By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: In this randomized clinical trial of standard-dose vs. high-dose oxytocin regimens for labor augmentation among 1,003 nulliparous women, the primary outcome (cesarean delivery) was similar between the two groups. However, secondary outcomes were lower, labor duration was shorter, and umbilical artery acidemia occurred less frequently.
SOURCE: Son M, Roy A, Stetson BT, et al. High-dose compared with standard-dose oxytocin regimens to augment labor in nulliparous women: A randomized controlled trial. Obstet Gynecol 2021;137:991-998.
Oxytocin is the most common medication used in obstetrics (either alone or in combination with mechanical methods and prostaglandin E1/E2 analogues) for labor induction, labor augmentation, and the management of postpartum hemorrhage.1 Because of its ubiquitous use, medical errors related to oxytocin use during labor are some of the most common in obstetrics practice, such that the Institute for the Safety of Medical Practice lists oxytocin as one of the few medications with which caution should be exercised during its use.2
Oxytocin is an effective stimulant of uterine contractions. When used intravenously for labor augmentation, it is started at an initial dose of 0.5 mU/minute to 2 mU/minute (standard dose) or at 4 mU/minute to 6 mU/minute (high dose) to augment labor, with incremental doses of 0.5 mU/minute to 2 mU/minute (standard dosing) or 3 mU/minute to 6 mU/minute (for high-dosing regimens) at 20- to 30-minute intervals.3 With continuous administration during labor augmentation, oxytocin reaches steady state at approximately 20-30 minutes.3,4 It is metabolized rapidly and has a plasma half-life of approximately 8-10 minutes; it is eliminated completely from maternal circulation in approximately 30 minutes after cessation of intravenous infusion. Since oxytocin has a relatively short plasma half-life, its adverse effects (nausea, vomiting, headaches, hypotension, and syndrome of inappropriate antidiuretic hormone secretion) are relatively uncommon. Because of the relatively safe profile of oxytocin, it is the agent of choice for labor induction. Although there have been several studies comparing low- vs. high-dose oxytocin in labor augmentation, the optimal dose of oxytocin to use for labor augmentation is difficult to determine, since oxytocin has varying degrees of efficacy.5 Therefore, Son and colleagues designed this study to determine the effects of standard-dose vs. high-dose oxytocin regimens when used in nulliparous women.6
This study was a double-blind, superiority, randomized controlled trial conducted primarily at the Northwestern Memorial Hospital in Chicago. Inclusion criteria were nulliparous pregnant women ≥ 36 weeks of gestation admitted after spontaneous labor, and who subsequently needed labor augmentation because of slow labor progression. Women were excluded if they were non-English speaking, < 18 years of age, multiparous, had a history of prior uterine surgery (e.g., prior myomectomy), had abnormal fetal presentations, or had lethal fetal anomalies. Women undergoing induction of labor and women who could not provide informed consent also were excluded.6 Participants were randomized to a 1:1 ratio.
The primary outcome was cesarean delivery. Maternal secondary outcomes included intrapartum clinical chorioamnionitis, labor duration after commencement of oxytocin for augmentation, postpartum hemorrhage rate, and endometritis postpartum.6 Perinatal secondary outcomes included neonatal acidemia at birth (umbilical artery pH less than 7.0 or base excess greater than 12 mmol/L), five-minute Apgar score ≤ 3, admission to the neonatal intensive care unit (NICU), and perinatal death. In addition, a composite outcome of perinatal morbidity and mortality was defined as the occurrence of one or more of the following: major birth injury, neonatal seizure, neonatal encephalopathy, severe respiratory distress requiring cardiorespiratory support or ventilation > 12 hours, neonatal sepsis, receipt of hypothermic treatment (cooling), or perinatal fetal death.6
From September 2015 to September 2020, 1,003 nulliparous pregnant women met inclusion criteria after 26,894 women were screened for eligibility. Five hundred two women were randomized to the high-dose oxytocin arm, and 501 women were randomized to the standard oxytocin group. The baseline characteristics were similar in both groups. The primary outcome (cesarean delivery rate) was 14.5% in the high-dose group and 14.4% in the standard-dose groups (1.01; 95% confidence interval [CI], 0.75, 1.37; P = 0.94).6 Nulliparous women randomized to the high-dose oxytocin regimen had an appreciably shorter duration of labor compared to nulliparous women randomized to the standard oxytocin group (9.1 hours vs. 10.5 hours; mean difference, 1.4 hours; 95% CI, -2.2 hours to -0.6 hours). Interestingly, nulliparous women randomized to the high-dose oxytocin regimen were significantly less likely than those randomized to the standard-dose regimen to develop clinical chorioamnionitis (10.4% vs. 15.6%; relative risk [RR], 0.67; 95% CI, 0.48, 0.92). The rates of endometritis and postpartum hemorrhage were similar between the two groups. There were no cases of uterine rupture, hysterectomy, stillbirth, neonatal death, or maternal death, and no difference in the rates of umbilical artery acidemia (RR, 0.55; 95% CI, 0.29-1.04), five-minute Apgar score ≤ 3, NICU admission, and the severe perinatal morbidity composite.6
COMMENTARY
Because of oxytocin’s half-life of approximately 8-10 minutes and a time to achieve steady state of approximately 20 minutes, the incremental dosing interval usually is 20-30 minutes.3 Irrespective of dosing regimen, the American College of Obstetricians and Gynecologists (ACOG) recommends that labor and delivery units of hospitals in the United States should develop guidelines for oxytocin use during labor augmentation, and should periodically assess oxytocin use and adverse effects from a safety and quality improvement perspective.7 Although various dosing regimens are used across different labor and delivery units in the United States (standard-dose vs. high-dose regimens), the ultimate objective is using the lowest effective safe dose of oxytocin to augment uterine contractions (achieving uterine contraction strength of > 200 Montevideo units) to facilitate labor and decrease the interval to delivery while preventing maternal and fetal adverse effects.
Although the study by Son et al did not show statistically significant differences in cesarean delivery rates, the secondary outcomes were significant. In the past, several studies demonstrated that high-dose oxytocin regimens had the potential to cause more adverse effects when compared to standard-dose regimens. This is because higher doses of oxytocin have been associated with an increased risk of uterine hyperstimulation and category II/III fetal heart rate tracings when compared to standard oxytocin regimens.8,9 However, other studies did not show increased maternal and perinatal adverse effects when high-dose oxytocin regimens were compared to standard doses.10,11 Although the high-dose oxytocin group had a lower prevalence of clinical chorioamnionitis and a shorter time to delivery in this randomized clinical trial, the authors discussed that the baseline rate of cesarean delivery was lower than expected, so it is possible that the study was underpowered to detect significant differences in cesarean delivery rates between the two groups. The authors also described possible alteration of nursing behavior during the study (heightened vigilance) as a possible reason for the study results. Overall, the high-dose oxytocin regimen had an advantage over standard dosing in nulliparous women in this randomized clinical trial.
In conclusion, clinicians should consider using a high-dose oxytocin regimen during labor augmentation in nulliparous women, since the evidence from this randomized trial suggests that high-dose regimens, when used in nulliparous patients, was associated with lower maternal and fetal complications. However, whenever augmentation of labor with oxytocin is planned, monitoring maternal contractions and fetal heart rate continuously is recommended.
REFERENCES
- Zhang J, Branch DW, Ramirez MM, et al. Oxytocin regimen for labor augmentation, labor progression, and perinatal outcomes. Obstet Gynecol 2011;118:249-256.
- Medication Institute for Safe Medication Practices. High-alert medications in acute care settings. Aug. 23, 2018. https://www.ismp.org/recommendations/high-alert-medications-acute-list
- Dawood MY. Novel approach to oxytocin induction-augmentation of labor. Application of oxytocin physiology during pregnancy. Adv Exp Med Biol 1995;395:585-594.
- Seitchik J, Amico J, Robinson AG, Castillo M. Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. Am J Obstet Gynecol 1984;150:225-228.
- Grobman WA, Bailit JL, Rice MM, et al. Can differences in obstetric outcomes be explained by differences in the care provided? The MFMU Network APEX study. Am J Obstet Gynecol 2014;211:147.e1-147.e16.
- Son M, Roy A, Stetson BT, et al. High-dose compared with standard-dose oxytocin regimens to augment labor in nulliparous women: A randomized controlled trial. Obstet Gynecol 2021;137:991-998.
- [No authors listed]. ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009;114:386-397.
- Heuser CC, Knight S, Esplin MS, et al. Tachysystole in term labor: Incidence, risk factors, outcomes, and effect on fetal heart tracings. Am J Obstet Gynecol 2013;209:32.e1-6.
- Aboshama RA, Abdelhakim AM, Shareef MA, et al. High dose vs. low dose oxytocin for labor augmentation: A systematic review and meta-analysis of randomized controlled trials. J Perinat Med 2020;49:178-190.
- Clark SL, Simpson KR, Knox GE, Garite TJ. Oxytocin: New perspectives on an old drug. Am J Obstet Gynecol 2009;200:35.e1-6.
- Hayes EJ, Weinstein L. Improving patient safety and uniformity of care by a standardized regimen for the use of oxytocin. Am J Obstet Gynecol 2008;198:622.e1-7.
In this randomized clinical trial of standard-dose vs. high-dose oxytocin regimens for labor augmentation among 1,003 nulliparous women, the primary outcome (cesarean delivery) was similar between the two groups. However, secondary outcomes were lower, labor duration was shorter, and umbilical artery acidemia occurred less frequently.
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