The objective of this systematic review was to estimate the efficacy and safety of high-dose vs low-dose oxytocin for labor augmentation on the risk of cesarean section and on indicators of maternal and neonatal morbidity. We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library for randomized clinical trials published until January 2010. Ten randomized clinical trials, including 5423 women, met the inclusion criteria. High-dose oxytocin was associated with a moderate decrease in the risk of cesarean section (relative risk [RR], 0.85; 95% confidence interval [CI], 0.75–0.97), a small increase in spontaneous vaginal delivery (RR, 1.07; 95% CI, 1.02–1.12), and a decrease in labor duration (mean difference: –1.54 hours, 95% CI, –2.44 to –0.64). While hyperstimulation was increased with high-dose oxytocin (RR, 1.91; 95% CI, 1.49–2.45), there was no evidence of an increase in maternal or neonatal morbidity. We conclude that high-dose oxytocin for labor augmentation is associated with a decrease in cesarean section and shortened labor.
The rise in cesarean section continues to be a matter of obstetric concern. Recent reports suggest that high cesarean rates may have an adverse impact on maternal and neonatal morbidity and mortality. Dystocia is the leading indication for primary cesarean section. Inadequate uterine activity has been described as the most frequent cause of dystocia.
Augmentation of labor with oxytocin is a frequent intervention in modern obstetric practice. When labor fails to progress, oxytocin is administered to augment contractile effort and to correct dystocia with the objective on achieving a normal vaginal delivery. Oxytocin has been demonstrated to increase the frequency and intensity of uterine contractions when spontaneous uterine contraction is inadequate and the progress of labor is slow. Oxytocin protocols can be categorized as high-dose or low-dose protocols depending on the initial dose and the amount and rate of sequential increases in dose. Despite the frequency with which oxytocin is used in clinical practice, there is little consensus regarding the optimal dose of oxytocin for labor augmentation.
Over the last 2 decades, a number of randomized clinical trials have assessed the relative effectiveness of different oxytocin protocols for the treatment of dystocia, including varying dose regimens. This systematic review was designed to estimate the efficacy and safety of high-dose vs low-dose oxytocin in the augmentation of labor on method of delivery and on indicators of maternal and neonatal morbidity.
Materials and Methods
Data sources
A comprehensive literature search was performed using several search strategies. Published studies were identified through manual searches and through a computerized search of the Cochrane Collaboration Pregnancy and Childbirth Group Trial Register, PubMed, MEDLINE, and EMBASE in any language until January 2010. The key words were: oxytocin, dose, active management of labor (AML), randomized clinical trials, augmentation, and labor. References cited in these articles were manually searched to obtain additional articles.
Study selection
Two investigators (S-Q.W. and H-P.Q.) independently scrutinized the electronic searches and obtained full manuscripts of all citations that were potentially eligible studies for inclusion.
Included studies had to meet the following criteria. (1) Study design was a randomized controlled trial. (2) Population consisted of pregnant women in spontaneous labor and without prior use of oxytocin. (3) The study contrasted 2 interventions for labor augmentation: high-dose vs low-dose oxytocin. “High dose” was defined as an initial dose of ≥4 mU/min and dose increments of at least 4 mU/min; “low-dose” protocols were defined as those with an initial dose ranging between 1-4 mU/min with increments of 1-2 mU/min. (4) Outcomes measured at least 1 of the following: cesarean section, spontaneous vaginal delivery, operative vaginal delivery, duration of labor, hyperstimulation, postpartum hemorrhage, use of epidural analgesia, maternal blood transfusion, Apgar score, and neonatal complications.
Studies were excluded if the dose of oxytocin in 1 or both groups was not specified. Reporting of time intervals in labor varied across studies. Some reported the total duration of labor by study group, others reported the interval from admission to delivery, and 1 study reported the interval from the study intervention to delivery. Prolonged labor was defined as total labor duration of >12 hours. Postpartum hemorrhage was defined as blood loss >500 mL.
Tabulation and integration
The quality of the controlled trials was assessed separately by 2 independent reviewers (S-Q.W. and W.D.F.) in duplicate for 4 types of potential bias: selection bias, performance bias, detection bias, and attrition bias–based on the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Disagreements between evaluators were resolved by discussion with a third reviewer (Z-C.L.) to achieve consensus. In 1 trial, randomization was performed <30 weeks’ gestation and approximately one third of the women were excluded from the analysis after randomization as they became ineligible for the intervention. Only cesarean section was reported by intention to treat. This study was only included for the cesarean section outcome. Data were abstracted independently by the 2 reviewers and results compiled.
Of the 10 trials included in the systematic review, 5 studies contrasted AML to a more conservative approach to care, ie, early administration of high-dose oxytocin compared to a delayed low-dose oxytocin regimen. In the remaining 5 studies, the contrast consisted of a simple comparison of high-dose to low-dose oxytocin for labor augmentation. For the analysis of our main outcome, cesarean section, studies were stratified according to these 2 types of comparison.
The data were extracted and statistical analysis carried out using Review Manager (RevMan) 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). Data on dichotomous outcomes were combined using the Mantel-Haenszel method, and measures of effect are presented as relative risk (RR) with 95% confidence interval (CI). For continuous data, we used the sample size weighted mean difference when outcomes were measured in the same way between trials. We used forest plots to shows the point estimate for each study (with 95% CIs), with a diamond at the bottom representing the pooled point estimate with 95% CIs for each outcome of interest. The presence of significant heterogeneity was explored by the interaction test (I 2 ) statistic. In cases where I 2 exceeded 50%, we pooled results using random effects models and explored the results for sources of variation.
Results
The search strategy resulted in 426 potentially relevant citations. Preferred reporting items for systematic reviews and metaanalyses flow diagram ( Figure 1 ) shows an overview of the study selection process. Twenty-seven relevant randomized controlled trials were retrieved for more detailed assessments ( Table 1 ). Seventeen trials were excluded for the following reasons: 14 trials were excluded as early oxytocin administration and/or amniotomy was compared to routine care; a trial comparing pulsatile to continuous oxytocin infusion was excluded; and 2 trials comparing 2 high-dose or 2 low-dose oxytocin regimens were excluded. Ten trials, including 5423 women, were included in the final analysis. The included trials and characteristics of the women at the time of randomization are summarized in Table 2 . All 10 trials that met the eligibility criteria were evaluated by 2 reviewers independently with respect to the 4 criteria relating to potential bias. The oxytocin dosage was double-masked in only 1 trial –the bags containing high-dose or low-dose oxytocin solutions were prepared by the hospital pharmacy. Randomization blinding, when performed, was achieved by centralization of the process in the hospital pharmacy in 1 study or by sealed envelopes in the remaining studies. Three trials enrolled women with established delays in labor progress. The remaining trials enrolled women who were in normal spontaneous labor at the time of randomization.
| Randomized controlled trials | Reasons for exclusion or inclusion |
|---|---|
| Blanch et al ; Hemminki et al ; Hinshaw et al ; Hunter ; Pattinson et al ; Read et al ; Shennan et al | Excluded as compared early oxytocin for labor augmentation to routine care |
| Bréart et al ; Cammu and Van Eeckhout ; Cluett et al ; Cohen et al ; Hogston and Noble ; Serman et al ; Somprasit et al | Excluded as compared early oxytocin and early amniotomy to routine care |
| Cummiskey et al | Excluded as compared pulsatile-infusion oxytocin to continuous-infusion oxytocin |
| Lazor et al | Excluded as compared 2 low-dose oxytocin protocols |
| Satin et al | Excluded as compared 2 high-dose oxytocin protocols |
| Bidgood and Steer ; Frigoletto et al ; Jamal and Kalantari ; Lopez-Zeno et al ; Majoko ; Merrill and Zlatnik ; Rogers et al ; Sadler et al ; Tabowei and Oboro ; Xenakis et al | Included as met inclusion criteria: compared policy of high-dose to low-dose oxytocin for augmentation of labor |
| Study | Country | Study design | Total sample size, n | Participants | Mean CD at randomization, cm | Labor progress at randomization | Interventions (detailed drug regimens) |
|---|---|---|---|---|---|---|---|
| Bidgood and Steer | United Kingdom | RCT | 40 | Nulliparae in spontaneous labor at term, vertex presentation | – | Dystocia: progression of CD <0.5 cm/h | High dose: oxytocin infusion started at 7 mU/min increased by 7 mU/min every 15 min, limited by frequency of 7 contractions in 15 min or by abnormality in FHR trace; Low dose: oxytocin infusion started at initial rate of 2 mU/min and increased by 2 mU/min every 15 min until stable phase of uterine activity detected |
| Frigoletto et al | USA | RCT | 1915 | Nulliparae in spontaneous labor, single term fetus, vertex presentation, without medical or obstetric complication | – | Normal | High dose: oxytocin initiated at 4 mU/min and increased by 4 mU/min every 15 min up to maximum 40 mU/min; Low dose: oxytocin initiated at 1-2 mU/min and increased periodically by 1-2 mU/min |
| Jamal and Kalantari | Iran | RCT | 200 | Women with CD ≥3 cm and gestational age ≥37 wk | 3.6 | Ineffective uterine contractions in beginning of active labor | High dose: oxytocin initiated at 4.5 mU/min and increased by 4.5 mU/min every 30 min; Low dose: oxytocin initiated at 1.5 mU/min and increased by 1.5 mU/min every 30 min |
| Lopez-Zeno et al | USA | RCT | 705 | Nulliparae in spontaneous labor at term, cephalic presentation, without previous uterine surgery | 3.2 | Normal | High dose: oxytocin initiated at 6 mU/min and increased by 6 mU/min every 15 min; Low dose: oxytocin initiated at 1 mU/min and increased by 1-2 mU/min every 15 min |
| Majoko | Zimbabwe | RCT | 258 | Nulliparae in spontaneous labor, singleton fetus, cephalic presentation, with normal fetal heart pattern | 6.2 | Normal | High dose: oxytocin initiated at 10 mIU/min and infusion rate doubled every 60 min; Low dose: oxytocin initiated at 4 mIU/min and infusion rate doubled every 30 min |
| Merrill and Zlatnik | USA | RCT | 491 | CD ≥3 cm, at least 10 uterine contractions/h, >24 wk gestation with living fetus | 4.8 | Normal | High dose: oxytocin initiated at 4.5 mU/min and increased by 4.5 mU/min every 30 min; Low dose: oxytocin initiated at 1.5 mU/min and increased by 1.5 mU/min every 30 min |
| Rogers et al | USA | RCT | 405 | Nulliparous women at term who had attended for antenatal care, cephalic presentation, without medical or obstetric complication or fetal abnormities | 2.9 | Normal | High dose: oxytocin initiated at 6 mU/min and increased by 6 mU/min every 30 min; Low dose: oxytocin initiated at 1 mU/min and increased by 1 mU/min every 30-40 min |
| Sadler et al | New Zealand | RCT | 651 | Nulliparous women in spontaneous labor, singleton pregnancy, no severe cardiac disease, no uterine scar, and no proven contracted pelvis | 4.5 | Normal | High dose: oxytocin initiated at 6 mU/min and increased by 6 mU/min every 20 min up to 42 mU/min; Low dose: oxytocin initiated at 1 mU/min and increased by 1 mU/min every 20 min up to 8 mU/min, then increased by 2 mU/min up to 20 mU/min |
| Tabowei and Oboro | Nigeria | RCT | 448 | Nulliparae, singleton fetus, cephalic presentation | – | Normal | High dose: oxytocin initiated at 6 mU/min and increased by 6 mU/min every 15 min until either a frequency of 5 contractions/10 min, each lasting at least 40 seconds is achieved or a maximum of 36 mU/min oxytocin infusion rate is reached; Low dose: oxytocin initiated at 2 mU/min and increased by 2 mU/min every 30 min, until a frequency of at least 3 contractions/10 min, lasting at least 40 seconds each is achieved |
| Xenakis et al | USA | RCT | 310 | Nulliparous and multiparous patients in term in active labor | 5.8 | Arrest of dilatation: no cervical change for 2 h after latent phase of labor completed and cervix dilated ≥4 cm; or arrest of dilatation: no change in station of presenting part, at full dilatation, for >1 h | High dose: oxytocin initiated at 4 mU/min and increased by 4 mU/min every 15 min until adequate uterine contractility achieved; Low dose: oxytocin initiated at 1 mU/min increased by 1 mU/min every 30 min up to 4 mU/min, then increased by 1 mU/min |
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