OBJECTIVE: To characterize the frequency and timing of cardiotocographic abnormalities associated with the use of 3 commercially available prostaglandin analogues, misoprostol, dinoprostone gel, and dinoprostone pessary, as labor preinduction agents.
METHODS: One-hundred and eleven women undergoing induction of labor with an unfavorable cervix were randomized to receive either misoprostol 50 μg every 6 hours × 2 doses, dinoprostone gel 0.5 mg every 6 hours × 2 doses, or dinoprostone pessary 10 mg × 1 dose for 12 hours intravaginally. Oxytocin induction was initiated per standardized protocol. Cardiotocographic tracings were blindly reviewed, with abnormalities coded using established definitions.
RESULTS: Fifty-five percent of women treated with misoprostol demonstrated an abnormal tracing event within the initial 24 hours of induction, compared with 21.1% with dinoprostone pessary and 31.4% with the dinoprostone gel. The mean (± standard deviation) number of abnormal events was significantly greater in women treated with misoprostol (5.0 ± 5.9) versus the dinoprostone pessary (1.6 ± 2.5) and gel (2.2 ± 3.1) (P < .05). In addition, these events occurred earlier after initial misoprostol dosing (5.0 ± 4.0 hours), compared with the dinoprostone pessary (9.4 ± 5.6 hours) and gel (7.7 ± 6.6). Thirty-nine percent of the misoprostol-treated women had abnormal patterns within 6 hours of initial dosing, compared with those treated with the dinoprostone pessary (7.9%) and gel (17.1%).
CONCLUSION: Cardiotocographic abnormalities are more frequent after misoprostol administration compared with the dinoprostone analogues. The early onset and frequent nature of the tracing abnormalities associated with misoprostol raises concern for the potential use of misoprostol for outpatient cervical ripening.
LEVEL OF EVIDENCE: II-1
Cardiotocographic abnormalities are more frequent following intravaginal administration of misoprostol for cervical ripening/labor induction compared with the dinoprostone prostaglandin analogues.
From the Divisions of Maternal-Fetal Medicine, Departments of Obstetrics/Gynecology, *Center for Research in Women's Health, University of Alabama at Birmingham, Birmingham, Alabama; †Mayo Medical Center, Rochester, Minnesota; ‡Stony Brook University Hospital, Stony Brook, New York; and §University of Minnesota, Minneapolis, Minnesota.
Oral presentation and recipient of the Zuspan Award for Excellence in Perinatal Research at the 33rd Annual Society of Obstetric Anesthesia and Perinatology (SOAP) meeting, San Diego, California, April 27, 2001.
Address reprint requests to: Patrick S. Ramsey, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics/Gynecology, University of Alabama at Birmingham, 619 20th Street South –458 Old Hillman Building, Birmingham, AL 35333–7333; e-mail: email@example.com.
Received June 16, 2004. Received in revised form August 22, 2004. Accepted August 25, 2004.
Prostaglandins are effective agents that are useful in promoting cervical ripening and facilitating labor induction.1–3 Currently, the prostaglandin E2 analogues (dinoprostone gel [Prepidil, Upjohn, Kalamazoo, MI] and dinoprostone pessary [Cervidil, Forest Pharmaceuticals, St. Louis, MO]) are currently the only regimens for cervical ripening in the United States approved by the U.S. Food and Drug Administration (FDA). A great deal of interest has, however, focused on the use of misoprostol, a synthetic prostaglandin E1 analogue, for cervical ripening and labor induction. Misoprostol (Cytotec, Searle, Chicago, IL) is currently marketed in the United States for the prevention of gastric ulceration in patients at high risk for developing peptic ulcerative disease. Misoprostol also has potent uterotonic properties. Multiple prospective randomized clinical trials have demonstrated that misoprostol, administered both orally and intravaginally, significantly increased cervical Bishop scores, shortened induction-to-delivery intervals, lowered maximum doses of oxytocin, and reduced days of induction when compared with placebo controls or standard preinduction regimens.4–13 In addition, the use of misoprostol for labor induction has been reported to be associated with a significant reduction in the rate of cesarean delivery in defined study populations.5,8,9
Although prostaglandin cervical ripening and labor induction has been shown to be safe and effective when used in an inpatient setting, the outpatient use of these preparations has not been well studied. The specific concern with the use of outpatient prostaglandin cervical ripening is the potential for the development of uterine hyperstimulation and fetal compromise. This issue is of particular importance with reference to misoprostol because several investigations have demonstrated an increased incidence of uterine tachysystole (10–50%), defined as 6 or more contractions within a 10-minute period over 2 consecutive 10-minute windows, and hypertonus (10–30%), defined as a single uterine contraction of greater than 2 minutes in duration, in women treated with misoprostol for induction compared with oxytocin alone or the dinoprostone gel and pessary.5–7,9,12 Although the use of misoprostol has been associated with an increased incidence of these contraction abnormalities, associated fetal heart rate abnormalities are rare and have not resulted in a significant increase in the incidence of fetal distress, risk for operative intervention, or adverse neonatal outcome.5–7,9,10,12–14 In light of the relatively frequent occurrence of cardiotocographic abnormalities associated with misoprostol use, as well as the use of this FDA class X drug use for an off-label indication, concern has been raised regarding the safety of misoprostol as an outpatient cervical ripening agent.
To date, preliminary data from 5 prospective randomized studies have evaluated the use of outpatient misoprostol for cervical ripening and to prevent postterm pregnancy (Lyons C, Rumney P, Huang W, Morrison E, Thomas S, Nageotte, Asrat T. Outpatient cervical ripening with oral misoprostol postterm: induction rates reduced [abstract]. Am J Obstet Gynecol 2001;184:S116; Ascher-Walsh C, Burke B, Baxi L. Outpatient management of prolonged pregnancy with misoprostol: a randomized, double-blind, placebo-controlled study-preliminary data [abstract]. Am J Obstet Gynecol 2000;182:S20).15–17 Although results from these studies suggest that misoprostol may be effective, the investigations have insufficient statistical power to fully address the safety issue. Despite the large body of literature detailing the efficacy of misoprostol and the dinoprostone analogues for cervical ripening/labor induction, few studies have specifically addressed the frequency and timing of the cardiotocographic abnormalities associated with misoprostol and dinoprostone cervical ripening/labor induction. To address this important issue, we conducted a comprehensive evaluation of the cardiotocographic tracings of women enrolled in a prospective randomized study comparing the 3 commercially available prostaglandin cervical ripening agents (misoprostol, dinoprostone gel, and dinoprostone vaginal pessary).
MATERIALS AND METHODS
The investigation was conducted as an ancillary study as part of a prospective randomized clinical trial designed to compare the efficacy of the 3 commercially available prostaglandin cervical ripening agents in women undergoing labor induction with an unfavorable cervix at the Mayo Medical Center from April 1996 to August 1997.18 All women with a medical or obstetric indication for labor induction were eligible for the investigation. Inclusion criteria were 1) unfavorable cervical Bishop score of 5 or less, 2) singleton pregnancy with vertex presentation and no contraindication to vaginal delivery, 3) absence of spontaneous uterine contractions (ie, < 4 spontaneous contractions per hour), and 4) reactive nonstress test. Exclusion criteria included 1) known hypersensitivity to prostaglandins, 2) ruptured membranes, 3) suspected chorioamnionitis, 4) parity more than five, 5) previous cesarean delivery or history of uterine surgery, and 6) previous attempted induction of labor for this pregnancy. Women who met the above requirements were invited to participate, and those who gave informed consent were enrolled. This investigation was approved by the Mayo Medical Center Institutional Review Board.
All study candidates were admitted to the labor and delivery unit 12 hours before scheduled induction of labor and cardiotocography performed to rule out fetal distress and presence of uterine contractions. A cervical Bishop score was assigned on admission by a single-blinded physician for all patients enrolled in the study before randomization.18,19 Randomization was done independently through our central hospital pharmacy using dynamic allocation with stratification by parity (primiparous versus multiparous) and initial Bishop Score (≤ 2 versus > 2).18 Participants were then randomly assigned to preinduction cervical ripening with either misoprostol (Cytotec) 50 μg intravaginally in the posterior fornix initially with repeat dosing one time 6 hours later, dinoprostone gel (Prepidil) 0.5 mg administered intracervically initially with repeat dosing one time 6 hours later, or dinoprostone vaginal insert (Cervidil) 10 mg administered into the posterior fornix for a total of 12 hours. Preinduction agents were administered by an on-call physician in the labor and delivery ward and not by the physician assigning the Bishop scores. Patients with established contraction pattern of greater than 3 contractions in 10 minutes were not redosed with study agent.
After the preinduction interval, a repeat Bishop score was assigned by the same initial examiner. Patients not in an adequate labor pattern after the preinduction interval received standard oxytocin (Pitocin, Parke-Davis Products, Morris Plains, NJ) infusion at an initial rate of 2 mU/min, with 2 mU/min increments at 20-minute intervals to a maximum of 30 mU/min, until an adequate contraction pattern was obtained. Patients in active-phase labor (at least 4 cm dilation with regular uterine contractions) with arrest of dilation despite adequate contractions (no change in cervical dilation for 2 or more hours) received oxytocin augmentation. Continuous electronic fetal heart rate and tocodynamic monitoring was used throughout labor. Standardized intrapartum management guidelines were followed for all patients. Patients who developed uterine hyperstimulation received a single dose of subcutaneous terbutaline (0.25 mg), along with position change and oxygen administration. Cardiotocographic tracings were independently reviewed by a blinded investigator and abnormalities coded as hypertonus, tachysystole, and hyperstimulation syndrome using the following established definitions: hypertonus, a single contraction with duration of at least 2 minutes; tachysystole, at least 6 contractions in 10 minutes for 2 consecutive 10-minute periods; and hyperstimulation syndrome, the presence of tachysystole or hypertonus associated with fetal tachycardia, late deceleration, fetal bradycardia, and/or loss of beat-to-beat variability.4 Statistical analysis included analysis of variance with Tukey posttest, Wilcoxon rank sum test, Fisher exact test, and χ2 test, where appropriate. Statistical significance was defined as P < .05.
One hundred and eleven women with an unfavorable cervix and indication for labor induction were enrolled in the primary investigation.18 All women had continuous cardiotocography obtained during labor. No significant differences were noted among the 3 treatment groups with respect to maternal age, maternal weight, gestational age, initial Bishop score, or parity (Table 1). Indication for induction was also similar among the study groups.18 Fifty-five percent (21/38) of women treated with intravaginal misoprostol demonstrated an abnormal tracing event during the initial 24 hours of induction, compared with 21.1% (8/38) with the dinoprostone pessary and 31.4% (11/35) with the dinoprostone gel (Table 2). Hypertonus was more common among women who received misoprostol, but the difference was only significant when compared with women receiving the dinoprostone gel (P < .01). The incidence of tachysystole was significantly more common in those women treated with misoprostol compared with either the dinoprostone gel or pessary (P < .01, Table 2). Despite this increased incidence of tachysystole and hypertonus noted with misoprostol use, the incidence of hyperstimulation syndrome was similar among the 3 treatment groups (Table 2). The mean (± standard deviation) number of abnormal cardiotocographic events was significantly greater in patients treated with misoprostol (5.0 ± 5.9) versus the dinoprostone pessary (1.6 ± 2.5) and the dinoprostone gel (2.2 ± 3.1) (P < .05, Table 3). Both hypertonus and tachysystole events were significantly more frequent in women treated with misoprostol compared with either the dinoprostone gel or pessary (Table 3). The mean number of occurrences of hyperstimulation syndrome was similar among the 3 treatment arms (Table 3).
Overall, abnormal cardiotocographic events occurred earlier after initial misoprostol dosing (5.0 ± 4.0 hours, range 0.1–18.7 hours) compared with the dinoprostone pessary (9.4 ± 5.6 hours, range 0.1–21.8 hours) and dinoprostone gel (7.7 ± 6.6 hours, range 0.3–17.0 hours), but these differences were not statistically significant (P = .24). Thirty-nine percent of the misoprostol-treated women had abnormal cardiotocographic patterns noted within 6 hours of initial dosing compared with dinoprostone pessary (7.9%) and dinoprostone gel treatment groups (17.1%) (P < .05, misoprostol versus both the dinoprostone gel and pessary). Women treated with misoprostol also had a significantly higher incidence of abnormal cardiotocographic patterns occurring within the initial 12 hours of cervical ripening (47.4%) compared with women treated with either the dinoprostone pessary (10.5%) or gel (20.0%) (P < .05).
Because of the higher incidence and frequency of cardiotocographic abnormalities noted after misoprostol treatment, we compared the demographic characteristics and the obstetric/neonatal outcomes between the misoprostol-treated women with and without cardiotocographic abnormalities (Table 4). No significant differences were noted between the 2 groups with regard to maternal age, maternal weight, maternal body mass index, gestational age at time of induction, number of doses of misoprostol administered, vaginal pH, on concurrent use of magnesium sulfate (Table 4). Maternal parity was, however, significantly lower in those women who developed cardiotocographic abnormalities than in those who did not. With respect to obstetric and neonatal outcomes, no significant differences were noted in the cesarean delivery rate, meconium passage rate, birth weight, and 1- and 5-minute Apgar scores (Table 4). Umbilical artery cord pH was significantly higher among those women with tracing abnormalities than among those without tracing abnormalities.
Labor induction presents a significant problem for women with an unfavorable cervix. Prostaglandins are highly efficacious cervical ripening agents that are useful clinically as an adjuvant to labor induction in such patients to shorten induction-to-delivery intervals, improve induction success, and reduce morbidities associated with prolonged labor induction.4–13 The use of these agents, however, is associated with the potential for uterine contraction and fetal heart tracing abnormalities.5–7,9,12 These associations are important considerations as we begin to evaluate the potential use of these agents for outpatient cervical ripening in this era of health care reform and cost-containment. We have demonstrated that cardiotocographic abnormalities are more frequent after misoprostol administration compared with the dinoprostone analogues when used for cervical ripening/labor induction. These findings are consistent with previously reported investigations that have individually compared several of these preparations.5–7,9,12 Both tachysystole and hypertonus are increased significantly in women receiving intravaginal misoprostol for preinduction cervical ripening compared with the dinoprostone analogues. In addition to the increased incidence of these contraction abnormalities, we have demonstrated that misoprostol use is associated with an earlier onset and more frequent development of such abnormalities.
To date, preliminary data from 5 prospective randomized clinical trials have been reported, which have evaluated the efficacy of misoprostol as an outpatient cervical ripening agent (Lyons et al, Am J Obstet Gynecol 2001; Ascher-Walsh et al, Am J Obstet Gynecol 2000).15–17 In total, the composite number of women in whom this approach has been evaluated to date is fewer than 160. Hence, it is difficult to make sweeping conclusions regarding the safety of misoprostol for outpatient cervical ripening, especially in light of the early and frequent onset of contraction abnormalities associated with misoprostol use noted in our study. Although data from these studies have demonstrated that misoprostol is efficacious for cervical ripening to facilitate labor induction and prevent postterm pregnancy, data from a larger prospective randomized clinical trial is needed to address the safety concerns with regard to the outpatient use of misoprostol. Of significant concern are the findings reported by Asher-Walsh et al (Am J Obstet Gynecol 2000) regarding a prospective placebo-controlled randomized study of 30 women with an unfavorable cervix. Women in this investigation were enrolled between 40 and 41 weeks of gestation and were randomized to receive placebo (n = 10), 100 μg of misoprostol orally × 1 (n = 10) dose, or 200 μg of misoprostol orally × 1 dose (n = 10). All women were monitored for a minimum of 2–3 hours posttreatment before discharge home. Women who did not labor after the initial dose were retreated every 3 days until delivery. Although these investigators reported a significant reduction in the time from initiation of treatment to delivery, they noted that 40–50% of women treated with misoprostol labored following the initial misoprostol dose, thus raising important questions regarding the true outpatient nature of the therapy. The findings from this investigation raise important concerns regarding the potential outpatient use of misoprostol for cervical ripening/labor induction.
Concerns such as the optimal dose and route of administration, the most appropriate postdrug administration monitoring interval, and the ultimate safety of misoprostol for outpatient use clearly need to be more thoroughly investigated with a randomized clinical trial with sufficient power to evaluate safety before this agent can be recommended for outpatient cervical ripening. In light of the relatively frequent occurrence of cardiotocographic abnormalities, as well as its FDA class X drug use for an off-label indication, misoprostol should be used cautiously in an inpatient setting with continuous fetal heart rate and tocodynamic monitoring.10 Until further safety data are reported, the use of misoprostol for outpatient cervical ripening should be approached with great caution and limited to prospective randomized clinical investigations.
1. Hayashi RH. Spontaneous and induced cervical ripening: natural dilation and effacement process and current cervical ripening techniques. J Reprod Med 1993;38:66–72.
2. Trofatter KF Jr. Cervical ripening. Clin Obstet Gynecol 1992;35:476–86.
3. Keirse MJNC. Prostaglandins in preinduction cervical ripening: meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89–100.
4. Ramsey PS, Ramin KD. Misoprostol, a prostaglandin E1
analog, for prelabor ripening of the unfavorable uterine cervix. Fetal Matern Med Rev 1996;8:217–27.
5. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol 1997;89:633–42.
6. Wing DA. Labor induction with misoprostol. Am J Obstet Gynecol 1999;181:339–45.
7. Hofmeyr GJ, Gulmezoglu AM, Alfirevic Z. Misoprostol for induction of labour: a systematic review. Br J Obstet Gynaecol 1999;106:798–803.
8. American College of Obstetricians and Gynecologists. Induction of labor. ACOG Practice Bulletin 10. Washington, DC: ACOG; 1999.
9. Sanchez-Ramos L, Kaunitz AM. Misoprostol for cervical ripening and labor induction: a systematic review of the literature. Clin Obstet Gynecol 2000;43:475–88.
10. Ramsey PS, Ramin KD, Ramin SM. Labor induction. Curr Opin Obstet Gynecol 2000;12:463–73.
11. American College of Obstetricians and Gynecologists. Induction of labor with misoprostol. Committee Opinion 228. Washington, DC: ACOG; 1999.
12. American College of Obstetricians and Gynecologists. Response to Searle's drug warning on misoprostol. Committee Opinion 248. Washington, DC: ACOG; 2000.
13. Goldberg AB, Greenberg MB, Darney PD. Drug therapy: misoprostol and pregnancy. N Engl J Med 2001;344:38–47.
14. Hale RW, Zinberg S. Use of misoprostol in pregnancy. N Engl J Med 2001;344:59–60.
15. Incerpi MH, Fassett MJ, Kjos SL, Tran SH, Wing DA. Vaginally administered misoprostol for outpatient cervical ripening in pregnancies complicated by diabetes mellitus. Am J Obstet Gynecol 2001;185:916–9.
16. Stitely ML, Browning J, Fowler M, Gendron RT, Gherman RB. Outpatient cervical ripening with intravaginal misoprostol. Obstet Gynecol 2000;96:684–8.
17. McKenna DS, Easter JB, Proffitt M, Waddell KR. Misoprostol outpatient cervical ripening without subsequent induction of labor: a randomized trial. Obstet Gynecol 2004;104:579–84.
18. Ramsey PS, Harris DY, Ogburn PL Jr, Heise RH, Magtibay PM, Ramin KD. Comparative efficacy and cost of the prostaglandin analogs dinoprostone and misoprostol as labor preinduction agents. Am J Obstet Gynecol 2003;188:560–5.
19. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266–8.