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Outpatient Cervical Ripening With Intravaginal Misoprostol

From the Department of Obstetrics and Gynecology, National Naval Medical Center, Bethesda, Maryland; Department of Obstetrics and Gynecology, Division of Maternal/Fetal Medicine, Naval Medical Center, Portsmouth, Virginia; Uniformed Services University of Health Sciences, Bethesda, Maryland; and Pharmacy Department, Naval Medical Center, Portsmouth, Virginia.

	Abstract

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Objective: To determine if outpatient cervical ripening using misoprostol can initiate labor within 48 hours of medication administration and to determine if time from medication administration to time of delivery is decreased using outpatient cervical ripening.

Methods: Uncomplicated singleton, vertex pregnancies at 41 weeks’ gestation or later with Bishop score of 4 or less were eligible for enrollment. Other inclusion criteria included intact membranes, less than eight uterine contractions per hour, a reactive nonstress test, and amniotic fluid index (AFI) over 5 cm. After randomization, 25 µcg of misoprostol or placebo was placed within the posterior vaginal fornix. Patients were continuously monitored for 4 hours, then discharged if not in active labor. Patients returned in 24 hours for a repeat administration of the respective medication. Patients not delivered within 48 hours were admitted for inpatient induction of labor. Statistical analysis was performed with the Fisher, Student t, ², and Mann-Whitney U tests, with P < .05 considered statistically significant.

Results: Among the 60 patients enrolled, 27 (45%) received misoprostol and 33 (55%) received placebo. The majority (24 of 27, 88.9%) of study group patients entered active labor within 48 hours after dosing, compared with 16.7% (five of 33) of placebo group patients (P < .001). The time from initial dose to delivery was significantly shorter in the misoprostol group (36.9 ± 3.8 compared with 61.3 ± 3.8 hours, P < .001).

Conclusion: Intravaginal misoprostol is effective for outpatient cervical ripening. No adverse effects were encountered, although further study is required to determine the safety of this treatment regimen.

Labor induction is one of the most commonly performed obstetric procedures, with up to 40% of all patients undergoing inpatient cervical ripening.¹ Postdate gestations account for approximately 10% of these labor inductions.² For cesarean delivery, nulliparous and multiparous patients who undergo labor induction are at 2.8- and 3.5-fold increased risk, respectively.¹ Postdate pregnancies are also associated with increased rates of oligohydramnios, intrauterine fetal demise, placental insufficiency, and meconium passage.^3–6

Several authors have attempted to accelerate cervical ripening in the outpatient setting with intravaginal application of prostaglandin E₂ gel either daily,^7,8 twice weekly,⁹ in conjunction with scheduled nonstress tests,^10,11 or at 38 weeks’ gestation.¹² Other studies have evaluated the efficacy of hydrophilic polymer of polyacrylonitrile¹³ and daily membrane stripping¹⁰ as outpatient cervical ripening modalities. To date, however, there have been no published studies that have employed misoprostol for this indication. Misoprostol is less expensive, easier to administer, and may yield better efficacy in the outpatient setting. Our objective was to determine if outpatient cervical ripening using intravaginal misoprostol can initiate labor within 48 hours of medication administration, and to determine if time from medication administration to time of delivery is decreased using outpatient cervical ripening.

	Materials and Methods

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This clinical study was conducted between December 7, 1997 and December 10, 1999 at Naval Medical Center, Portsmouth (Portsmouth, VA) and National Naval Medical Center (Bethesda, MD). The study protocol was approved by the Clinical Investigation and Review Department of each participating hospital prior to patient enrollment. In March 1998, the Food and Drug Administration (FDA) granted an investigational new drug application for off-label usage of misoprostol. All subjects were thoroughly counseled with respect to the potential risks, and written informed consent was obtained before study participation.

All gravid patients with an estimated gestational age between 41 weeks and 41 weeks, 6 days were eligible for study inclusion. Gestational age was determined using criteria of fetal heart tones as documented by nonelectronic fetoscope for greater than 20 weeks, or for greater than 30 weeks by Doppler; positive hCG (urine or serum) for at least 36 weeks; an ultrasound performed between 6–11 weeks or an ultrasound performed between 12–20 weeks. This confirmed the gestational age obtained by physical examination, clinical history, or last menstrual period. Other inclusion criteria were singleton gestation; intact membranes; Bishop score of 4 or less; uterine contractions of less than eight per hour; cephalic presentation; amniotic fluid index (AFI) over 5 cm; reactive nonstress test; and maternal age of at least 18 years but less than 50 years.

Exclusion criteria consisted of the following: multiple gestation; nonreactive nonstress test or AFI less than 5 cm; fetal malpresentation; estimated fetal weight over 4500 or under 2000 g as determined clinically or by ultrasonography; uterine contractions over nine per hour; ruptured membranes; placenta previa, vasa previa, or other unexplained vaginal bleeding; active herpes simplex lesion; hypersensitivity to prostaglandins; prior uterine surgery or previous cesarean delivery; evidence of intra-amniotic infection; severe asthma or cardiovascular disease; and renal or hepatic dysfunction.

The 25 µcg dosage form of misoprostol used in this study was prepared by the hospital’s inpatient pharmacy by dividing 100 µcg tablets in half. These pieces were again divided by hand into two approximately equal pieces and placed into sealed, light-protected unit dose concentration. Two doses of medication were then placed into a light-protected bottle and labeled with a randomization vial sequence number and expiration date. We chose a 25 µcg dose because this is the amount of misoprostol currently administered by our hospital for inpatient cervical ripening, and because we also hoped to minimize any risk of uterine hyperstimulation.

Dicalcium phosphate tablets, divided into five equal pieces by the inpatient pharmacy division, served as the placebo. The placebo was packaged and labeled as previously described for misoprostol and was visually indistinguishable from the study medication.

The master list for sequence randomization was generated and maintained by the inpatient pharmacy. The person who implemented the randomization process was not involved in patient enrollment, treatment, or evaluation. A computer-generated random number table, in a permuted block design, was used to determine the allocation sequence. Group assignment was concealed from the primary investigators until data analysis had been completed. Primary obstetric caregivers were also masked to study group allocation.

All outpatient dosing and observation occurred in the antepartum testing unit, or the triage area of labor and delivery. Prior to obtaining informed consent, all patients had a reactive nonstress test and AFI of greater than 5 cm. They were monitored for a minimum of 20 minutes and if contracting, monitored for a total of 60 minutes prior to receiving a dose of study medication. After a Bishop score was obtained, either placebo or misoprostol was placed into the patient’s posterior vaginal fornix. Study subjects were then observed for another 4 hours, with continuous fetal heart rate (FHR) and uterine activity monitoring. If there was evidence of ruptured membranes, active labor, nonreactive nonstress test, or positive contraction stress test, the patient was admitted to the hospital for further evaluation.

Patients subsequently returned for 24 hours later and underwent repeat evaluation of the FHR and AFI. A Bishop score was again assigned. Patients were maintained within the same study group to which they were initially randomized. If there was a nonreactive nonstress test, positive contraction stress test, or oligohydramnios (AFI less than 5 cm), labor was induced. Redosing of either placebo or misoprostol was allowed if the Bishop score was less than 9 and there were eight contractions or less per hour. After a 4-hour period of continuous maternal and fetal observation, patients were discharged if there was no evidence of labor or rupture of membranes.

Twenty-four hours later, patients returned to the hospital for a final evaluation. If the Bishop score was under 6 and there were less than eight contractions per hour, preinduction cervical ripening with 25 µcg of intravaginal misoprostol was performed. If the cervical Bishop score was greater than 6, intravenous oxytocin was administered. The study investigators were not involved with the patient’s inpatient cervical ripening or intrapartum labor management.

The primary outcome measure was the number of inpatient inductions needed by study day 3. Sample size calculations were performed assuming that 50% of patients in the placebo group would deliver within 48 hours of study entry. Increasing this number by 50% (ie, to 75% delivering within 48 hours) was deemed to be clinically important. Assuming a type I error of 0.05 and type error of 0.2 (power = 80%), we determined that 58 patients per arm would be needed. Interim data analysis was performed at intervals of 30 patients to observe any possible trend toward adverse outcomes.

All patients were analyzed on an intent-to-treat basis. Using StatView 4.5 (Abacus Concepts Inc., Berkeley, CA), parametric data were analyzed with two-tailed unpaired t tests while ², Fisher exact, and Mann-Whitney U tests (where appropriate) were employed for nonparametric data. P < .05 was considered statistically significant.

	Results

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Among the 60 enrolled patients, 27 (45%) received misoprostol and 33 (55%) received placebo. No patient disenrolled once entering the study and all patients returned for scheduled follow-up visits and medication administration as described in the study protocol. Of the 45 patients requiring two doses, 37 (82.2%) patients had the same examiner assigning the Bishop score.

As listed in Table 1, the two groups, at time of enrollment, were similar with respect to maternal age, gravidity, parity, and estimated gestational age. There were no statistically significant differences between the study and control patients with respect to birth weight, mode of delivery, incidence of meconium passage, or need for neonatal intensive care unit admission. No infant in either group had a 5-minute Apgar score of less than 7. Indications for cesarean delivery in the intravaginal misoprostol group were nonreassuring FHR monitoring (n = 1) and arrest of dilatation (n = 3). Among the eight placebo patients who underwent cesarean delivery, the indications were nonreassuring FHR monitoring (n = 1), failed induction (n = 1), arrest of dilation (n = 5), and arrest of descent (n = 1).

A patient who received a single dose of intravaginal misoprostol experienced a 4-minute spontaneous deceleration of FHR to 100 beats per minute, 30 minutes after dosing. There was spontaneous resolution of this abnormality, and the patient progressed uneventfully into active labor and delivered vaginally without complications. Approximately 30 minutes after the initial dose of misoprostol, another patient had spontaneous rupture of membranes and a 4-minute FHR deceleration to 90 beats per minute. Spontaneous recovery of the abnormal FHR tracing was noted and the patient’s vaginal delivery was complicated only by shoulder dystocia. Tachysystole (greater than five contractions in two consecutive, 10-minute periods) without associated FHR changes was found in a misoprostol patient on study day 1. She was observed overnight on labor and delivery and experienced spontaneous resolution of the abnormal contraction pattern. One patient who had received the placebo experienced a 3-minute spontaneous deceleration of FHR to 80 beats per minute immediately after admission for the scheduled inpatient induction on study day 3. After birth, the neonate experienced persistent pulmonary hypertension that required extracorporeal membrane oxygenation therapy. Finally, one patient in the placebo arm had a brief deceleration of FHR to 100 beats per minute after the initial dosing.

	Discussion

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Using the key words misoprostol, cervical ripening, cervical priming, induction, outpatient, and ambulatory cervical ripening, we performed a MEDLINE search of English-language articles published between 1966 and 1999. No publications were found that described an outpatient protocol for cervical ripening with misoprostol. In our trial, most of the patients who were randomized to daily administration of a single 25 µcg dose of intravaginal misoprostol entered active labor within 48 hours of dosing, thereby effectively reducing the number of inpatient inductions. The overall time from the first dose of intravaginal misoprostol to delivery was also significantly shortened compared with the placebo group.

Physiologic spontaneous cervical ripening is a process that normally occurs from several days to weeks. Outpatient cervical ripening is used to recapitulate this process, providing time for the chosen agent to effect cervical change. Other potential benefits of outpatient cervical ripening include a decreased number of inpatient labor inductions, decreased cost of antepartum testing, reduced inpatient hospitalization, and convenience for both physician and patient.

Prior studies have also shown a significant reduction in the number of inpatient inductions. In McKenna’s recent study, 50% of women who received a single dose of intracervical 0.5 mg prostaglandin E₂ gel, delivered within 2 days, compared with 16% of the placebo group.¹² Magann’s study evaluated daily placement of dinoprostone in pregnancies that reached 41 weeks’ gestation with a Bishop score of 4 or less. He found that only 20% of patients required induction 1 week later compared with 62.8% of control patients.¹⁰ Application of prostaglandin E₂ at the time of scheduled antepartum testing in postdates pregnancies decreased the induction rate from 54.6% to 30% among patients with intermediate Bishop scores.¹¹ Daily, low-dose, patient-administered intravaginal prostaglandin E₂ suppositories have shown to decrease the gestational length and cost of uncomplicated postdates pregnancies.⁷ Finally, nearly 40% of the patients studied by Elliot et al entered active labor prior to their scheduled inductions.⁸

Interim analysis, performed midway through the study, revealed that intravaginal misoprostol had a far greater effect on our outcome measure than had been initially anticipated in the a priori power calculation. By decreasing the number of inpatient inductions on study day 3 from 84.8% to 11.1%, this study had a power of greater than 95% to detect a statistically significant difference. Although there were no adverse fetal outcomes among patients who received intravaginal misoprostol, the sample size was insufficient to detect these rare events. Furthermore, based upon the observed rates of cesarean delivery in each study arm, a total of 598 patients would have been required to detect a statistically significant difference.

This protocol could also be used for other outpatient cervical ripening candidates such as timed delivery for known fetal anomalies, stable medical conditions which documented lung maturity, fetuses with borderline fetal growth restriction, a prior history of intrauterine fetal demise, or multiple gestations.¹⁴ Based on our findings, we believe that outpatient cervical ripening with intravaginal misoprostol is a reasonable alternative to the customary management of postdates pregnancy.

	Footnotes

 
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense, Department of the Navy, or the United States Government.

This study was supported by the Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program (grants CIP #98–006 and #B99–005).

PII S0029-7844(00)01034-6

Received December 21, 1999. Received in revised form May 1, 2000. Accepted May 18, 2000.

	References

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8. Elliot 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]

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