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Obstetrics & Gynecology 2001;97:375-380
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Balloon Cervical Ripening With Extra-Amniotic Infusion of Saline or Prostaglandin E2: A Double-Blind, Randomized Controlled Study

DAN J. SHERMAN, MD, EUGENIA FRENKEL, MD, MORDECHAI PANSKY, MD, ELIAHU CASPI, MD, IAN BUKOVSKY, MD and RAMI LANGER, MD

From the Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Address reprint requests to: Dan J. Sherman, MD, Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, 70300 Zerifin, Israel, E-mail: dsherman{at}netvision.net.il


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To compare extra-amniotic infusion of diluted prostaglandin (PG) E2 solution with saline infusion in balloon cervical ripening and labor induction.

Methods: Women with pregnancy complications and Bishop scores of 3 or lower (n = 116) were assigned randomly to receive extra-amniotic infusion (1 mL/minute) of normal saline or PGE2 in saline (0.5 µg/mL) through a Foley catheter with a 30-mL inflated balloon. We induced labor using intravenous oxytocin only when labor had not developed by 6 hours after balloon expulsion. Analysis was by intent-to-treat. We assessed ripening efficiency and course of labor in women who had spontaneous balloon expulsion (n = 110) and trial of labor (n = 107), respectively.

Results: Ripening with PGE2 was associated with significantly shorter mean (± standard error of the mean [SEM]) time for balloon expulsion (4.7 ± 0.4 versus 6.5 ± 0.6 hours) and with significantly higher Bishop scores (P < .002), compared with ripening with saline. In the PGE2 group, rates of labor induction (15%) and oxytocin use (37%) were significantly lower than in the saline group (51% and 72%, respectively). The groups did not differ significantly in other labor abnormalities, labor duration, mode of delivery, birth weight, Apgar scores, and puerperal morbidity.

Conclusion: Cervical ripening by extra-amniotic balloon and PGE2 infusion is faster and more effective than by balloon and saline infusion, resulting in a higher rate of spontaneous labor and a lower rate of oxytocin use.

The unripe cervix is known to impede labor induction. Cervical ripening can be accomplished mechanically or medically using hormones. Numerous studies have shown locally applied prostaglandins (PG), principally PGE2 and PGE1, to increase cervical compliance and dilation.1,2 Prostaglandin E-induced cervical ripening is associated with enzymatic collagen degradation and increased water content in the cervical extracellular matrix. Independent of their local effects on the cervix, PGs also stimulate the myometrium, resulting in uterine contractions and possibly hyperstimulation.3 Mechanical methods of cervical ripening act primarily by dilating and stretching the lower uterine segment and cervix and usually are not associated with uterine contractions. Several studies suggested that cervical ripening with an extra-amniotic catheter balloon has advantages of simplicity, low cost, reversibility, and lack of systemic or serious side effects.4 Moreover, in recent randomized studies, the ripening efficacy of the catheter balloon was better or similar to that with local PGE2, PGE1, or PGF2-alpha.4–10 However, studies of balloon ripening with and without extra-amniotic saline instillation suggest that spontaneous labor follows in only 35–60% of women4 and it is associated with a significant rate of dysfunctional labor, oxytocin augmentation, and cesarean delivery because of halted labor progression.4,6,9,10

The combination of mechanical and pharmacologic methods of cervical ripening might be superior to each method alone, so we studied whether balloon ripening with extra-amniotic PGE2 infusion offered any advantages over normal saline infusion for cervical ripening and labor induction, possibly resulting in a higher rate of spontaneous unaugmented labor.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
The study was conducted in the Department of Obstetrics at Assaf Harofeh medical center between June 1991 and April 1992, with approval of the local institutional review board for human investigations. Eligible women had obstetric or medical indications for labor induction, intact membranes, singleton pregnancies, vertex presentations, and low Bishop scores (up to 3). Exclusion criteria were clinically detected vaginal infections, placenta previa, low-lying placenta, unexplained vaginal bleeding, nonvertex presentation, fetal death, uterine contractions (up to three contractions per 30 minutes), ruptured membranes, ultrasonic estimated fetal weight (EFW) at least 4300 g, prior cesarean delivery, or otherwise-scarred uterus. Women also were excluded if delivery could not be postponed to the morning hours when the study procedures were done.

Eligible women were admitted to the High-risk Pregnancy Unit and invited to participate. After signing an informed consent, they were randomized into two groups using consecutive, sealed opaque envelopes that contained computer-generated assignments to balloon ripening and continuous extra-amniotic infusion with saline or diluted PGE2 (Prostin E2, dinoprostone solution 10 mg/mL, Pharmacia & Upjohn N.V./S.A., Puurs, Belgium) solution (0.5 µg PGE2/mL saline) in identical bags. The study solutions were prepared and coded by a nurse who was not directly involved with patient care. Information on group assignment was guarded carefully by the senior investigator, who was not directly involved with patient care, but was notified only of serious adverse effects, which required unblinding of the solution used. Subjects and attending nurses and physicians who were directly involved in patient care and management decision making were masked to solutions used.

Cervical ripening was started in the early morning hours in the High-Risk Pregnancy Unit. Cardiotocographic monitoring was done for at least 1 hour before catheter placement. In both groups a 22-gauge Foley catheter was inserted through the external cervical os, and the balloon was inflated above the internal os with 30 mL sterile water. The study solution was infused through the catheter’s port at a constant rate of 1 mL/minute by an infusion pump. The catheter was neither clamped nor taped under traction, and the infused fluid was allowed to spill out into the vagina. Fetal heart rate (FHR) and uterine activity were monitored from initiation of the infusion until balloon expulsion. Attending nurses performed gentle traction on the catheter at hourly intervals to check for balloon expulsion. If balloon expulsion was not spontaneous by 24 hours from insertion, the balloon was deflated and extracted. Cervical scores11 were estimated just before balloon insertion and after expulsion by the same examiner. Subjects were observed for side effects relating to ripening procedure, pain, nausea or vomiting, uterine hyperstimulation (defined as six contractions in 10 minutes) or nonreassuring FHR. The study protocol dictated that extra-amniotic infusion be stopped when any side effects occurred. If complete recovery was not observed, the balloon was deflated and the woman was excluded from further study. Women in whom balloons were extracted before spontaneous expulsion were considered unsuccessful or incomplete ripenings.

Women were transferred to the Labor & Delivery Unit when spontaneous labor was diagnosed (regular, painful uterine contractions up to every 5 minutes). If spontaneous labor had not developed by 6 hours after balloon expulsion, labor was induced by intravenous oxytocin and amniotomy. A trial of labor was not given if, after expulsion, maternal or fetal condition mandated immediate delivery by cesarean, or if vaginal delivery was contraindicated. Routine intrapartum management was under the guidance of the obstetrician in charge of the Labor & Delivery Unit. Subjects were observed for dystocia, other intrapartum complications, oxytocin use, and postpartum morbidity.

We used the rate of spontaneous labor within 6 hours from balloon expulsion as the primary outcome variable, upon which the power calculation was based. Assuming a 50% rate of spontaneous labor, a calculated sample of 58 women per group was needed to show a 50% increase in rate of spontaneous labor with a power of 80% and alpha = .05. Secondary outcome variables included Bishop score after balloon expulsion, ripening time (ie, between balloon inflation and spontaneous expulsion), and labor duration (ie, between balloon expulsion in women with spontaneous labor or onset of intravenous oxytocin in women with induced labor, and delivery time), use of oxytocin, mode of delivery, and maternal morbidity. Intent-to-treat analysis was done on all randomized subjects. Ripening efficiency (Bishop score) of each method was evaluated only in women who had spontaneous balloon expulsion. We assessed labor progress and mode of delivery in women who had trials of labor. Continuous variables were analyzed by Student t test, ordinal measures by Wilcoxon rank-sum test, and categoric data by {chi}2 or Fisher exact test. P < .05 was considered statistically significant. Relative risk (RR) and 95% confidence interval (CI) were calculated when appropriate.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
During the study period, 145 women needed balloon cervical ripening, 29 of whom (20%) did not meet inclusion criteria, did not consent, or whose deliveries could not be postponed to the morning hours. The remaining 116 women were equally divided into two study groups similar in maternal age, parity, gestational age, preripening Bishop score, and the indications for induction of labor (Table 1Go). The balloon was deflated in six women (5%), and they were considered unsuccessful or incomplete ripenings (Figure 1Go). The remaining 55 women in each group had spontaneous balloon expulsions. Three of the PGE2 group had frequent and painful uterine contractions soon after the catheter’s dead-space was flushed. The contractions abated after cessation of extra-amniotic infusion and did not reappear when infusion was resumed 15–30 minutes later. No ominous FHR changes were associated with those episodes and all three women had normal vaginal deliveries with healthy newborns.


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  		Table 1. Subject Characteristics
 


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  		Figure 1. Study flow chart. *NR-FHR = nonreassuring fetal heart rate; Breech = change to breech presentation; PROM = premature rupture of the membranes; No expulsion = no spontaneous expulsion within 24 hours.

 
The mean (± standard error of the mean [SEM]) time required for spontaneous balloon expulsion in the PGE2 group was significantly shorter than the saline group (Table 2Go). Postballoon Bishop scores of the PGE2 group were significantly higher than the saline group (Wilcoxon rank-sum test, Z = 3.26, P < .002, Table 2Go). After balloon expulsion, one woman from the PGE2 group and two from the saline group were not subjected to trials of labor because of FHR abnormalities (Figure 1Go).


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  		Table 2. Bishop Scores and Ripening Time in Women With Spontaneous Balloon Expulsion
 
Labor was spontaneous in 85% and 51% of women with trials of labor after ripening with PGE2 and saline, respectively (P < .001, Table 3Go). The RR for induction of labor after balloon and saline were 3.3 times higher than after balloon and PGE2 (95% CI 1.65, 6.6). The characteristics of labor progress in women who received trials of labor were not significantly different between groups (Table 3Go), except for a higher rate of oxytocin use when the cervix was ripened by balloon and saline. There were no significant differences between groups in mode of delivery, mean birth weight, and rate of low Apgar scores (Table 4Go). Cesarean delivery rates among women who had trials of labor were 5.5% in the PGE2 group and 13.2% in the saline group (P = 0.2, RR 2.4, 95% CI 0.6, 8.7). The mean (±SEM) duration of labor was 12.1 ± 1.1 and 12.3 ± 1.0 hours in women who delivered vaginally after balloon ripening with PGE2 and saline, respectively (P = .90). However, the mean (±SEM) interval between the start of cervical ripening and delivery was significantly shorter (P < .03) in women who delivered after ripening with PGE2 (17.5 ± 1.3 hours) than saline (22.0 ± 1.6 hours). Among the PGE2 and saline groups, respectively, early postpartum hemorrhage or uterine atony were observed in four (7%) and one (2%) women, and puerperal fever in three (5%) and two (3%), differences that were not statistically significant.


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  		Table 3. Labor Progress in Women With Trial of Labor
 

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  		Table 4. Mode and Outcome of Delivery
 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study showed that continuous extra-amniotic instillation of PGE2 with balloon ripening results in a higher rate of spontaneous unaugmented labor than balloon and saline instillation. That effect might be related to direct stimulation of prostaglandins on the myometrium and an indirect effect by increasing myometrial concentrations of gap junctions and oxytocin receptors.12 We also found that balloon and PGE2 ripening resulted in significantly higher Bishop scores and shorter balloon insertion-expulsion and insertion-delivery intervals than balloon and saline.

Continuous extra-amniotic infusion of PGE2 to induce labor at term was first reported in 1974 by Calder et al,13 who used a plain Nelaton urethral catheter without a balloon. Only in later series14,15 was continuous extra-amniotic infusion of prostaglandins done, as in the present study, through a Foley catheter with the balloon inflated to 30–50 mL. Those studies13–15 used a wide range of infusion rates (0.33–3 µg PGE2/minute), and the initial infusion rate (0.33–0.5 µg PGE2/minute) was increased every 15–30 minutes until labor was established.13,15 That method never achieved wide acceptance and appears to have been abandoned. We speculated that better cervical ripening might be achieved without stimulating uterine contractions that can cause premature expulsion of the balloon; therefore, we used a constant and relatively low dose of PGE2 (0.5 µg/minute). Other studies that combined balloon ripening and extra-amniotic PGs used a single instillation into the extra-amniotic space of 0.25–0.5 mg PGE2 suspended in gel.16–18 That technique had better outcomes than ripening by intravenous oxytocin, oral, or intravaginal PGE2.16,18 As in the present study, labor became established and delivery occurred without further stimulation in 50–70% of the women.16–18 Other studies19 observed similarly that labor during ripening is more likely (OR 2.3) with extra-amniotic than vaginal administration of PGE2. Our rates of spontaneous labor and oxytocin use after ripening by balloon and PGE2 also compare favorably with the cumulative rates reported after ripening with vaginal PGE1 (misoprostol).20

Another advantage of our method was the ability to titrate the PG dose infused into the extra-amniotic space. Thus, the uterine hyperstimulation in three of our subjects after PGE2 infusion abated shortly after cessation of infusion. That kind of control might not be possible with single or repeated applications of a fixed PG dose.3 In several series in which endocervical PGE2 was used, uterine hyperstimulation occurred in 2–10% of subjects.21 Additionally, PGE1 had been associated with increased incidence of meconium staining and uterine hyperstimulation with and without FHR changes compared with ripening by PGE2 or balloon.6,20,22,23

Because mechanical and pharmacologic methods of cervical ripening might have different types of action, it might be postulated that a higher success rate and lower rate of side effects and complications can be achieved by combining them. That was shown in the present study and in other randomized studies that compared balloon plus intracervical PGE2 with PGE2 gel alone24 or balloon plus intravaginal PGE2 with intravaginal PGE1.23 However, those studies were not masked and there was a possibility of bias that affected clinical management and assessment of outcomes, whereas ours was a double-masked controlled trial (both methods were similar and attending staff was masked to group assignment). We also did preinduction ripening and management of labor and delivery in separate locations and by different staff members, obviating bias in clinical decision making and outcome assessment. However, masking might have been affected in our study by an expected increase in uterine contraction frequency during ripening with PGE2. No effort was made to quantitate uterine activity during cervical ripening and that information was not used for decision making unless hyperstimulation developed. The main shortcoming of our study was that we did not adhere to strict or consistent criteria between groups for use of oxytocin, but left that to the discretion of the obstetrician in charge. However, a review of patients’ charts found no major deviations from departmental guidelines.

No study has ever shown a significant decrease in the cesarean delivery rate as a result of the method of cervical ripening used. In the present study, there were fewer cesarean deliveries among women with balloon and PGE2 ripening compared with balloon and saline, and a 50% reduction in cesareans for halted progression in the PGE2 group, but those differences did not reach statistical significance. A power calculation (b = 0.8, a = 0.05) recommended a sample of 457 women per arm for those differences in cesareans done for halted progression to become statistically significant. Furthermore, numerous variables go into a decision for cesarean delivery, including preferences of patient and physician.

Maternal and fetal morbidity were similar in both groups and there were no differences in perinatal outcomes. Most side effects have already been reported with catheter balloon ripening,4–6,9 and it appears that the combination with extra-amniotic PGE2 is not associated with more frequent or serious side effects. Although this study was not large enough to exclude possible uncommon adverse effects, it appears that the combination of extra-amniotic balloon inflation and continuous infusion of diluted PGE2 solution offers a safe, reversible, and effective method for ripening the unfavorable cervix. Recommendation for the routine use of this technique awaits further clinical experience.


   Footnotes
 
PII S0029-7844(00)01168-6

Received July 14, 2000. Received in revised form October 18, 2000. Accepted November 9, 2000.


   References
Top
Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Calder AA. Review of prostaglandin use in labour induction. Br J Obstet Gynaecol 1997;104(suppl 15):2–7.

2. Keirse MJ. Prostaglandins in preinduction cervical ripening. Meta-analysis of worldwide clinical experience. J Reprod Med 1993;38: 89–100.[Medline]

3. Husslein P. Use of prostaglandins for induction of labor. Semin Perinatol 1991;15:173–81.[Medline]

4. Sherman DJ, Frenkel E, Tovbin J, Arieli S, Caspi E, Bukovsky I. Ripening of the unfavorable cervix with extraamniotic catheter balloon: Clinical experience and review. Obstet Gynecol Surv 1996;51:621–7.[Medline]

5. Sciscione AC, McCullough H, Manley JS, Shlossman PA, Pollock M, Colmorgen GH. A prospective, randomized comparison of Foley catheter insertion versus intracervical prostaglandin E2 gel for preinduction cervical ripening. Am J Obstet Gynecol 1999;180:55–60.[Medline]

6. Vengalil SR, Guinn DA, Olabi NF, Burd LI, Owen J. A randomized trial of misoprostol and extra-amniotic saline infusion for cervical ripening and labor induction. Obstet Gynecol 1998;91:774–9.[Abstract]

7. Orhue AA. Induction of labour at term in primigravidae with low Bishop’s score: A comparison of three methods. Eur J Obstet Gynecol Reprod Biol 1995;58:119–25.[Medline]

8. Goldman JB, Wigton TR. A randomized comparison of extra-amniotic saline infusion and intracervical dinoprostone gel for cervical ripening. Obstet Gynecol 1999;93:271–4.[Abstract/Free Full Text]

9. Guinn DA, Goepfert AR, Christine M, Owen J, Hauth JC. Extra-amniotic saline, laminaria, or prostaglandin E(2) gel for labor induction with unfavorable cervix: A randomized controlled trial. Obstet Gynecol 2000;96:106–12.[Abstract/Free Full Text]

10. Hemlin J, Moller B. Extraamniotic saline infusion is promising in preparing the cervix for induction of labor. Acta Obstet Gynecol Scand 1998;77:45–9.[Medline]

11. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266–8.[Free Full Text]

12. Chan WY, Berezin I, Daniel EE. Effects of inhibition of prostaglandin synthesis on uterine oxytocin receptor concentration and myometrial gap junction density in parturient rats. Biol Reprod 1988;39:1117–28.[Abstract]

13. Calder AA, Embrey MP, Hillier K. Extra-amniotic prostaglandin E2 for the induction of labour at term. J Obstet Gynaecol Br Commonw 1974;81:39–46.[Medline]

14. Miller AWF, Mack DS. Induction of labour by extra-amniotic prostaglandins. J Obstet Gynaecol Br Commonw 1974;81:706–8.[Medline]

15. Calder A, Embrey MP. Prostaglandins and the unfavourable cervix [letter]. Lancet 1973;2:1322–3.

16. Wilson PD. A comparison of four methods of ripening the unfavourable cervix. Br J Obstet Gynaecol 1978;85:941–4.[Medline]

17. Thiery M, Defoort P, Benijts G, Van Eyck J, Henray T, Van Kets H et al. Effectiveness of extra-ovular injection of prostaglandin E2 in tylose gel to ripen the cervix prior to elective induction of labor at term. Prostaglandins 1977;14:381–8.[Medline]

18. Stewart P, Kennedy JH, Hillan E, Calder AA. The unripe cervix: Management with vaginal or extra-amniotic prostaglandin E2. J Obstet Gynaecol 1981;4:90–3.

19. Keirse MJNC. Extra-amniotic vs vaginal PGE2 for cervical ripening. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews. London: BMJ Publishing Group, 1995.

20. 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.[Abstract]

21. Keirse MJNC. Endocervical PGE2 for cervical ripening. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and childbirth module of the Cochrane database of systematic reviews. London: BMJ Publishing Group, 1995.

22. Hofmeyr GJ, Gulmezoglu AM, Alfirevic Z. Misoprostol for induction of labour: A systematic review [see comments]. Br J Obstet Gynaecol 1999;106:798–803.[Medline]

23. Perry KG Jr, Larmon JE, May WL, Robinette LG, Martin RW. Cervical ripening: A randomized comparison between intravaginal misoprostol and an intracervical balloon catheter combined with intravaginal dinoprostone. Am J Obstet Gynecol 1998;178: 1333–40.[Medline]

24. Sullivan CA, Benton LW, Roach H, Smith LG Jr, Martin RW, Morrison JC. Combining medical and mechanical methods of cervical ripening. Does it increase the likelihood of successful induction of labor? J Reprod Med 1996;41:823–8.[Medline]




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