Abnormalities of the active phase complicate labor in up to 25% of nulliparous women and up to 15% of those who are multiparous.1 Management options include labor augmentation or cesarean delivery, the latter of which is generally unacceptable in the absence of an adequate trial of labor.2 Labor augmentation in the United States occurs almost exclusively with titrated intravenous oxytocin, whereas misoprostol, a synthetic prostaglandin E1 analog, has been traditionally reserved for cervical ripening and induction of labor.3 A recent Cochrane review of more than 40 trials confirmed that misoprostol is indeed an effective agent for labor induction, and many investigators have found the oral route to be as efficacious as induction with intravenous oxytocin.4–12 There are limited data, however, regarding the use of oral misoprostol as an augmentation agent.13
Misoprostol's uterotonic properties make it a logical alternative to oxytocin for labor augmentation. There are inherent concerns, however, regarding its use as a contractile agent in women who are already spontaneously contracting, albeit ineffectively. This is particularly true when considering misoprostol's longer half-life (20–40 minutes) compared with that of oxytocin (4 minutes).14,15 For this reason, before development of the study now reported, we performed a dose-finding study in which we evaluated uterine response to five different oral misoprostol dosing regimens in nulliparous women needing labor augmentation.16 We found that an oral 75-microgram dose produced sufficient uterine activity while minimizing uterine tachysystole and hypertonus.
MATERIALS AND METHODS
This randomized, controlled trial was conducted from December 2008 through January 2011 at Parkland Memorial Hospital. Parkland Hospital is a tax-supported institution serving Dallas County. Labor and Delivery is staffed by house officers, midwives, and faculty of the Department of Obstetrics and Gynecology at the University of Texas Southwestern Medical Center. This study was approved by the University's Institutional Review Board and written informed consent was obtained from each participant.
Labor management at our institution is standardized. If a woman in the active phase, defined as cervical dilation of 4 cm or more, experiences no cervical change over 2–3 hours in the setting of intact membranes, amniotomy is performed and a fetal scalp electrode and intrauterine pressure catheter are placed. If cervical change is deemed inadequate (less than 1 cm/h), fewer than 200 Montevideo units are present, or both, women are considered eligible for labor augmentation. Women with spontaneous labor were eligible for inclusion if they reached the active phase of labor but did not progress. Additional inclusion criteria included maternal age 16 years or older, gestational age 36 weeks or more, singleton, cephalic presentation, reassuring fetal heart rate (FHR), cervical dilation between 4 and 8 cm, and English or Spanish speaking. In addition, eligible individuals were required to have ruptured membranes with an intrauterine pressure catheter in place confirming the presence of fewer than 200 Montevideo units of uterine activity, the absence of tachysystole, defined as six or more contractions in a single 10-minute period, and the absence of uterine hypertonus, defined as a single contraction lasting longer than 120 seconds. Other exclusion criteria included a nonreassuring FHR pattern, meconium-stained amniotic fluid, previous uterine incision, maternal fever (defined as temperature 38°C or higher), known fetal anomalies, placenta previa or unexplained vaginal bleeding, estimated fetal weight 4,500 g or more, abnormal bony pelvis, and parity of six or more.
On enrollment, an opaque envelope corresponding to the participant's enrollment number was opened assigning women to either the oral misoprostol or the intravenous oxytocin group determined by a computer-generated randomization sequence. Randomization was stratified as either nulliparous or parous. A 20-minute baseline FHR and contraction pattern was obtained before administration of the study drug. Women assigned to the intravenous oxytocin arm were managed according to the standard titrated oxytocin protocol in use at our hospital. This regimen consists of a 6-milliunit/min starting dose followed by incremental increases of 6 milliunits/min at 40-minute intervals, up to a maximum dose of 42 milliunits/min. The protocol also specifies use of 3-milliunit/min or 1-milliunit/min doses if tachysystole or hypertonus are encountered. The oxytocin was prepared as a 20 unit/L solution in isotonic saline and administered by using calibrated infusion pumps. Women randomized to the misoprostol arm were given 75 micrograms orally for up to two doses 4 hours apart. The study drug was prepared by Parkland Hospital's Investigational Drug Service by cutting generic 100 microgram misoprostol tablets into one-half and one-quarter tablets. Women were eligible for a second dose of misoprostol if they had a reassuring FHR tracing and did not experience uterine tachysystole or hypertonus after the first dose. All women in the misoprostol arm were assessed for drug failure 2 hours after administration of the second dose. If they experienced less than 200 Montevideo units and minimal cervical change, intravenous oxytocin was initiated. All other clinical decision making, including the decision to perform cesarean or operative vaginal delivery, was made by the attending physicians. If women randomized to the misoprostol arm developed a nonreassuring FHR, uterine tachysystole, or hypertonus before the administration of misoprostol, the study drug was withheld and labor augmented with intravenous oxytocin. A nonreassuring FHR was defined by tachycardia, prolonged or late decelerations, moderate to severe variable decelerations (nadir of up to 90 beats per minute for more than 30 seconds or a duration of 60 seconds or longer), or any combination of these. Women with uterine tachysystole, hypertonus, or both in the setting of nonreassuring FHR were managed with intravenous fluid bolus, oxygen administration, and placement in the left lateral decubitus position.
All tracings were evaluated for nonreassuring FHR, uterine hypertonus, and uterine tachysystole by a single blinded investigator (A.B.). The primary outcome was the incidence of uterine tachysystole, hypertonus, or both in a 10-minute period. This interval was selected because it was used in previous studies at our institution and permitted us to choose an a priori sample size based on our own experiences. However, we also evaluated uterine tachysystole in a 20-minute interval as this would allow for better comparison with tachysystole rates in the current oral misoprostol literature. For these purposes, uterine tachysystole was defined as six contractions in two consecutive 10-minute periods. Selected neonatal and maternal outcomes were also assessed to include labor characteristics. Neonatal outcomes of interest included birth weight, Apgar score less than 4 at 5 minutes of life, umbilical cord artery pH less than 7.1, and admission to the neonatal intensive care unit (NICU). Maternal outcomes included chorioamnionitis (defined as a temperature of 38°C or higher in the absence of other sources of infection) and maternal blood transfusion for hypovolemia. In addition, the mode of delivery, elapsed time from start of labor augmentation to complete cervical dilatation, elapsed time from the start of labor augmentation to delivery, maximum number of Montevideo units, and the diagnosis of nonreassuring FHR were evaluated.
The a priori sample size for this study was based on the incidence of uterine tachysystole, hypertonus, or both using the standard oxytocin protocol at our institution, 30%.17 Assuming a 30% incidence, we estimated that we would need to randomize a total of 324 women to detect a 50% increase in uterine tachysystole or hypertonus or both (ie, a 45% incidence in the misoprostol group compared with an expected 30% incidence in the oxytocin group). This would provide us with a power of 80% and a two-sided alpha of 0.05. To account for participant attrition, we planned to randomize 350 women.
All data were analyzed as intent to treat. Statistical analysis included Student t test, Pearson χ2, and Wilcoxon rank-sum test.
A total of 439 women met inclusion criteria and were approached regarding study participation (Fig. 1). Eighty-nine (20%) women declined. Three hundred fifty women consented and were randomized, 176 (50%) to the oral misoprostol arm and 174 (50%) to the intravenous oxytocin arm. Seventy-one participants did not receive the assigned study drug, 40 (23%) in the misoprostol group and 31 (18%) in the oxytocin group. Reasons for not receiving the study drug included progression of cervical dilatation precluding the need for labor augmentation, nonreassuring FHR, refusal of study drug, and uterine tachysystole or hypertonus.
There were no differences in maternal age, gestational age, body mass index, or race or ethnicity (Table 1). Ninety-eight women (56%) in the misoprostol arm and 101 (58%) in the oxytocin arm were nulliparous (P=.66). The median cervical dilation in both groups was 4 cm (4, 5), and there was no difference in the duration of membrane rupture at the time of delivery (P=.70). Maternal outcomes are shown in Table 2. Route of delivery did not differ significantly between groups. The cesarean delivery rate was 11% in the misoprostol group compared with 10% in women given oxytocin with no significant differences in the indications for cesarean delivery between the two study arms. Three emergency cesareans were performed for nonreassuring FHR in women enrolled in this study. One woman given misoprostol developed fetal bradycardia associated with uterine tachysystole shortly after administration of the study drug. Two women in the oxytocin group underwent emergency cesarean delivery for nonreassuring FHR occurring without associated uterine tachystole or hypertonus. One of these occurred before initiation of augmentation. Neonatal outcomes are shown in Table 3; there were no differences in outcomes between the study groups.
Labor outcomes are shown in Table 4. The admission–to–study drug interval was significantly shorter in those women randomized to misoprostol, 330 minutes (252, 408) compared with 402 minutes (330, 492; P<.001). There was no significant difference, however, in the time interval between initiation of the study drug and delivery, 306 minutes (150, 534) in the misoprostol group compared with 276 minutes (162, 462) in the oxytocin group (P=.29). Of those who received oral misoprostol, 59 (43%) were ineligible for a second dose; however, the majority of women, 107 of 136 (79%), delivered after just one dose.
The overall incidence of uterine tachysystole, hypertonus, or both was higher in the misoprostol compared with the oxytocin group, 76% and 64%, respectively (P=.02). There was significantly more uterine hypertonus in the misoprostol arm (24% compared with 11%, P=.002); however, the incidence of tachysystole did not differ between groups (P=.74). When tachysystole was evaluated based on 20-minute rather than 10-minute intervals, the incidence was much lower: 28% in the misoprostol arm and 24% in the oxytocin arm (P=.30). Women in the misoprostol arm were no more likely to experience a nonreassuring FHR in the setting of tachysystole, hypertonus, or tachysystole and hypertonus (P=.20). Of interest, women in the oxytocin arm achieved a higher maximum number of Montevideo units with a median of 260 compared with 230 in the misoprostol group (P=.001).
An as-treated analysis was also performed to compared the 136 women who actually received misoprostol as randomized (Fig. 1) with the 162 who were allocated to oxytocin and received this study drug (Table 5). When analyzed as treated, there were no differences in baseline characteristics between the two groups. Labor intervals were similar to those found in the intent-to-treat analysis. In the as-treated analysis, overall uterine tachysystole was not significantly different between groups when analyzed using either 10-minute or 20-minute intervals. Uterine hypertonus, however, remained higher in the misoprostol group (P=.004).
As designed and using intent-to-treat, our study showed that the primary outcome, uterine tachysystole or hypertonus or both, was associated with misoprostol administration. This was primarily attributable to hypertonus. However, such uterine activity was not associated with emergency cesarean delivery nor with any other adverse maternal or neonatal outcomes we analyzed. Similar results were obtained when analysis was repeated comparing women who actually received their allocated study drug. One finding of interest was the significantly shorter interval (approximately 1 hour shorter) from admission to study drug in the misoprostol arm. This difference is presumably due to the ease of administrating oral misoprostol compared with implementing an intravenous oxytocin infusion.
At the time we set out to investigate use of misoprostol for augmentation of labor, we felt it necessary to study dosing regimens before embarking on a randomized trial of the efficacy of misoprostol compared with oxytocin. To this end, Villano and colleagues from our institution tested five misoprostol dosing regimens to include 25-, 50-, 75-, and 100-microgram doses given at 4-hour intervals and a 50-microgram dose given at 2-hour intervals.16 It was found that the best fit when comparing efficacy and hyperstimulation was a 75-microgram dose of misoprostol. Specifically, 60% of women given 75 micrograms achieved more than 200 Montevideo units of uterine activity and only 30% experienced uterine tachysystole or hypertonus or both. It is on this basis that we selected misoprostol 75 micrograms for this study of labor augmentation.
In a PubMed search using the terms “misoprostol,” “augmentation,” “active labor,” and “arrest of dilatation,” we were able to locate one previously reported study on the use of misoprostol for augmentation of spontaneous labor. Ho and colleagues in Taiwan in 2010 randomized 231 women to titrated oral misoprostol starting with a 20-microgram dose given every hour compared with intravenous oxytocin (1 milliunit/min starting dose, increased by 1 milliunit/min at 20-minute intervals).13 They concluded that misoprostol was comparable with oxytocin in efficacy. Of interest, they found that the cumulative misoprostol dose necessary to augment labor was 60 micrograms, which is similar to the 75-microgram total dose used in 80% of women given misoprostol in our study.
What is the ideal (correct) definition of uterine tachysystole for testing drugs that simulate uterine contractions? Our experience in this study now reported suggests to us that the definitions used clearly determine the incidence. Specifically, the incidence of uterine tachysystole decreased by approximately half when a 20-minute period was used compared with a 10-minute interval. And this halving of the rate of uterine tachysystole when using a 20-minute window was not associated with an apparent increase in adverse maternal or neonatal outcomes. It is likely that the rate of uterine tachysystole would decrease even further if a 30-minute period were used as recommended by American Congress of Obstetrics and Gynecologists.18
Certain caveats are necessary in this study of misoprostol labor augmentation compared with oxytocin infusion. First, the study was unavoidably an open study. Allocation sequence was blinded; however, it was not possible to blind treatment allocation once it had been assigned. This raises the possibility of management bias. Secondly, although our sample size was suitable for an assessment of efficacy of labor augmentation, it was not powered to account for the uncommon neonatal outcomes necessary to assess neonatal safety or adverse maternal outcomes such as postpartum hemorrhage, uterine atony, and need for cesarean hysterectomy. That is, there is a real possibility that insufficient sample size may have hampered our ability to detect uncommon neonatal outcomes. We are of the view that our study suggests that oral misoprostol is an effective agent for augmentation of labor, although this study has not established its safety when uncommon outcomes are considered.
1. Sokol RJ, Stojkov J, Chik L, Rosen MG. Normal and abnormal labor progress: I. A quantitative assessment and survey of the literature. J Reprod Med 1977;18:47–53.
2. Dystocia and augmentation of labor. ACOG Practice Bulletin No. 49. American College of Obstetricians and Gynecologists. Obstet Gynecol 2003;102:1445–54.
3. Induction of labor. ACOG Practice Bulletin No. 107. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:386–97.
4. Alfirevic Z, Weeks A. Oral misoprostol for induction of labour. The Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001338. DOI: 10.1002/14651858.CD001338.pub2.
5. Wing DA, Fassett MJ, Guberman C, Tran S, Parrish A, Guinn D. A comparison of orally administered misoprostol to intravenous oxytocin for labor induction in women with favorable cervical examinations. Am J Obstet Gynecol 2004;190:1689–94; discussion 1694–6.
6. Lo JY, Alexander JM, McIntire DD, Leveno KJ. Ruptured membranes at term: randomized, double-blind trial of oral misoprostol for labor induction. Obstet Gynecol 2003;101:685–9.
7. Al-Hussaini TK, Abdel-Aal SA, Youssef MA. Oral misoprostol vs. intravenous oxytocin for labor induction in women with prelabor rupture of membranes at term. Int J Gynaecol Obstet 2003;82:73–5.
8. Ngai SW, Chan YM, Lam SW, Lao TT. Labour characteristics and uterine activity: misoprostol compared with oxytocin in women at term with prelabour rupture of the membranes. BJOG 2000;107:222–7.
9. Crane JM, Delaney T, Hutchens D. Oral misoprostol for premature rupture of membranes at term. Am J Obstet Gynecol 2003;189:720–4.
10. Mozurkewich E, Horrocks J, Daley S, Von Oeyen P, Halvorson M, Johnson M, et al.. The MisoPROM study: A multicenter randomized comparison of oral misoprostol and oxytocin for premature rupture of membranes at term. Am J Obstet Gynecol 2003;189:1026–30.
11. Nigam A, Singh VK, Dubay P, Pandey K, Bhagoliwal A, Prakash A. Misoprostol vs. oxytocin for induction of labor at term. Int J Gynaecol Obstet 2004;86:398–400.
12. Butt KD, Bennett KA, Crane JM, Hutchens D, Young DC. Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture. Obstet Gynecol 1999;94:994–9.
13. Ho M, Cheng S, Li TC. Titrated oral misoprostol solution compared with intravenous oxytocin for labor augmentation: a randomized controlled trial. Obstet Gynecol 2010;116:612–8.
15. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007;99(suppl 2):S160–7.
16. Villano KS, Lo JY, Alexander JM, McIntire DD, Leveno KJ. A dose-finding study of oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011;204:560e.1–5.
17. Satin AJ, Leveno KJ, Sherman ML, McIntire D. High-dose oxytocin: 20- versus 40-minute dosage interval. Obstet Gynecol 1994;83:234–8.
18. Management of intrapartum fetal heart rate tracings. ACOG Practice Bulletin No. 116. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010;116:1232–40.