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Obstetrics & Gynecology 2005;105:294-299
© 2005 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Maternal Hemodynamics After Oxytocin Bolus Compared With Infusion in the Third Stage of Labor: A Randomized Controlled Trial

Gregory A. L. Davies, MD, Julie L. Tessier, MD, Mary C. Woodman, RN (EC), Adrienne Lipson, MD and Philip M. Hahn, MSc

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario, Canada.

Address reprint requests to: Dr. G. A. L. Davies, Victory 4, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7; e-mail: gd7{at}post.queensu.ca.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess the effects of oxytocin bolus or infusion on maternal hemodynamics in the third stage of labor.

METHODS: In a randomized, double-blind, double-dummy fashion, 99 women received an intravenous oxytocin bolus (10 IU push) and 102 women received an infusion (10 IU in 500 mL saline at 125 mL/h) at delivery of the anterior shoulder. Mean arterial pressure and heart rate were measured every minute for 10 minutes, then every 5 minutes for the next 20 minutes. These serial measurements were analyzed using a 2-factor analysis of variance for repeated measures.

RESULTS: Serial mean arterial pressure measures varied significantly between groups (interaction effect, P = .002). Mean arterial pressure (± standard deviation) nadirs were reached after 10 minutes, 80.9 (± 11.0) mm Hg in the bolus group compared with 77.0 (± 12.1) mm Hg in the dilute infusion group. The mean difference (95% confidence interval) between groups was 4.0 (0.7–7.2) mm Hg. Serial heart rate measures also varied between groups (interaction effect, P < .001). Mean heart rate (± standard deviation) peaked 1 minute after the oxytocin infusion, 115 (± 27) beats per minute (bpm) in the bolus group compared with 109 (± 21) bpm in the dilute infusion group. The mean difference (95% confidence interval) between groups was 6.6 bpm (–0.1 to 13.3). The dilute oxytocin infusion group experienced a greater mean estimated blood loss (423.7 mL compared with 358.1 mL, P = .029, t test), increased use of additional oxytocics (35.3% compared with 22.2%, P = .044, Fisher exact test) and a greater drop in hemoglobin (admission minus postpartum) (17.4g/L compared with 11.4g/L, P = .002, t test) compared with the oxytocin bolus group.

CONCLUSION: Bolus oxytocin of 10 IU is not associated with adverse hemodynamic responses and can safely be administered to women with intravenous access in the third stage of labor for postpartum hemorrhage prophylaxis.

LEVEL OF EVIDENCE: I

The use of prophylactic oxytocin in the third stage of labor has been shown to decrease the incidence of postpartum hemorrhage by 50–60%. Obstetric texts advocate the use of oxytocin, either intramuscularly or as a dilute infusion, but warn against the use of intravenous bolus oxytocin, fearing significant maternal hemodynamic consequences.5,6 Two commonly used obstetric references state that intravenous oxytocin bolus is contraindicated and provide the following warnings: "bolus injection of as little as 5 units may be associated with maternal hypotension,"5 and "oxytocin should never be given as an undiluted bolus dose as serious hypotension or cardiac arrhythmias may follow."6 These statements are either not referenced5 or use case reports and small studies to justify the warning.6 Secher et al7 describe the hemodynamic response to oxytocin of 9 women undergoing termination of pregnancy in the first trimester during general anesthesia. They found a 40% decrease in femoral arterial pressure after a 10 IU bolus of oxytocin, but no hemodynamic change when dilute oxytocin was infused.7 Hendricks and Brenner8 described a woman, hypotensive from postpartum hemorrhage, who received an intravenous bolus of 5 IU of oxytocin. The authors relate a subsequent fall in blood pressure to the oxytocin received. Understanding the hemodynamic effects of oxytocin is complicated by the heterogeneity of the studied populations: men, nonpregnant women, and women undergoing termination of pregnancy in the first trimester. This study is designed to clarify the maternal hemodynamic response to bolus oxytocin in the third stage of labor.


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Women in active labor at Kingston General Hospital, Kingston, Ontario, Canada, who were expected to deliver vaginally and who required an intravenous (epidural anesthesia, antibiotics, etc.) were approached for participation in the study and informed consent was obtained. The protocol was approved by the Queen's University Health Sciences Research Ethics Board.

Immediately after vaginal delivery of the neonate, and before delivery of the placenta, participants received oxytocin either as a bolus or a dilute infusion in a double-blind, double-dummy fashion. In this study design type each group of subjects receives one of the active interventions and a placebo (in this case called a dummy) that looks the same as the other intervention. Such a design is particularly useful when comparing interventions with different modes of administration (such as bolus compared with continuous intravenous infusion).12

Randomization was performed by the study pharmacist using a computer-generated random numbers table. The study pharmacist provided sealed, numbered packages containing 2 vials (1 containing 10 IU of oxytocin, the other containing an equal volume of saline) that were labeled as "port" for the bolus and "bag" for the infusion. The oxytocin was not visually decipherable from saline. The bolus oxytocin group received 10 IU of oxytocin as an intravenous push (with an equal volume of saline injected into 500 mL of normal saline and infused at 125 mL/h as the dummy). The oxytocin infusion group received 10 IU of oxytocin in 500 mL of normal saline at 125 mL/h (with an equal volume of saline intravenous push as the dummy). Blood pressure and heart rate were measured on all participants using a single calibrated automated sphygmomanometer (Critikon Inc., Tampa, FL). A baseline (time 0) blood pressure and heart rate were obtained between contractions just before delivery. Immediately after the oxytocin was administered, maternal blood pressure and heart rate were measured every minute for the first 10 minutes, then every 5 minutes for the next 20 minutes, for a total of 30 minutes. Estimated blood loss was recorded. Additional oxytocics (oxytocin, ergot, prostaglandin F2{alpha}) were available for excessive postpartum bleeding, and the attending physician made the diagnosis of postpartum hemorrhage.

Serial mean arterial pressure (MAP) and heart rate measures were analyzed by a 2-factor repeated-measures analysis of variance (ANOVA). The group factor had 2 levels (bolus compared with dilute infusion) and the time factor had 15 levels (t0 to t30). The Huynh and Feldt epsilon value was used to compensate for the absence of sphericity by adjusting the associated degrees of freedom. Missing values were replaced by averaging the closest before and after values within subjects. The use of P values for baseline comparisons is considered inappropriate and do not appear in Tables 1 and 2. 13,14 Chance differences between the 2 groups were followed up with appropriate adjusted or subgroup analyses. Continuous outcomes (birth weight, length of third stage, estimated blood loss, postpartum hemoglobin) were analyzed by t tests. Changes in hemoglobin values were calculated by subtracting postpartum values from admission values. Categorical outcomes (third stage > 30 minutes, retained placenta, additional oxytocics, estimated blood loss ≥ 500 mL and ≥ 1,000 mL, blood transfusion, postpartum hemoglobin < 90 g/L) were analyzed by Fisher exact tests. Statistical significance was set at P < 0.05. Statistical computations were generated using SPSS 12.0 for Windows (SPSS Inc., Chicago, IL).


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  		Table 1. Baseline Characteristics of Participants by Treatment Group

 


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  		Table 2. Intrapartum Characteristics of Participants and Events by Treatment Group

 
The sample size of 200 subjects was arbitrarily chosen. Appropriate maternal hemodynamic estimates (MAP and heart rate) and measures of dispersion (standard deviations) were unavailable in previous reports. Available studies recruited subjects in the first trimester or who were under general anesthesia, factors associated with cardiovascular effects dramatically different from the term and awake population we planned to study.


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between January 1998 and August 1999, 201 women were randomly assigned to receive oxytocin either as a bolus (n = 99) or dilute infusion (n = 102). Baseline characteristics of the participants by treatment group are shown in Table 1, and intrapartum characteristics and events are presented in Table 2. Two subjects from the dilute infusion group with less than 4 of the 15 MAP or HR measurements were excluded from the repeated measures ANOVA. By chance, 12.9% more subjects received oxytocin induction or augmentation in the dilute infusion group. As described below, this potential confounder was further analyzed with adjusted and subgroup analyses.

Average MAP measures (+ standard error of the mean) after intravenous bolus or dilute infusion of oxytocin are shown in Figure 1. A significant time x group interaction (P = .002) indicated that the serial MAP measures varied between groups. Nadirs for MAP (± standard deviation) were reached after 10 minutes, 80.9 (± 11.0) mm Hg in the bolus group compared with 77.0 (± 12.1) mm Hg in the dilute infusion group. The mean difference (95% confidence interval [CI]) after ten minutes between groups was 4.0 (0.7–7.2) mm Hg. Measures of MAP then rebounded and reached similar levels at 30 minutes.



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  		Fig. 1. Average maternal mean arterial pressure (MAP) (+ standard error of the mean) after intravenous bolus or dilute infusion of oxytocin. Time 0 refers to baseline measurement during second stage of labor.

Davies. Oxytocin Hemodynamics. Obstet Gynecol 2004.

 

Mean heart rate measures (+ standard error of the mean) after intravenous bolus or dilute infusion of oxytocin are shown in Figure 2. A significant time x group interaction (P < .001) indicated that the serial HR measures varied between groups. Mean heart rate (± standard deviation) peaked 1 minute after the oxytocin infusion, 115 (± 27) beats per minute (bpm) in the bolus group compared with 109 (± 21) bpm in the dilute infusion group. The mean difference (95% CI) after 1 minute between groups was 6.6 bpm (–0.1 to 13.3). On average, heart rate returned to baseline within 4 minutes in those receiving a dilute oxytocin infusion. Heart rate for this group remained stable and then decreased marginally between 15 and 30 minutes. Similarly, heart rate returned to baseline within 4 minutes in those receiving a bolus oxytocin infusion. Thereafter, heart rate for this group continued on a slight decline, stabilizing after 10 minutes and not fully rebounding by 30 minutes.



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  		Fig. 2. Mean maternal heart rate (+ standard error of the mean) after intravenous bolus or dilute infusion of oxytocin. Time 0 refers to baseline measurement during second stage of labor. bpm, beats per minute.

Davies. Oxytocin Hemodynamics. Obstet Gynecol 2004.

 

There were no patients in either group who experienced side effects associated with oxytocin infusion. Continuous cardiac monitoring was not performed. No woman complained of symptoms suggestive of, was diagnosed with, or treated for an arrhythmia.

Postpartum outcomes by treatment group are shown in Table 3. Birth weights were within the normal range, and the mean difference between groups of 133.9 g was not statistically significant. Length of the third stage and rates of retained placenta were similar between the 2 groups. More subjects (13.1%) in the dilute infusion group required additional oxytocics. Mean estimated blood loss (95% CI) was greater by 65.6 mL (6.7–124.6) in the dilute infusion group. More subjects (9.1%) in the dilute infusion group were estimated to have blood losses ≥ 500 mL, and 1 more woman in this group had an estimated blood loss of ≥ 1,000 mL. The mean difference (95% CI) of 4.0 g/L (–1.1 to 9.1) in postpartum hemoglobin was not statistically significant. The decrease (95% CI) in hemoglobin from baseline was 6.0 g/L (2.3–9.7) greater in the infusion group. Two more women in the dilute infusion group required a blood transfusion. It can be estimated that for every 53 women receiving a bolus oxytocin infusion compared with the dilute infusion regimen, there would be 1 less blood transfusion required.


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  		Table 3. Postpartum Outcomes by Treatment Group

 

As stated above, by chance, 12.9% more subjects received oxytocin induction or augmentation in the dilute infusion group (Table 2). To assess whether MAP measures were associated with predelivery exposure to oxytocin, we reanalyzed the repeated-measures ANOVA adding a third factor (predelivery oxytocin exposure) to the model. The time x group interaction remained statistically significant (P = .001), reconfirming serial MAP measures varied between groups (bolus compared with dilute infusion). The group x predelivery oxytocin exposure and time x predelivery oxytocin exposure interactions were not statistically significant (P = .553 and P = .738, respectively). Therefore, adjusting for predelivery oxytocin exposure did not change the interpretation for the MAP data.

To assess whether any outcomes listed in Table 3 were associated with predelivery exposure to oxytocin, we conducted subgroup analyses (Tables 4 and 5). No statistically significant differences were found. All but 1 subject with a postpartum hemoglobin less than 90 g/L were exposed to predelivery oxytocin. In the bolus infusion group 11.6% more women exposed to predelivery oxytocin had estimated blood losses of 500 mL or more. A reduction in power related to stratifying the analyses contributed to the possibility of false negatives (type II errors).


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  		Table 4. Subgroup Analysis of Postpartum Outcomes by Predelivery Oxytocin Exposure for the Bolus Group

 


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  		Table 5. Subgroup Analysis of Postpartum Outcomes by Predelivery Oxytocin Exposure for the Dilute Infusion Group

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Current obstetric teaching warns against the use of bolus intravenous oxytocin for prophylaxis against postpartum hemorrhage as it may cause unexpected hypotension.5,6 Case reports and uncontrolled studies have been used to justify this concern, but may not be generalizable to a postpartum population not under general anesthesia. Weis et al9 studied 26 women having first trimester termination of pregnancy under general anesthetic and noted a transient decrease in mean arterial pressure and systemic vascular resistance, but an increase in cardiac output with a 5 to 10 IU bolus of oxytocin. Andersen et al10 noted similar findings in 22 women given a 10 IU bolus of oxytocin at cesarean delivery. Thirteen of these subjects received general anesthetic. They noted less of an impact on MAP in women who had an epidural or spinal anesthetic. In contrast, Sorbe15 described using a 10 IU bolus of oxytocin in 506 women for postpartum hemorrhage prophylaxis. Although blood pressure was not recorded, no patients described symptoms or clinical signs of hypotension.

Previous studies of the human response to bolus oxytocin have primarily described men, nonpregnant women, and women in the first trimester under general anesthesia. In these small studies, bolus oxytocin of 10 IU has resulted in a fall in systemic vascular resistance and MAP compensated by an increase in heart rate and consequently cardiac output.7 This fall in MAP was less in nonpregnant women placed in the lithotomy position, presumably due to improved venous return.11 The different response experienced by our subjects may be due to the 3-L increase in blood volume and 25% reduction in systemic vascular resistance of late pregnancy. After an oxytocin bolus an already low systemic vascular resistance may not respond further or be more rapidly compensated by the expanded blood volume. Autotransfusion associated with uterine contraction immediately postpartum increases preload volumes maintaining MAP. The difference in our findings compared with those of Anderson et al10 may be explained by the fact that most of our patients were in the lithotomy position, and none received general anesthetic. The rise in heart rate observed in the bolus group at 1 minute is consistent with the findings of others and suggests that despite the documented hemodynamic stability there may be some minor and brief change in MAP before the 1-minute assessment that is associated with a compensatory increase in HR.8 As demonstrated in Figure 2, heart rate in the bolus group is less than that in the dilute infusion group by minute 3.

Our study identified that women receiving bolus oxytocin for postpartum hemorrhage prophylaxis after vaginal delivery had a higher MAP than those who received a dilute oxytocin infusion. Women receiving bolus oxytocin also experienced less blood loss, less postpartum hemorrhage, and less change in hemoglobin levels. We recognize that estimates of blood loss are frequently inaccurate and notoriously underestimated by physicians.16 However, given the double-blinded nature of our protocol, there is no reason to believe that a bias exists in reporting blood loss in one group compared with another.

The estimates of blood loss and change in hemoglobin were significantly greater in the infusion group. These findings are likely related to the fact that women in the infusion group were exposed to very little oxytocin during the 30 minutes of observation. An infusion containing 10 IU of oxytocin in 500 mL of saline infusing at 125 mL/h would deliver only 1.25 IU of oxytocin to the uterus in 30 minutes. Blood loss may have been less had a faster infusion of dilute oxytocin been used. Bolus oxytocin of 10 IU can safely be given to women with intravenous access in the third stage of labor for postpartum hemorrhage prophylaxis.


   Footnotes
 
The authors thank Alistair MacLean, phd, c psych, Department of Psychology, Queen's University, for his statistical advice.

Received May 14, 2004. Received in revised form September 20, 2004. Accepted September 23, 2004.

doi:10.1097/01.AOG.0000148264.20909.bb


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Prendiville WJ, Elbourne D, Chalmers I. The effects of routine oxytocic administration in the management of the third stage of labour: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1988;95:3–16.[Medline]

2. Prendiville WJ, Harsing JE, Elbourne DR, Stirrat GM. The Bristol third stage trial: active versus physiological management of the third stage of labour. BMJ 1988;297:1295–301.

3. Elbourne DR, Prendiville WJ, Carroli G, Wood J, McDonald S. Prophylactic use of oxytocin in the third stage of labour (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester: John Wiley & Sons, Ltd.

4. Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labour (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester: John Wiley & Sons, Ltd.

5. Benedetti TJ. Obstetric hemorrhage. In: Gabbe SG, Niebyl JR, Simpson JL, editors. Obstetrics: normal and problem pregnancies. 3rd ed. New York (NY): Churchill Livingstone; 1996. p. 499–532.

6. Obstetrical hemorrhage. In: Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC, Hankins GDV, Clark SL, editors. Williams obstetrics. 20th ed. Stamford (CT): Appleton & Lange; 1997. p. 745–782.

7. Secher NJ, Arnsbo P, Wallin L. Haemodynamic effects of oxytocin (syntocinon) and methyl ergometrine (methergin) on the systemic and pulmonary circulations of pregnant anaesthetized women. Acta Obstet Gynecol Scand 1978;57:97–103.[Medline]

8. Hendricks CH, Brenner WE. Cardiovascular effects of oxytocic drugs used postpartum. Am J Obstet Gynecol 1970;108:751–60.[Medline]

9. Weis FR Jr., Markello R, Mo B, Bochiechio P. Cardiovascular effects of oxytocin. Obstet Gynecol 1975;46:211–4.[Abstract/Free Full Text]

10. Andersen TW, DePadua CB, Strenger V, Prystowsky H. Cardiovascular effects of rapid intravenous injection of synthetic oxytocin during elective cesarean section. Clin Pharmacol Ther 1965;6:345–9.

11. Johnstone M. The cardiovascular effects of oxytocic drugs. Br J Anaesth 1972;44:826–34.[Abstract/Free Full Text]

12. Jadad AR. Randomised controlled trials: a user's guide. London: BMJ Books; 1998. p. 22.

13. Altman DG. Practical statistics for medical research. New York (NY): Chapman & Hall; 1991. p. 396–419.

14. Cummings P. Reporting statistical information in medical journals. Arch Pediatr Adolesc Med 2003;157:321–4.[Free Full Text]

15. Sorbe B. Active pharmacologic management of the third stage of labor: a comparison of oxytocin and ergometrine. Obstet Gynecol 1978;52:694–7.[Abstract/Free Full Text]

16. Brucker MC. Management of the third stage of labor: an evidence-based approach. J Midwifery Womens Health 2001;46:381–92.[Medline]




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