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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma; Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey, Maternal-Fetal Medicine, Newark, New Jersey; Department of Obstetrics and Gynecology, the University of Texas, SW Medical Center at Dallas, Dallas, Texas; Department of Obstetrics and Gynecology, University of Louisville, Louisville, Kentucky; and St. Peters Medical Center, New Brunswick, New Jersey.
Address reprint requests to: William F. Rayburn, MD Department of Obstetrics and Gynecology University of New Mexico, Health Sciences Center 2211 Lomas Boulevard, NE Albuquerque, NM 87131-5286 E-mail: wrayburn{at}obgyn.unm.edu
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Abstract |
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Methods: This was a randomized, multicenter investigation involving term pregnant women who each had one previous low-transverse cesarean and an unfavorable cervix (Bishop score no more than 6), and who was a candidate for vaginal delivery. They were assigned to receive 0.5 mg of PGE2, (Prepidil; Pharmacia-Upjohn, Kalamazoo, MI) intracervically at 39 weeks’ gestation, repeated at weekly office visits for up to three doses, or expectant treatment. The main outcome variable was vaginal birth.
Results: Of 294 cases, 143 received gel and 151 were treated expectantly. No differences between groups were found for maternal age, race, or Bishop score. Compared with the expectant treatment group, the PGE2 gel group was not more likely to deliver sooner or vaginally (57% versus 55%, P = .68). The onset of labor, duration of labor among those delivering vaginally, and 1- and 5-minute Apgar scores were not different between groups. No uterine ruptures occurred, and adverse effects were equally likely in both groups.
Conclusion: Although its safety was confirmed for outpatient use, weekly doses of intracervical PGE2 did not improve the likelihood of vaginal births after cesareans.
About 24% of pregnancies nationwide are delivered by cesarean, and one in three of those are repeat cesareans.1–3 Interest in trials of labor after cesareans resulted from concern over the increased cesarean rate in the United States. Safely replacing a large number of elective repeat cesareans with vaginal deliveries can reduce postpartum maternal morbidity and lengths of hospital stays.1 Thus, an increase in vaginal births after cesarean resulted in fewer major surgeries and attendant costs.
Most women who had uterine incisions for previous deliveries and no contraindications for vaginal birth are candidates for trials of labor. Acceptably low maternal and neonatal risks during labor after cesarean were reported.4–6 Incidence of rupture is less than 1% in women with prior lower-segment, transverse uterine incision.5 That risk was considerably lower than reported for those who delivered by low-vertical or classical uterine incision (8% or higher).4,5
Women who labor spontaneously have shorter durations of labor and lower rates of dystocia than those who have labor induced. It is logical that a similar subgroup of women with prior cesarean deliveries would be at lowest risk of uterine ruptures and have a low rate of abdominal deliveries. Results of published trials7 support that expectation. The best outcome was seen with spontaneous or amniotomy-induced labor; the number of vaginal deliveries was less if oxytocin was required, especially for induction. Studies of cervical ripening with prostaglandin (PG) gel have reported significantly increased incidence of labor and more favorable cervices at admission or induction.8–10 Labor onset after PG treatment was associated with a high probability of success similar to that of spontaneous labor. Success of amniotomy was related to favorability of the cervix. The effects of PG cervical ripening treatment seem ideally suited for women with prior cesareans who want trials of labor and vaginal births.
The objective of this open-label, randomized investigation was to compare the clinical effectiveness of PGE2 gel (Prepidil; Pharmacia-Upjohn, Kalamazoo, MI) given at 39–41 weeks’ gestation with that of expectant management for women who agreed to trials of labor after single cesareans. The main outcome variable was successful vaginal delivery. Clinical effectiveness was assessed by onset of spontaneous labor, need for oxytocin to augment or induce labor, gestational age at delivery, and newborn outcome.
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Materials and Methods |
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Exclusion criteria included any medical complications (such as insulin-dependent diabetes or pregnancy-induced hypertension) that contraindicated expectant treatment, more than one prior cesarean, uterine incisions other than in a low-transverse direction, and any contraindication, as described by the manufacturer, to oxytocic drugs, such as grand multiparity, hypertonic uterine patterns, nonvertex presentation, multifetal gestation, ruptured membranes, known hypersensitivity to prostaglandins, placenta previa or unexplained vaginal bleeding, active genital herpes infection, and suspected cephalopelvic disproportion.
Subjects were examined before enrollment to establish Bishop scores of no more than 6. The FHR and uterine activity were monitored for 20 minutes. Those who met inclusion criteria and had reassuring monitor tracings were randomly assigned to receive the PGE2 gel or to be treated expectantly. Randomization was generated by pharmaceutical company computer and the investigators were masked to assignments. Blocks of the list were sent with the drug to the study centers, where new subjects were assigned the next number on the list to determine treatment group.
The treatment period was from the beginning of randomization at the 39th week clinic visit until delivery. Subjects assigned to the expectant treatment group were instructed to return at 40 and 41 weeks for routine reassessments. Fetal heart rate monitoring was done only if clinically indicated at 40 weeks and routinely at 41 weeks. Those assigned to the cervical ripening group were given the gel that day and at return office visits at 40 weeks and 41 weeks, when appropriate. Unless intervention was indicated, subjects waited until the onset of spontaneous labor.
Subjects assigned to receive PGE2 therapy were placed supine on an examining table in the clinic. Once the gel was brought to room temperature (usually 10 minutes), the entire product (0.5 mg in 2.5 mL) was instilled, using a catheter under direct view with a vaginal speculum, into the cervical canal, just below the internal os. After administration of the gel, subjects remained supine for at least 15 minutes to minimize leakage into the upper vagina. Electronic FHR and uterine monitoring were continued for at least 2 hours after administration. Evidence of FHR decelerations or uterine contractions indicated additional monitoring at the discretion of investigators. Uterine hyperstimulation was defined as more than 5 contractions in 10 minutes (tachysystole) or a contraction lasting more than 2 minutes (hypertonus).11,12
Clinical assessments included side effects (vomiting, diarrhea, fever above 37.5C), Bishop score changes at weekly visits or when any intervention was required, gestational age at delivery, any oxytocin used to augment or induce delivery, route of delivery, newborn outcome, and postpartum febrile morbidity (at least 38C). If subsequent applications of the study medication were not given for any reason, or if the subject withdrew from the investigation, the subject’s hospital course for labor and delivery and neonatal outcome were still assessed. Subjects who dropped out after protocol treatment was instituted were not replaced. Data were recorded on case report forms supplied by the manufacturer.
Sample size was estimated using a 30% cesarean delivery rate in women in the expectant treatment group and 15% in the treatment group. A total of 300 subjects (150 per group) was calculated to be necessary for an alpha error of 0.05 and a power of 80%. Descriptive statistics (number, mean, standard deviation, minimum, maximum) and frequency distributions, confidence intervals (CI), and graphs were calculated as appropriate. Baseline comparisons of demographics were made between treatment groups to verify that randomization produced equivalent groups. Comparisons between groups were done for efficacy variables (gestational age at delivery, route of delivery, oxytocin requirement, newborn outcome, and postpartum fever). For statistical analysis, variables were classified as continuous or discrete (categorical). Discrete categorical data were evaluated using the Fisher exact test. All continuous and discrete ordinal variables were analyzed using analysis of variance techniques. A difference was considered significant if P < .05.
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Results |
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. The groups were comparable in maternal age, race, and preentry Bishop score. The percentages of women with Bishop scores of 0–2 were comparable between groups.
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. Although most women had uterine contractions on monitor tracings after PGE2 gel insertion, only one (0.7%) had uterine hyperstimulation. Tachysystole was present in the first 30 minutes. That finding warranted hospital admission for eventual successful vaginal delivery. The presence of FHR decelerations in 8% of each group occurred during the first 30 minutes, and no case required a tocolytic drug or longer than 2 hours to observe the FHR pattern. Maternal gastrointestinal side effects (nausea, vomiting, diarrhea) were infrequent and similar between groups.
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are intervals from enrollment to delivery. The percentages of women who delivered by 39, 40, and 41 completed weeks were not different between groups. Only nine pregnancies reached gestational ages of 2 weeks beyond estimated dates of confinement. Labor was eventually induced with similar frequency in the PGE2 group (38 cases, 26.6%) and the expectant treatment group (34 cases, 22.5%; P = .50). Primary indications for an induction were prolonged pregnancy (beyond 41 weeks) and hypertension.
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. The percentage of women who delivered vaginally was not significantly greater with outpatient PGE2 than with expectant treatment (82 cases [57%] versus 83 cases [55%]; P = .68). The mean duration of labor was 10.8 hours, regardless of group assignment. The most common indication for cesarean delivery was failure to progress. Women who elected to proceed with repeat cesareans were beyond their estimated delivery dates, decided against trials of labor after the spontaneous onset of contractions, or had rupture of amniotic membranes. Indications for cesarean included attainment of 42 weeks’ gestation with an unfavorable cervix, suspected fetal macrosomia, undiagnosed breech presentation, and preeclampsia with an unfavorable cervix, and they were equally represented in both groups. An FHR pattern of decelerations requiring cesarean delivery was uncommon in either group. There were no cases of uterine rupture.
Measures of neonatal outcome are shown in Table 4. The mean birth weight and frequency of fetal macrosomia (more than 4000 g) were not different between groups. Nearly all infants breathed spontaneously. Low Apgar scores, associated with resuscitative efforts, were attributable to meconium, umbilical cord entanglement, or a temporary problem associated with an FHR deceleration pattern that improved with supplemental oxygen. Nearly all infants were discharged in satisfactory condition, regardless of group allocation. The same reasons for prolonged nursery stays (hyperbilirubinemia, suspected sepsis, breathing complications, heart murmur) were present in both groups. Signs of postpartum endometritis were observed with similar frequency for those given PGE2 and those treated expectantly (8 cases [5.6%] versus 7 cases [4.6%]; P = .79).
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Discussion |
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A few studies provided information about the safety of outpatient cervical ripening. The low dose of PGE2 gel used in the current investigation was similar to doses recommended for outpatient cervical ripening. Those studies are difficult to compare because of differences in study design, subject selection, and specific dosage and delivery of PG. Our safety results concurred with those in randomized, masked studies by Elliott et al,13 using the same 0.5-mg intracervical dose; Smith et al14; and Sawai et al,15 using a 2.0–2.5-mg intravaginal dose. In each outpatient study, the changes of maternal adverse effects were no higher than with placebo, and the risks of uterine hyperstimulation (0.5% with the 0.5 mg of intracervical gel) or an abnormal FHR tracing were not different than with placebo.11,16 In the present study, there was one case (0.7%) of hyperstimulation, but cesarean was unnecessary. Findings from our investigation supported the limited data available on safety of a 30- to 40-minute observation period after administration.12,16 Any FHR abnormalities were expected to begin within 30 minutes of treatment.16 No adverse neonatal complications were associated directly with this low dose of outpatient PG.
Our study of well-dated, low-risk, multiparous pregnancies had sufficient sample size to detect benefit of outpatient cervical ripening in reducing the likelihood of repeat cesareans. Our results were similar to those of Smith et al14 and Sawai et al,15 who examined such outpatient therapy in women with no prior uterine surgeries. No differences between our groups were found for gestational age at delivery, route of delivery, or neonatal outcomes. In another study of low-risk pregnancies, O’Brien et al17 showed a median time from randomization to delivery of 4 days when 2 g of intravaginal PGE2 was used compared with 10 days in a placebo-controlled group. The gel was administered for 5 consecutive days unless labor occurred. The 7-day interval between doses in our study might have been too long because it did not significantly hasten cervical ripening or trigger spontaneous labor. That interval seemed to be more realistic for a clinicians rather than costly and time-consuming daily dosing. Our expectation of a 40% rate of labor onset after treatment was based on results of sponsored trials of single-application, preinduction treatment. The failure of treatment to result in that rate of labor onset was not likely caused by problems in PGE2 gel handling or transport because that was standardized and managed by the sponsoring pharmaceutical company.
We acknowledge certain limitations with this investigation. The control group was not treated with placebo, so double-masking was not done, but we do not believe that affected enrollment, outcome ascertainment, or antepartum care. The physicians responsible for the eventual intrapartum care were not masked to group allocations. It is possible that their treatment decisions, such as use of oxytocin, could have introduced bias into our results. Those physicians had little (if any) knowledge of the study, thereby minimizing the changes that such ascertainment or postrandomization selection bias would have affected our findings.
Our rate of repeat cesarean was high (PGE2 gel 42%, expectant treatment 45%). Reports over the past several years provided evidence that 20–40% of trials of labor resulted in repeat cesarean births.1 Rates of successful vaginal births varied because of nonclinical variables such as subject self-selection.18–20 Our subjects had unfavorable cervices and no obstetric or medical complications, and were willing to enroll at 39 weeks of a well-dated pregnancy.
We believe that this randomized study can assist clinical decisions. Our results confirmed the safety of serial applications of a low-dose, commercially prepared PGE2 gel for outpatient cervical ripening; however, weekly instillations of the gel did not shorten time until delivery or reducing repeat cesareans. Outpatient cervical ripening did not offer any maternal or neonatal advantages in this circumstance, so that additional time and cost associated with it are unjustified.
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Footnotes |
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Presented at the 46th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists, New Orleans, May 4, 1998.
This research was supported by grants to the participating institutions from Pharmacia & Upjohn Company. Kalamazoo MI, which markets prostaglandin E2 gel as Prepidil.
Received July 13, 1998. Received in revised form January 19, 1999. Accepted February 3, 1999.
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References |
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2. Notzon FC, Cnattingius S, Bergsjo P, Cole S, Taffel S, Irgens L, et al. Cesarean section delivery in the 1980s: International comparison by indication. Am J Obstet Gynecol 1994;170:495–504.[Medline]
3. National Center for Health Statistics. 1993 Summer: National hospital discharge survey, advance data from vital and health statistics. No. 264. Hyattsville, Maryland: National Center for Health Statistics, 1995.
4. Rosen M, Dickinson JC, Westhoff CL. Vaginal birth after cesarean: A meta-analysis of morbidity and mortality. Obstet Gynecol 1991; 77:465–70.
5. Flamm BL, Goings JR, Liu Y, Wolde-Tsadik G. Elective repeat cesarean delivery versus trial of labor: A prospective multicenter study. Obstet Gynecol 1994;83:927–32.[Medline]
6. Naef RW 3rd, Ray MA, Chauhan SP, Roach H, Blake PG, Martin N Jr. Trial of labor after cesarean delivery with a lower-segment, vertical uterine incision: Is it safe? Am J Obstet Gynecol 1995;172: 1666–73.[Medline]
7. Sakala EP, Kaye S, Murray RD, Munson LJ. Oxytocin use after previous cesarean: Why a higher rate of failed labor trial? Obstet Gynecol 1990;75:356–9.
8. Chez RA. Cervical ripening and labor induction after previous cesarean delivery. Clin Obstet Gynecol 1995;38:287–92.[Medline]
9. Trofatter KF Jr, Bowers SD, Gall SA, Kilam AP. Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel. Am J Obstet Gynecol 1985;153–268–71.
10. Noah ML, DeCoster JM, Fraser TJ, Orr JD. Preinduction cervical softening with endocervical PGE2 gel: A multicenter trial. Acta Obstet Gynecol Scand 1987;66:3–7.[Medline]
11. Egarter CH, Husslein PW, Rayburn WF. Uterine hyperstimulation after low-dose prostaglandin E2 therapy: Tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990;163:794–6.[Medline]
12. Sawai SK, O’Brien WF. Outpatient cervical ripening. Clin Obstet Gynecol 1995;38:301–9.[Medline]
13. Elliott JP, Clewell WH, Radin TG. Intracervical prostaglandin E2 gel. Safety for outpatient cervical ripening before induction of labor. J Reprod Med 1992;37:713–6.[Medline]
14. Smith MA, Swan L, Caruthers BS, Heaton C. Outpatient use of prostaglandin gel for ripening for the cervix and induction of labor. J Fam Pract 1990;30:656–64.[Medline]
15. Sawai SK, O’Brien WF, Mastrogiannis DS, Krammer J, Mastry MG, Porter GW. Patient-administered outpatient intravaginal prostaglandin E2 suppositories in post-date pregnancies: A double-blind, randomized, placebo-controlled study. Obstet Gynecol 1994;84: 807–10.
16. Rayburn, WF. Prostaglandin E2 gel for cervical ripening and induction of labor: A critical analysis. Am J Obstet Gynecol 1989;160:529–34.[Medline]
17. O’Brien JM, Mercer BM, Cleary NT, Sibai BM. Efficacy of outpatient induction with low-dose intravaginal prostaglandin E2: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995;173:1855–9.[Medline]
18. Hueston WJ, Rudy M. Factors predicting elective repeat cesarean delivery. Obstet Gynecol 1994;83:741–4.[Medline]
19. Goldman G, Pineault R, Potvin L, Blais R, Bilodeau H. Factors influencing the practice of vaginal birth after cesarean section. Am J Public Health 1993;83:1104–8.
20. Stafford RS. The impact of nonclinical factors on repeat cesarean section. JAMA 1991;265–59–63.
This article has been cited by other articles:
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  J.-M. Guise, M. Berlin, M. McDonagh, P. Osterweil, B. Chan, and M. Helfand Safety of Vaginal Birth After Cesarean: A Systematic Review Obstet. Gynecol., January 1, 1989; 103(3): 420 - 429. [Abstract] [Full Text]
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