Zhang, Jun PhD, MD; Branch, D. Ware MD; Ramirez, Mildred M. MD; Laughon, S. Katherine MD, MS; Reddy, Uma MD, MPH; Hoffman, Mathew MD, MPH; Bailit, Jennifer MD, MPH; Kominiarek, Michelle MD; Chen, Zhen PhD; Hibbard, Judith U. MD
From the Division of Epidemiology, Statistics and Prevention Research, and the Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; MOE and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; the University of Texas Health Science Center at Houston, Houston, Texas; Christiana Care Health System, Newark, Delaware; MetroHealth Medical Center, Cleveland, Ohio; and the University of Illinois at Chicago, Chicago, Illinois.
For a list of institutions that participated in this study, see the Appendix online at http://links.lww.com/AOG/A246.
The data included in this article were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through contract HHSN267200603425C.
Corresponding author: Dr. Jun Zhang, MOE and Shanghai Key Laboratory of Children's Environmental Health Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kong Jiang Road, Shanghai 200092, China; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
Oxytocin for the purposes of augmentation and induction of labor is one of the most frequently used medications in obstetrics. Recent studies show that oxytocin is used in more than 50% of laboring women in some hospitals.1 Yet, there is tremendous variability in the dose and dosing interval in clinical practice. The Institute for Safe Medication Practices designated oxytocin as a high-alert medication.2 Concerns have been raised whether such frequent use, particularly with high-dose regimens, has potential unwanted consequences.3 A recent meta-analysis of 10 randomized controlled trials concluded that high-dose oxytocin for labor augmentation was associated with a decrease in cesarean delivery and shortened labor with no increase in adverse maternal or perinatal outcomes.4 However, these 10 trials were conducted on five continents and were published from 1987 to 2004. The dose regimen also varied among the studies. Given the frequent use of oxytocin in obstetric management and increasing cesarean delivery rate, we reexamined the dose regimens that are commonly used in the United States in a contemporary population.
MATERIALS AND METHODS
The Consortium on Safe Labor is a retrospective observational study conducted by the EuniceKennedyShriver National Institute of Child Health and Human Development, National Institutes of Health, in collaboration with 12 institutions across the United States. A detailed description of the study is provided elsewhere.5 The goal of the study was to collect comprehensive information on contemporary labor and delivery practice in multiple institutions. Participating institutions extracted detailed information from their electronic medical records on maternal demographic characteristics, medical history, reproductive and prenatal history, labor and delivery summary, and postpartum and newborn information. Information from the neonatal intensive care unit was linked to the newborn records. Data on oxytocin use were extracted from a medication database. A validation study on several key variables indicated that the electronic medical records are an accurate representation of the medical charts.5 This project was approved by the Institutional Review Boards of all participating institutions.
Not all participating hospitals had detailed information on oxytocin regimen, dose, and increments. We chose six hospitals that had such data (N=73,628). We compared women in these hospitals with those in the excluded hospitals on model of delivery and neonatal outcomes. No substantial differences were found (data not shown). The following patients were selected in a descending order: singleton gestation (remaining n=72,041), spontaneous onset of labor (46,523), live birth (46,374), no previous uterine scar (37,002), no congenital anomalies (34,477), use of oxytocin augmentation (17,351), vertex presentation (17,043), and gestational age between 37 and 41 completed weeks (15,054). Only oxytocin for labor augmentation before delivery was studied.
Women were grouped based on their oxytocin starting dose and incremental dosing: 1, 2, and 4 millliunits/min. Maternal characteristics were compared according to starting dose of oxytocin. We then compared maternal and perinatal outcomes by starting dose. Because severe maternal and neonatal morbidity is rare, we created two composite indices in addition to relatively more common outcomes. The maternal complication composite index includes any of the following conditions: intrapartum placental abruption, postpartum hemorrhage, intrapartum and postpartum blood transfusion, and hysterectomy. The neonatal complication composite index includes asphyxia, hypoxia-ischemic encephalopathy, neonatal seizure, neonatal death, respiratory distress syndrome, continuous positive airway pressure, ventilation use, and transient tachypnea.
All data analyses were stratified by parity (nulliparous compared with multiparous women). The χ2 test was used for categorical variables, analysis of variance was used for continuous variables with a normal distribution, and Kruskal-Wallis test was used for continuous variables with a nonnormal distribution. We then estimated adjusted odds ratios for binary outcomes and adjusted differences for continuous outcomes. For the adjusted odds ratio, a multivariable logistic regression model was used to adjust for maternal age (continuous), race or ethnicity (white, African American, Hispanic, and other), insurance type (private compared with public), use of fetal scalp electrode (yes or no), epidural analgesia (yes or no), birth weight (continuous), gestational age (continuous), body mass index at admission (continuous), cervical dilation (continuous), effacement (continuous), fetal station (continuous), frequency of uterine contraction at admission (continuous), cervical dilation at oxytocin administration (continuous), and hospital site (six categories). For the adjusted difference, a generalized linear mixed model was used to adjust for these factors. Hospital was used as a random-effects variable. All analyses were conducted in SAS 9.2 (PROC LOGISTIC and PROC GLIMMIX, SAS).
The oxytocin regimen for augmentation in the selected hospitals is summarized in Table 1. We compared the institutional oxytocin protocol with detailed oxytocin data. It should be noted that none of these hospitals had a specific active management of labor protocol. In total, the starting doses of 1, 2, and 4 millliunits/min were used in 2,691, 4,994, and 7,369 women, respectively. Women in the high-dose group received substantially higher maximal doses than those in the low-dose groups.
A number of baseline characteristics of nulliparous women differed by starting dose of oxytocin (Table 2). However, no statistical significance was found in maternal body mass index at admission, prevalence of hypertensive disorders, or diabetes. There were no clinically important differences in gestational age or birth weights. At the start of oxytocin, cervical dilation was at 3–4 cm. The median maximal doses for the three groups were 7, 9.5, and 12 millliunits/min (P<.001).
The unadjusted and adjusted labor outcomes among these three different oxytocin regimens in nulliparous women are presented in Tables 3 and 4. Cesarean delivery was lower in the starting dose of 4 millliunits/min group (14% compared with 17% in the other two regimens); however, after we adjusted for potential confounders and hospitals, the risk of cesarean delivery was the same with all three oxytocin regimens. No other maternal and neonatal outcomes (except one) significantly differed among the regimens, including intrapartum fetal distress, shoulder dystocia, or third-degree or fourth-degree perineal laceration. However, higher oxytocin doses were associated with a 60% reduced risk of Apgar score less than 7 at 5 minutes, but the confidence interval (CI) ranged from 0.1 and approached 1.0. The duration of the first stage of labor from admission to complete cervical dilation was decreased in a dose–response pattern. Compared with 1 millliunit/min, the regimens starting at 2 millliunits/min and 4 millliunits/min reduced the duration of first stage of labor by 0.8 hours (95% CI 0.5–1.1) and 1.3 hours (95% CI 1.0–1.7), respectively, in nulliparous women. No effect was observed on the duration of the second stage of labor.
The results in multiparous women differed from those of nulliparous women (Tables 5, 6, and 7). After adjusting for a number of potential confounders, the high-dose oxytocin was associated with a reduced risk of meconium staining, chorioamnionitis, and newborn fever (Table 7). Compared with 1 millliunit/min, the regimens starting at 2 millliunits/min and 4 millliunits/min reduced the duration of first stage of labor by 0.7 hours (95% CI 0.4–0.9) and 1.1 hours (95% CI 0.9–1.4), respectively. Oxytocin dose had no effect on the second stage of labor.
Our database does not have information on the incidence of hyperstimulation. Thus, we used the need for intrapartum tocolytics as a surrogate. The use of tocolytics was infrequent (95% CI 1.0%–1.8%, Tables 3 and 6) and the differences were not clinically significant.
We further examined the effects of oxytocin regimen by cervical dilation at the start of oxytocin augmentation (less than 6 cm compared with 6 cm or more) because we have previously shown this to be the cervical dilation associated with onset of active labor.6 The overall patterns of dose effects were similar regardless of early compared with late initiation (results not shown).
Our large observational study demonstrates that in parturient women who received oxytocin for labor augmentation, the duration of the first stage of labor is significantly reduced with increasing oxytocin dose in a dose–response pattern. No effect was found on the second stage of labor. These patterns are consistent in nulliparous and multiparous women. A shorter duration of labor may also decrease the risk of meconium staining, chorioamnionitis, and newborn fever in multiparous women. However, we found no reduction in cesarean delivery rate among the high-dose group.
Our findings are largely consistent with those in a recent meta-analysis of 10 randomized controlled trials.4 The latter showed that the duration of labor was reduced by 1.54 hours (95% CI 0.64–2.44) in the high-dose compared with low-dose groups. It also found a decreased risk of chorioamnionitis (relative risk 0.75, 95% CI 0.50–1.14) and intrapartum meconium (relative risk 0.82, 95% CI 0.62–1.09), although neither of them was statistically significant.
It is noteworthy that the oxytocin regimens are more homogenous among our study hospitals than those in the meta-analysis of various studies. Our regimens also more closely reflect contemporary obstetric practice. Nonetheless, our retrospective observational study did not have a common labor management protocol, although one may argue that the differences in labor management style may even be greater among previous trials conducted on five continents than among our study hospitals in the United States. Hyperstimulation was also not assessed in our study. However, the similar cesarean delivery rates and lack of differences in neonatal outcomes support the safety of the higher-dose regimen. Finally, although we do not have information on patient satisfaction, the shorter duration of labor with the high-dose regimen may be considered an advantage.
The significant reduction in the risk of poor Apgar score at 5 minutes by 60% in nulliparous women is difficult to explain. The event was rare and the CIs were wide. In addition, none of other neonatal outcomes was associated with oxytocin regimen. Given the large number of outcomes and comparisons made, we speculate that this finding may be attributable to chance.
In summary, our study found that high-dose oxytocin regimen (starting dose at 4 millliunits/min and increments of 4 millliunits/min) is associated with a shorter duration of the first stage of labor in both nulliparous and multiparous women without increasing the cesarean delivery rate or adversely affecting perinatal outcomes. It may, in turn, reduce the risk of meconium staining, chorioamnionitis, and newborn fever in multiparous women.
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5. Zhang J, Troendle J, Reddy U, Laughon SK, Branch DW, Burkman R, et al. Contemporary cesarean delivery practice in the United States. Am J Obstet Gynecol 2010;203:326.e1–10.
6. Zhang J, Landy HJ, Branch DW, Burkman R, Haberman S, Gregory K, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol 2010;116:1281–7.
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