Wong, Cynthia A. MD1; McCarthy, Robert J. PharmD1; Sullivan, John T. MD1; Scavone, Barbara M. MD1; Gerber, Susan E. MD, MPH2; Yaghmour, Edward A. MD1
Observational studies of epidural analgesia identified an association between timing of initiation of epidural analgesia and cesarean delivery: women who received epidural analgesia early in labor (cervical dilation less than 4 cm) had a cesarean delivery rate double that of women who first received epidural analgesia after the cervix was dilated to at least 4 cm.1,2 Traditionally, therefore, women who requested analgesia early in labor were offered systemic opioid analgesia. It was not clear, however, whether epidural analgesia increased the risk of cesarean delivery or whether the request for analgesia was merely a marker for some other risk factor for cesarean delivery (eg, dysfunctional labor, macrosomia, malpresentation). We hypothesized that initiating and maintaining neuraxial (combined spinal-epidural) analgesia early in labor with an opioid/low-dose local anesthetic technique would not increase the risk of cesarean delivery compared with systemic opioid analgesia in early labor followed by epidural analgesia in late labor. We designed two studies to test this hypothesis—one in nulliparous women in spontaneous labor and one in women with induced labors. In 2005, we reported that there was no difference in the rate of cesarean delivery in women in spontaneous labor who were randomized to receive early-labor neuraxial compared with systemic opioid analgesia.3 In this report, we describe the results of our study in women with induced labor.
MATERIALS AND METHODS
The study was approved by the Northwestern University Institutional Review Board. Nulliparas with term (more than 36 weeks of gestation), singleton pregnancies who were scheduled for induction of labor for any reason at Prentice Women’s Hospital and who desired neuraxial analgesia were eligible to participate. Patients were asked to participate by study personnel soon after admission to the Labor and Delivery Unit and gave written informed consent before any request for analgesia. Exclusion criteria included nonvertex presentation, spontaneous labor or spontaneous rupture of membranes before induction, any contraindication to neuraxial or systemic opioid analgesia, or cervical dilation of 4 cm or more. Women also were excluded if they received systemic hydromorphone analgesia for the placement of the extra-amniotic infusion catheter within 4 hours of the request for labor analgesia.
The cervix was examined at the time participants first requested analgesia. If cervical dilation was less than 4 cm, participants were randomized (in two blocks of 800 participants per block) through a computer-generated, random-number list generated by one of the investigators (R.J.M.) to either combined spinal-epidural (early) or systemic (late) analgesia. Group assignments were sealed in sequentially numbered opaque envelopes that were opened by study personnel only after analgesia was requested and cervical dilation was determined to be less than 4 cm. Patients and care providers were not blinded to group assignment.
Analgesia was initiated in the early group using a standard needle-through-needle combined spinal-epidural technique with intrathecal fentanyl 25 micrograms and an epidural test dose (lidocaine 15 mg/mL and epinephrine 5 micrograms/mL: 3 mL) (Fig. 1). At the second analgesia request, the cervix was examined again. Epidural analgesia was initiated with a dilute bupivacaine/fentanyl solution if the cervix was less than 4 cm. If the cervix was 4 cm or more, epidural analgesia was initiated with bupivacaine 1.25 mg/mL. If no cervical examination was performed at the second request for analgesia, the cervix was assumed to be at least 4 cm dilated. Thereafter, analgesia was maintained in all participants in the early group with patient-controlled epidural analgesia as described in Figure 1.
Analgesia was initiated in the late group with hydromorphone 1 mg intramuscularly and 1 mg intravenously. If the cervix was less than 4 cm at the second analgesia request, hydromorphone analgesia was repeated. Epidural analgesia was initiated with bupivacaine 1.25 mg/mL if the cervix was 4 cm or more. At the third analgesia request, epidural analgesia was initiated regardless of cervical dilation. Thereafter, epidural analgesia was maintained with patient-controlled epidural analgesia until delivery.
Patients were asked by study personnel to rate their pain using an 11-point verbal rating score for pain (0 to 10 scale: 0=no pain, 10=worst pain imaginable) at the first and second analgesia requests. At the second analgesia request, participants were asked to rate their “average contraction pain” since analgesic intervention as well as to rate nausea (none, mild, moderate, or severe) and report the presence or absence of vomiting.
Decisions regarding obstetric management were made by the obstetricians and midwives. Labor was induced by initiating an oxytocin infusion or by infusing extra-amniotic saline followed by oxytocin. All participants had continuous external electronic fetal heart rate (FHR) monitoring and tocodynamometry. Internal fetal scalp electrodes were placed when the external tracing was not interpretable, and intrauterine pressure catheters were used to measure the intensity of contractions when deemed necessary by the obstetric providers. Artificial rupture of membranes was performed, and nurses titrated oxytocin infusions according to institutional protocol. The decision to proceed to operative delivery was made by the obstetric team for maternal or fetal indications. Apgar scores were assigned by nurses or pediatricians responsible for neonatal assessment. Umbilical cord blood gases were obtained at the discretion of the obstetrical team.
The following data were collected for each participant: age, race, type of insurance, gestational age, weight, height, induction indication, induction method, maximum oxytocin dose, cervical examination at request for analgesia, time of initiation of analgesia and second/third requests for analgesia, time and mode of delivery (cesarean, instrumental, and spontaneous vaginal delivery), primary indication for cesarean delivery, maximum temperature during labor, and identity of the obstetric provider.
After delivery, FHR tracings without information about group assignment or other treatment modalities were assessed by a perinatologist (S.E.G.) beginning 30 minutes before until 60 minutes after the first analgesia administration. Fetal heart rate tracings were assessed as follows: variability was graded as abnormal (at or below 5 beats per minute [bpm]) or normal (above 6 bpm). The presence of prolonged decelerations (under 100 bpm for more than 60 seconds) was noted. Variable decelerations and late decelerations were graded as present or absent. The before and after analgesia tracings were assessed as reassuring or nonreassuring (patterns that would lead to an obstetric intervention if observed in real time by the perinatologist). Contraction frequency (more than 10 per 20 minutes) and duration (more than 70 seconds) were recorded.
We hypothesized that the timing of neuraxial analgesia would not influence the mode of delivery. The primary outcome was the rate of cesarean delivery. Prespecified secondary outcomes were indication for cesarean delivery, mode of vaginal delivery, analgesia quality, maximum oxytocin dose, presence of maternal fever (maximum maternal temperature during labor higher than 38°C), labor duration, incidence of reassuring fetal status in the 60-minute interval after initiation of analgesia, and neonatal outcome (Apgar scores at 1 minute and 5 minutes and umbilical artery and vein pH less than 7.1).
Based on the concept of an equivalency trial, group sample sizes of 800 in the early group and 800 in the late group achieve 80% power to detect equivalence when the margin of equivalence extends from 0.1 to 0.25. The actual difference was assumed to be 0.0, and the expected proportion in the late group, based on institutional data, was assumed to be 0.2. The calculations assume that two 1-sided Z tests are used, with a significance level of 0.05 (PASS 2008, NCSS, Kaysville, UT). An interim analysis was performed after enrolling 536 participants. At that time, the cesarean delivery rate was 28.5% in the early group compared with 29.3% in the late group. A conditional power analysis demonstrated a Bayesian probability of 0.18 of demonstrating a lower cesarean delivery rate in the early compared with the late group, assuming the alternate hypothesis with prior success rates of treatment of 0.25 and 0.2 for the early and late groups, respectively. The probability of accepting the null hypothesis under these assumptions was 0.74. Because of slow study enrollment and the improbability of enrolling the planned 1,600 participants within a reasonable time period, we arbitrarily elected to stop study enrollment on January 1, 2007, at the end of the funding period.
Categorical data were compared between groups using a χ2 test. The confidence intervals (CIs) for the differences in the medians were estimated using a 10,000-sample resampling bootstrapping method.4 The Student t test and the Mann-Whitney U test were used to analyze interval and ordinal data. Time intervals from the first analgesia request until delivery (duration of labor) stratified by mode of delivery and indication for cesarean delivery were analyzed using the log-rank test. All reported P-values are two-sided. A P<.05 was required to reject the null hypothesis. Statistical analyses were performed using SPSS 16.0.2 (Chicago, IL). Conditional probabilities were calculated using R 2.8.1 (cran.r-project.org).
A total of 1,026 women consented to participate in the study between October 2001 and December 2006 (Fig. 2). Two hundred eight women were excluded because cervical dilation was 4 cm or more at the first analgesia request. Twelve participants were excluded after randomization because they did not receive the allocated intervention and outcome data were not available. The remaining 806 participants were included in the analysis.
There were no differences between the early and late groups at baseline, including demographic characteristics, indication for induction, rate of extra-amniotic saline use, and cervical dilation, effacement, or station at first request for analgesia (Table 1). One hundred eight obstetric providers delivered the participants. The median number of deliveries per provider was seven (range 1 to 29). There were no differences in the cesarean delivery rate among providers. All patients received neuraxial analgesia. Neuraxial analgesia was initiated at a median cervical dilation of 2 cm (interquartile range 1.5–3) in the early group and 4 cm (3–4) in the late group (P<.001).
The cesarean delivery rate was not different between groups (early group 32.7% compared with late group 31.5%, relative risk 1.04, 95% CI 0.90–1.20) (Table 2). At the study termination, the conditional probability of demonstrating a lower cesarean delivery rate in the late group compared with the early group was 0.16, assuming either the prior success rates or the currently observed rates of cesarean delivery (32.7% and 31.5%) for the early and late groups, respectively. The power of the observed difference in this study was 7.5%, and a sample size of 30,500 would be required to detect a difference at the observed cesarean delivery rate. There were no differences in the rate of instrumental vaginal delivery (relative risk 0.98, 95% CI 0.80–1.20) or indications for cesarean delivery. The duration of labor was shorter in the participants allocated to receive early neuraxial analgesia (Table 3). When analyzed by mode of delivery, labor duration was shorter in early participants delivered by cesarean but not in those delivered vaginally; however, there were no differences between groups in labor duration when stratified by indication for cesarean delivery. The maximum oxytocin infusion rate did not differ between groups.
The average pain score between first and second analgesia request was significantly lower in the early compared with the late group, but the interval between first and second analgesia request was longer in the late group (Table 2). The incidence of nausea and vomiting and severity of nausea were lower in the early group. There was no difference in the incidence of maternal fever, although the duration of neuraxial analgesia was longer in the early group (Table 3).
The presence of prolonged decelerations was greater and FHR patterns judged to be reassuring was less in the early group before the initiation of analgesia (Table 4). After the analgesic intervention, the higher rate of prolonged decelerations persisted but not the difference in the rate of reassuring patterns between groups. After the initiation of analgesia, there was decreased variability in the late compared with the early group. There were no differences in the incidence of persistent variable decelerations, late decelerations, or uterine contraction patterns between groups. Neonatal outcomes were not different between groups (Table 2).
The important finding in this study is that early labor neuraxial analgesia did not increase the cesarean delivery rate compared with systemic opioid analgesia in nulliparous women undergoing induction of labor. These results extend those we reported in a similar study in nulliparas in spontaneous labor or with spontaneous rupture of membranes.3 We elected to study women undergoing induction of labor because the number of induced labors has increased steadily during the past decade, the distribution of risk factors for cesarean delivery is different, the overall rate of cesarean delivery is higher, and the mechanism(s) contributing to risk of cesarean delivery may be different in this patient population than in the spontaneously laboring population.5 The results of this study are in agreement with similar studies. Chestnut et al found no difference in cesarean delivery rate between nulliparas randomized to early or late epidural analgesia after systemic opioid in nulliparas who received oxytocin.6 The median cervical dilation in the early group, however, was 3.5 cm compared with 2 cm in the current study. Many women, particularly those admitted for induction of labor, request analgesia before cervical dilation of 3–4 cm. In a study of mixed spontaneous and induced labor in which the mean cervical dilation was 2.1 cm at the time of first analgesia, there was no difference in the cesarean delivery rate in women randomized to early compared with late epidural analgesia.7 Finally, in a systematic review of nine studies comparing early with late initiation of neuraxial analgesia (n=3,320 participants), Marucci et al calculated an odds ratio of 1.00 (95% CI 0.82 to 1.23) for risk of cesarean delivery between groups.8
The lack of causation found in the current study and other studies, despite the often-observed association between the early labor neuraxial analgesia and cesarean delivery,1,2 suggests that the request for analgesia, or greater analgesia use, may be markers for other risk factor(s) for cesarean delivery. Studies have shown that women who have more breakthrough pain during epidural analgesia9 or require greater amounts of systemic opioid analgesia10 have a higher cesarean delivery rate. Risk factors for cesarean delivery, for example, macrosomia, dysfunctional labor, and fetal malposition, may cause an increase in labor pain and are risk factors for cesarean delivery.11
Similar to our previous study in spontaneous labor3 and the study by Ohel et al (mixed spontaneous and induced labor),7 the overall duration of labor was shorter in the early compared with the late group. However, in our previous study, there was a significant difference of 81 minutes in the median duration of labor in those who delivered vaginally and no difference in the cesarean delivery participants. We found just the opposite in the current study. The study may have been underpowered to detect a difference in participants who delivered vaginally. We suspect that labor (particularly the latent phase) may have progressed more slowly in the late group, and, therefore, the decision to proceed with cesarean delivery for arrest of labor was made later. Because this difference in the duration of labor persisted across all indications for cesarean delivery, it does not appear that labor was shorter in the early group because of more cesarean deliveries for nonreassuring fetal status.
A meta-analysis comparing intrathecal with nonintrathecal opioid neuraxial analgesia techniques concluded that intrathecal opioid was associated with fetal bradycardia.12 In the current study, more parturients developed persistent variable and prolonged decelerations within 60 minutes of initiation of analgesia after neuraxial compared with systemic analgesia. However, the overall incidence was low and did not result in any adverse neonatal outcomes. One participant in the early neuraxial group had an urgent cesarean delivery (within 2 hours of initiation of analgesia). Labor was being induced for oligohydramnios, and the fetus had moderate persistent variable decelerations before and after neuraxial analgesia and increased frequency of contractions was noted after analgesia. Similar to the findings of Hill et al, systemic opioid analgesia resulted in decreased FHR variability.13
Epidural analgesia longer than 5 hours is associated with elevated maternal temperature.14,15 Although women randomized to the early group had a longer duration of neuraxial analgesia than the late group, the number of women with fever did not differ between groups.
There are several limitations to our study. It was not powered to detect a small difference between groups in the cesarean delivery rate. The study was not blinded. Different obstetric providers have different management styles, including the pattern of oxytocin use, and different triggers for performing cesarean delivery. These may influence labor outcome and were not controlled in the study.
Techniques used for neuraxial analgesia vary by institution and may influence the outcome of labor. For example, epidural analgesia with bupivacaine 2.5 mg/mL was associated with a higher rate of instrumental vaginal delivery compared with combined spinal-epidural analgesia (intrathecal sufentanil followed by low-dose bupivacaine/fentanyl).16 We chose to initiate neuraxial analgesia with a combined spinal-epidural technique because complete analgesia can be achieved with no or very little local anesthetic and a low dose of opioid, thus minimizing fetal exposure to drugs and minimizing the risk of maternal motor block. However, given that the currently published randomized trials of early compared with late neuraxial analgesia have used varying analgesia techniques and that none have found a difference in the rate of cesarean delivery, it is unlikely that the result of this trial is dependent on the specific analgesia techniques. Finally, the control groups in this and all but one study17 of early compared with late neuraxial analgesia have received systemic opioid analgesia. The effect of systemic opioid analgesia on the progress of labor and mode of delivery is unknown. A single, small (n=60) study of epidural compared with no analgesia in early labor found no difference in the cesarean delivery rate.17 A larger study, however, is unlikely to be performed because it would be difficult to perform a controlled trial in which one group is randomized to receive no analgesia.
1. Thorp JA, Hu DH, Albin RM, McNitt J, Meyer BA, Cohen GR, et al. The effect of intrapartum epidural analgesia on nulliparous labor: a randomized, controlled, prospective trial. Am J Obstet Gynecol 1993;169:851–8.
2. Seyb ST, Berka RJ, Socol ML, Dooley SL. Risk of cesarean delivery with elective induction of labor at term in nulliparous women. Obstet Gynecol 1999;94:600–7.
3. Wong CA, Scavone BM, Peaceman AM, McCarthy RJ, Sullivan JT, Diaz NT, et al. The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. N Engl J Med 2005;352:655–65.
4. Lunneborg CW. Data analysis by resampling: concepts and applications. Pacific Grove, CA: Brooks-Cole; 2000.
5. Grobman WA. Elective induction: When? Ever? Clin Obstet Gynecol 2007;50:537–46.
6. Chestnut DH, Vincent RD, McGrath JM, Choi WW, Bates JN. Does early administration of epidural analgesia affect obstetric outcome in nulliparous women who are receiving intravenous oxytocin? Anesthesiology 1994;90:1193–200.
7. Ohel G, Gonen R, Vaida S, Barak S, Gaitini L. Early versus late initiation of epidural analgesia in labor: does it increase the risk of cesarean section? A randomized trial. Am J Obstet Gynecol 2006;194:600–5.
8. Marucci M, Cinnella G, Perchiazzi G, Brienza N, Fiore T. Patient-requested neuraxial analgesia for labor: impact on rates of cesarean and instrumental vaginal delivery. Anesthesiology 2007;106:1035–45.
9. Hess PE, Pratt SD, Lucas TP, Miller CG, Corbett T, Oriol N, et al. Predictors of breakthrough pain during labor epidural analgesia. Anesth Analg 2001;93:414–8.
10. Alexander JM, Sharma SK, McIntire DD, Wiley J, Leveno KJ. Intensity of labor pain and cesarean delivery. Anesth Analg 2001;92:1524–8.
11. Hess PE, Pratt SD, Soni AK, Sarna MC, Oriol NE. An association between severe labor pain and cesarean delivery. Anesth Analg 2000;90:881–6.
12. Mardirosoff C, Dumont L, Boulvain M, Tramèr MR. Fetal bradycardia due to intrathecal opioids for labour analgesia: a systematic review. BJOG 2002;109:274–81.
13. Hill JB, Alexander JM, Sharma SK, McIntire DD, Leveno KJ. A comparison of the effects of epidural and meperidine analgesia during labor on fetal heart rate. Obstet Gynecol 2003;102:333–7.
14. Lieberman E, Lang JM, Frigoletto F Richardson DK, Ringer SA, Cohen A. Epidural analgesia, intrapartum fever, and neonatal sepsis evaluation. Pediatrics 1997;99:415–9.
15. Camann WR, Hortvet LA, Hughes N, Bader AM, Datta S. Maternal temperature regulation during extradural analgesia for labour. Br J Anaesth 1991;67:565–8.
16. Nageotte MP, Larson D, Rumney PJ, Sidhu M, Hollenbach K. Epidural analgesia compared with combined spinal-epidural analgesia during labor in nulliparous women. N Engl J Med 1997;337:1715–9.
17. Luxman D, Wolman I, Groutz A, Cohen JR, Lottan M, Pauzner D, et al. The effect of early epidural block administration on the progression and outcome of labor. Int J Obstet Anesth 1998;7:161–4.
© 2009 by The American College of Obstetricians and Gynecologists.