, proportions receiving high- versus low-rate oxytocin or additional uterotonic agents, and proportions with postpartum hemorrhage or red blood cell transfusion). Continuous data were tested for normality and expressed as mean ± standard deviation or median (interquartile range [IQR]) and compared with Student t test or Mann-Whitney U test, as appropriate (EGA, neonatal weight, EBL, and drop in hemoglobin concentration). Univariable and multivariable logistic regression models were constructed to test the association between oxytocin exposure and higher postpartum oxytocin infusion rates. Multivariable models were adjusted for clinically relevant confounders including nulliparity, hypertension, diabetes, multiple gestation, polyhydramnios, premature/preterm/prolonged rupture of membranes, placenta previa, placental abruption, chorioamnionitis, and fetal macrosomia. Odds ratios (ORs) and 95% CIs were calculated for the primary outcome variable. The primary outcome variable measured was the maximum infusion rate of oxytocin administered during the third stage and the immediate postpartum period (18 vs 36 IU/h). P < .05 was required to reject the null hypothesis. We chose a convenience sample of approximately 400 patients. Our baseline incidence of providing oxytocin at the higher 36 IU/h rate is approximately 20% (institutional data). A sample size of 400 provides >90% power to detect a 2-fold increase in administering oxytocin at 36 IU/h (ie, 40%) using α = .05.
A total of 426 patients were identified (Figure 1). Nineteen patients were not included in the final analysis as they had general anesthesia for cesarean delivery. Five were not included because charting for intraoperative oxytocin was incomplete. A total of 140 patients were exposed to oxytocin prior to cesarean delivery (OXY+) and 262 patients were not exposed (OXY−). Demographic data and obstetric comorbidities are listed in Tables 1 and 2. Patients in the OXY+ group were more likely to be nulliparous than those in the OXY− group (91/140 [65%] vs 64/262 [24%] [P < .0001]). OXY+ patients had longer EGA (39 [IQR 38–40] weeks vs 37 [IQR 34–39] weeks [P < .0001]), a higher proportion of chorioamnionitis (34/140 [24%] vs 9/262 [3%] [P < .0001]), and a lower proportion of multiple gestation (2/140 [1%] vs 26/262 [10%] [P = .001]) than OXY− patients. Neonatal weights in the OXY+ group were higher than those in the OXY− group (3293 [IQR 2685–3624] g vs 2978 [IQR 2140–3490] g [P = .003]); however, there was no difference in incidence of macrosomia between the 2 groups.
Patients in the OXY− group who labored were more likely to be nulliparous (22/60 [37%] vs 42/202 [21%] [P = .04]) and more likely to have chorioamnionitis (5/60 [8%] vs 4/202 [2%] [P =.03]) than those who did not labor. No other differences were noted.
High-rate oxytocin (36 vs 18 IU/h) was given to a larger percentage of women in the OXY+ group compared to the OXY− group (Table 3) (90/140 [64%] vs 105/262 [40%] [P < .0001]). The unadjusted OR for administration of high-rate oxytocin in OXY+ vs OXY− patients was 2.69 (95% CI, 1.76–4.11) (P < .0001). The adjusted OR was 1.94 (95% CI, 1.19–3.15) (P = .008). More OXY+ than OXY− women required other uterotonic medications (33/140 [24%] vs 28/262 [11%] [P =.0006]). No women in either group required procedures to decrease uterine bleeding. EBL, hemorrhage, and number of packed red blood cell transfusions did not differ between groups. There was a significantly larger drop in hemoglobin concentration postpartum in the OXY+ group compared to the OXY− group (2.0 [IQR 1.5–2.6] g/dL vs 1.7 [IQR 1.0–2.6] g/dL [P = .0001]).
Within the OXY+ group, the median maximum oxytocin administered during labor was 12.0 (IQR 6.0–20.0) mIU/min among women who required high-rate oxytocin (36 IU/h) postpartum and 6.5 (IQR 3.0–12.5) mIU/min among those who received only low-rate oxytocin (18 IU/h) postpartum (P = .003). Median duration of administration was 15.5 (IQR 9.0–29.3) hours vs 7.25 (IQR 3.9–16.0) hours in women who required high- versus low-rate postpartum oxytocin (P < .0001).
In this study, we found that women who were exposed to oxytocin prior to cesarean delivery more often required our institutional protocol’s high- versus low-rate oxytocin to establish and maintain adequate uterine tone postpartum than women not exposed to oxytocin. This provides clinical confirmation of a report of a higher ED90 for postpartum oxytocin among a group of oxytocin-exposed women compared to a non–oxytocin-exposed group.13 In the present study, obstetricians judged a majority of women who were not preexposed to have sufficient uterine tone with low-rate oxytocin (18 IU/h [0.3 IU/min]), which corresponds roughly to the ED90 for postpartum oxytocin in normal low-risk patients at cesarean delivery (17.4 IU/h [0.29 IU/min]).12 We also demonstrated that more oxytocin-exposed women required administration of at least 1 additional type of uterotonic medication (methylergonovine, carboprost, and misoprostol) to treat uterine atony compared to the nonexposed group.
Previous studies have confirmed oxytocin receptor desensitization in myometrial cells after exposure to oxytocin for a period of time.15 Specifically, oxytocin receptor numbers declined and mRNA decreased by 60-fold in myometrial samples from women who underwent oxytocin-augmented labor and 300-fold in samples from women who had oxytocin-induced labor. OXY+ patients were more likely than OXY− patients to have chorioamnionitis, a known risk factor for atony and hemorrhage.16 Factors such as this may also contribute to the higher ED90 required to control atony in this group.
We found no difference in EBL or number of blood transfusions between groups. This may be attributed to early escalation to high-rate oxytocin and administration of additional uterotonic agents per our institutional protocol for management of the third stage of labor and the early postpartum period. Conversely, although there was no significant difference in the proportion of women who experienced hemorrhage between groups, there was a trend toward this outcome in the OXY+ group. Also, a slightly larger drop in hemoglobin (postdelivery versus admission) occurred in the OXY+ group. It is therefore likely that OXY+ women did have more bleeding overall, as prior exposure to oxytocin is an independent risk factor for uterine atony and bleeding.17
Our incidence of postpartum hemorrhage (15% overall) was higher than the 3% reported nationally.18 Cesarean delivery itself is associated with increased risk of hemorrhage, especially cesarean delivery after labor16; also our institution serves a high-risk inner city population.14 Either of these elements could explain the high proportion of hemorrhage. Additionally, estimates of blood loss are often inaccurate, with clinicians overestimating smaller blood volumes and underestimating larger ones,19 so it is possible that the actual rate of bleeding in excess of 1000 mL was overestimated in this study.
This investigation contains several limitations. The surgical and anesthetic teams estimated blood loss in the operating room and such estimates are prone to error.19 We did not record data on blood transfusion on the postpartum floor and so may have missed some transfusion data. Additionally, the obstetric surgeons at our institution work with residents of different levels of training, and there is wide variability in duration of cesarean delivery. Operative time was not collected in our study, and it is possible that longer surgeries yielded larger blood loss and higher doses of oxytocin and other agents. Also, we did not note body mass index, race/ethnicity, indication for cesarean, or magnesium administration, which may affect uterine tone. Additionally, we were unable to determine a threshold intrapartum oxytocin dose or duration that merits concern for increased postpartum requirements from this study design. Finally, our group of OXY− patients included some who labored and some who did not, and these 2 patient subgroups exhibited differences in nulliparity and chorioamnionitis, factors that may influence response to oxytocin. However, even after adjusting for these and other factors, OXY+ patients were nearly twice as likely to need high-rate postpartum oxytocin than OXY− patients. Moreover, we believe that oxytocin exposure per se represents a clinically relevant variable, as it is easily identifiable by the clinician, and affects downregulation of receptors.15
In summary, a recent report demonstrating higher oxytocin requirements in women exposed to oxytocin during labor13 appears to carry clinical significance. Our data prompted us to amend our protocol for administration of postpartum oxytocin (Figure 2). Specifically, we recommend beginning an oxytocin infusion at 36 IU/h in women who were exposed to oxytocin prior to cesarean delivery (close to the documented ED90 of postpartum oxytocin [44.2 IU/h] in this subset of patients) and, if uterine atony develops, increasing it to 54 IU/h (approximately the upper limit of the 95% CI of the ED90 [55.6 IU/h] in this group). Further atony prompts administration of other uterotonic medications. Although it is possible that patients who receive oxytocin for augmentation or induction and then deliver vaginally have increased postpartum oxytocin requirements, such patients have lower hemorrhage risk than those who proceed to cesarean after planned vaginal delivery, and we use low-rate postpartum oxytocin in this patient group. Establishing uterine tone may require higher oxytocin rates than maintaining it,20 and therefore, oxytocin is decreased once uterine tone becomes adequate (usually assessed after 1 hour). The “300-600-900” approach described in Figure 2 approximates effective rates of oxytocin and carries the additional benefits of simplicity and being easy to remember. Further study is required to determine the optimal protocol for prophylaxis and treatment of postpartum uterine atony and hemorrhage.
Name: Amanda Foley, MD.
Contribution: This author helped design the study, abstract the data, and write the manuscript.
Name: Ashley Gunter, MD.
Contribution: This author helped design the study, abstract the data, and write the manuscript.
Name: Kenneth J. Nunes, MD.
Contribution: This author helped design the study and edit the manuscript.
Name: Sajid Shahul, MD, MPH.
Contribution: This author helped edit the manuscript and provide statistical support.
Name: Barbara M. Scavone, MD.
Contribution: This author helped design the study and edit the manuscript.
This manuscript was handled by: Jill M. Mhyre, MD.
1. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, et al. Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:980–1004.
2. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 76: Postpartum hemorrhage. Obstet Gynecol. 2006;108:1039–1047.
3. Pinder AJ, Dresner M, Calow C, O’Riordan J, Johnson R. Haemodynamic changes caused by oxytocin during caesarean section under spinal anaesthesia. Int J Obstet Anesth. 2002;11:156–159.
4. Archer TL, Knape K, Liles D, Wheeler AS, Carter B. The hemodynamics of oxytocin and other vasoactive agents during neuraxial anesthesia for cesarean delivery: findings in six cases. Int J Obstet Anesth. 2008;17:247–254.
5. Svanström MC, Biber B, Hanes M, Johansson G, Näslund U, Bålfors EM. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine during caesarean section. Br J Anaesth. 2008;100:683–689.
6. Jonsson M, Hanson U, Lidell C, Nordén-Lindeberg S. ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial. BJOG. 2010;117:76–83.
7. Thomas TA, Cooper GM. Maternal deaths from anaesthesia. an extract from why mothers die 1997–1999, the confidential enquiries into maternal deaths in the United Kingdom. Br J Anaesth. 2002;89:499–508.
8. 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;101:822–826.
9. 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;98:116–119.
10. Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin requirements at elective cesarean delivery: a dose-finding study. Obstet Gynecol. 2004;104:1005–1010.
11. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after cesarean delivery for labor arrest. Obstet Gynecol. 2006;107:45–50.
12. George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED(90) of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing cesarean delivery. Can J Anaesth. 2010;57:578–582.
13. 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;121:159–164.
14. Dagraca J, Malladi V, Nunes K, Scavone B. Outcomes after institution of a new oxytocin infusion protocol during the third stage of labor and immediate postpartum period. Int J Obstet Anesth. 2013;22:194–199.
15. Phaneuf S, Rodríguez Liñares B, TambyRaja RL, MacKenzie IZ, López Bernal A. Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour. J Reprod Fertil. 2000;120:91–97.
16. Oyelese Y, Ananth CV. Postpartum hemorrhage: epidemiology, risk factors, and causes. Clin Obstet Gynecol. 2010;53:147–156.
17. Grotegut CA, Paglia MJ, Johnson LN, Thames B, James AH. Oxytocin exposure during labor among women with postpartum hemorrhage secondary to uterine atony. Am J Obstet Gynecol. 2011;204:56.e1–56.e6.
18. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg. 2010;110:1368–1373.
19. Toledo P, McCarthy RJ, Hewlett BJ, Fitzgerald PC, Wong CA. The accuracy of blood loss estimation after simulated vaginal delivery. Anesth Analg. 2007;105:1736–1740.
20. Duffield A, McKenzie C, Carvalho B, et al. Effect of a high-rate versus a low-rate oxytocin infusion for maintaining uterine contractility during elective cesarean delivery: a prospective randomized clinical trial. Anesth Analg. 2017;124:857–862.