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Prostaglandin E₂ Cervical Ripening Without Subsequent Induction of Labor

From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.

	Abstract

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Objective: To determine whether outpatient administration of intracervical prostaglandin (PG) gel decreases the E₂ interval to delivery and duration of labor.

Methods: A randomized, double-blind, placebo-controlled trial compared the intracervical placement of 0.5 mg PGE₂ gel with placebo in 61 pregnant women at 38 weeks’ or greater gestation with Bishop scores less than 9. Transvaginal cervical length, fetal fibronectin, and Bishop score were assessed before gel placement. Subjects were then allowed to go into spontaneous labor unless an indication for induction developed.

Results: Thirty women were assigned to PGE₂ and 31 to placebo. There were no significant demographic differences between the groups and there were no differences in cervical length, fetal fibronectin status, or Bishop scores. Fifteen women in the PGE₂ group and five in the placebo group went into labor and delivered within the first 2 days after gel placement (P = .007). The median interval to delivery was significantly shorter in the PGE₂ group, at 2.5 days, compared with placebo, at 7 days (P = .02). Nulliparas in the PGE₂ group had a median interval to delivery of 2 days, compared with 7 days for nulliparas receiving placebo (P = .03). Active phases of labor were significantly shorter in the PGE₂ group and for women with a negative fetal fibronectin test who received PGE₂.

Conclusion: Outpatient administration of intracervical gel shortened intervals to delivery and shortened PGE₂ labor.

Labor is often induced at term for several fetal and maternal indications such as post-term pregnancy, fetal growth restriction, and insulin-dependent diabetes. Labor is also induced electively when there is suspicion of a large or small for gestational age fetus, when transient hypertension or gestational diabetes is present, or solely for convenience, despite ACOG’s condemnation of this practice. Attempted induction with a poor cervical score has been associated with failure of induction, prolonged labor, and increased cesarean delivery rates.^1–3 Induction with a poor cervical score often requires cervical ripening with a chemical or mechanical agent to improve the score.⁴

Cervical ripening is a complex process of softening, dilation, and effacement of the cervix. Ripening occurs naturally over several weeks, but is performed much more quickly when induction is needed. Typical induction protocols call for ripening of the cervix 12–24 hours before oxytocin administration.⁴ More than 70 prospective trials involving more than 5000 pregnancies have established the clinical effectiveness and safety of prostaglandin (PG) E₂ gel for preinduction ripening,⁵ and the safe use of outpatient administration of PGE₂ gel has been described in a number of reports.^6–10

Prostaglandin E₂ may initiate the natural ripening process and facilitate spontaneous labor when labor is not subsequently induced. We sought to determine whether the administration of a single dose of intracervical PGE₂ gel would affect the natural course of pregnancy. We hypothesized that shorter gestations and labors would result from intracervical placement of PGE₂ gel in women at term with unfavorable cervices.

	Materials and Methods

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This was a randomized, double-blind, placebo-controlled trial. The protocol was approved by the Ohio State University Human Subjects Committee, and written informed consent was obtained from each subject before participation. A research nurse screened patient charts at the 36-week prenatal visit and asked eligible women to participate. Screening criteria consisted of maternal age of at least 18 years, an unfavorable cervix for induction (Bishop score 8 or less), a well-dated pregnancy, and lack of a current indication for induction of labor. Women with multiple gestations, contraindications to trial of labor, insulin-dependent diabetes, or chronic hypertension were not eligible. Obstetric dating was per ACOG’s criteria for assessment of gestational age.¹¹

Pregnant women who completed at least 37 gestational weeks from their last menstrual period were randomized to receive outpatient intracervical administration of 0.5 mg PGE₂ gel or placebo, which consisted of an inert hydroxyethyl cellulose gel. Randomization was done by the Investigational Drug Pharmacy at The Ohio State University Hospitals with a random-number table,¹² and a sequential study number was assigned to each subject. The investigators were masked to group assignments.

The PGE₂ gel was prepared by heating a 20-mg PGE₂ suppository (Prostin E₂; The Upjohn Co., Kalamazoo, MI) and 20 mL of hydroxyethyl cellulose gel (K-Y Jelly; Johnson & Johnson, New Brunswick, NJ) in a double boiler to 37C.¹³ The gel was stirred continuously until evenly mixed to obtain a concentration of 0.5 mg/mL. Sterile technique was maintained throughout gel preparation, and care was taken to ensure a homogeneous mixture. Placebo consisted of the hydroxyethyl cellulose gel alone. A small amount of inert coloring agent (1% methylene blue) was added to the PGE₂ gel and the placebo to produce an identical appearance. A 1.5-mL volume of PGE₂ gel or placebo was drawn into identical 3-mL syringes and stored in the pharmacy refrigerator at 20C. Each batch of PGE₂ gel and placebo was stored for up to 4 weeks, at which time the remaining aliquots were discarded and a new batch was prepared.

Women who agreed to participate were scheduled to return for gel administration after they reached 38 weeks’ gestation. All outpatient gel administration and cervical examinations were performed by one of two investigators. Prenatal care was continued by the women’s physicians, who were often aware of their study participation, although masked to whether they received placebo or PGE₂ gel. Obstetric decisions regarding induction and management were made without input from the investigators.

A nonstress test (NST) was done immediately before gel administration. A specimen for fetal fibronectin was collected from the posterior vaginal fornix and external cervical os, placed in a sterile antiprotease buffer containing bovine serum albumin, and then frozen at -80C until assayed by previously described methods.¹⁴ Fetal fibronectin concentrations greater than 50 ng/mL were considered positive. If the women complained of leakage of fluid or if pooling of vaginal fluid was observed, they were evaluated for rupture of membranes by standard fern and nitrazine tests. Transvaginal sonography then was used to measure cervical length, a digital cervical examination was performed, and a Bishop score was assigned. Women were excluded at this point if the NST was nonreactive or nonreassuring, if rupture of membranes was present, or if the Bishop score exceeded 8.

A sterile speculum examination was performed, and 1.0 mL of PGE₂ or placebo gel was inserted intracervically under direct visualization through a flexible silicone 14-gauge catheter attached to the syringe. Subjects were monitored continuously for 1 hour after gel administration. If the woman had regular contractions after 1 hour, she was sent to labor and delivery for evaluation; otherwise she was discharged home. Admission, delivery, and neonatal outcome data were recorded when the subjects were admitted for active labor, premature rupture of membranes, or induction. Duration of labor was defined strictly as the time from initiation of the active phase of labor to completion of the second stage.

Statistical and data analyses were performed with JMP Statistical Discovery Software (SAS Institute Inc., Cary, NC) and Microsoft Excel (Microsoft Corporation, Redmond, WA). Alpha of .05 was considered significant. A power analysis determined that to achieve significance with a beta of 0.2, 44 subjects (22 per group) were required to find a difference in the mean length of gestation of 7 days (± standard deviation of 8 days). The Levene test was applied on continuous variables to test for equal variances. When the variances were equal, Student t test was used; otherwise Welch analysis of variance was done.¹⁵ Wilcoxon rank-sum test was used for nonparametric analyses. Fisher exact test was used for comparisons involving two groups of nominal or ordinal variables.

	Results

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The study took place from February 1997 to May 1998. Sixty-five eligible women consented to participate and were randomized. The participation rate was 3.9% of the full-term deliveries during the study period. Four women were excluded at the time of planned gel administration: two because of nonreassuring fetal heart rate tracings, one because of ruptured membranes, and one because the Bishop score was greater than 8. Thirty subjects received PGE₂ gel and 31 received placebo. Complete outcome data were collected on all 61 participants. Table 1 presents the demographic and preapplication characteristics. There was no significant difference between the groups in mean age, race, percentage of nulliparous women, gestational age, quantitative or qualitative cervicovaginal fetal fibronectin, Bishop score, or cervical length.

Table 3 contains the delivery data. The duration of labor was significantly shorter in women who received PGE₂ gel and in women who received PGE₂ gel with negative fetal fibronectin. When women who delivered within the first 2 days were excluded from the analysis, the median length of labor and interquartile range were still shorter in the PGE₂ group (n = 15; 5.6 hours, range 4.2–9.5) than in the placebo group (n = 26; 9.4 hours, range 6.0–13.1), but this did not reach statistical significance (P = .08). There was no significant difference between the groups in cesarean delivery rates, infant birth weights, or the number of attempted or successful vaginal births after cesarean. The indications for cesarean delivery were secondary arrest of descent and dilation (two in each group) and nonreassuring fetal heart rate tracings (two PGE₂, one placebo).

	Discussion

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Our trial found that outpatient administration of PGE₂ gel at term shortened gestation and the duration of active labor when spontaneous labor was allowed to develop. Fifty percent of the women receiving PGE₂ gel delivered within 2 days of gel placement, compared with 16% of the placebo group. When those who delivered within 2 days were excluded, the durations of gestation were not different between the groups. This suggests that stimulation of uterine contractions with cervical ripening may be part of the mechanism responsible for shorter intervals to delivery in the PGE₂ group.

Enhancing the natural process of cervical ripening has many potential benefits, including a decrease in the number of post-term pregnancies, decreased need for elective induction in many patients, and an increased rate of success when induction is performed. Prostaglandin E₂ gel has been shown to decrease the duration of gestation and the induction rate when administered to women who are undergoing antepartum testing in post-term pregnancies.^10,16 Administration of PGE₂ gel without subsequent induction may also be an acceptable alternative for women who may be induced for debatable indications, such as suspected macrosomia, small size for gestational age (but without growth restriction), and gestational hypertension without proteinuria. Our study provides a basis for further investigation into the management of the unripe cervix at term. It was not designed to evaluate the effects of outpatient administration of PGE₂ gel on the rates of induction or cesarean delivery, and a much larger trial would be needed to achieve the power to do so.

	Footnotes

 
The opinions and conclusions in this article are those of the authors and are not intended to represent the official position of the Department of Defense, United States Air Force, or any other government agency.

PII S0029-7844(99)00244-6

Received October 27, 1998. Received in revised form December 14, 1998. Accepted January 7, 1999.

	References

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4. American College of Obstetricians and Gynecologists. Induction of labor. ACOG technical bulletin no. 217. Washington, DC: American College of Obstetricians and Gynecologists, 1995.

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12. Geigy JR. Scientific tables. 6th ed. Ardsley, New York: Geigy Pharmaceuticals, 1962.

13. Lorenz RP, Demers LM. Preparation of prostaglandin E2 vaginal gel for preinduction ripening of the cervix. Prostaglandins Leukot Med 1984;14:47–53.[Medline]

14. Lockwood CJ, Senyei AE, Renate Dische M, Casal D, Shah KD, Thung SN, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991;325:669–74.[Abstract]

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