International Journal of Gynecology and Obstetrics (2006) 94, 91 95

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CLINICAL ARTICLE

Sublingual vs. vaginal misoprostol for induction of labor

F.E.L. Feitosa a,*, Z.S. Sampaio a, C.A. Alencar Jr a, M.M.R. Amorim b, R. Passini Jr c
Maternidade-Escola, Universidade Federal do Ceara , Fortaleza, State of Ceara , Brazil b Instituto Materno-Infantil de Pernambuco, Recife, State of Pernambuco, Brazil c Department of Obstetrics and Gynecology, School of Medicine from Universidade Estadual de Campinas (Unicamp), State of Sa o Paulo, Brazil
Received 21 November 2005; received in revised form 10 April 2006; accepted 11 April 2006
a

KEYWORDS
Misoprostol; Sublingual misoprostol; Vaginal misoprostol; Induction of labor; Effectiveness; Safety

Abstract Objective: To compare sublingual with vaginal misoprostol for the induction of labor. Methods: This double-blind clinical trial randomized 150 women to receive every 6 h 25 Ag of sublingual misoprostol and vaginal placebo or 25 Ag of vaginal misoprostol and sublingual placebo. Maternal and neonatal outcomes were analyzed and risk ratios (RRs) with 95% confidence intervals (CIs) calculated. The significance level was 5%. Results: Vaginal delivery rates were 57% in the sublingual group and 69% in the vaginal group (RR, 0.8; 95% CI, 0.61.1). There were 11 cases of fetal distress in the sublingual group and 4 cases in the vaginal group (RR, 2.7; 95% CI, 0.98.2). There were no significant differences in the number of doses needed, interval between first dose and delivery, incidence of contractility disturbances, or neonatal results. Conclusion: The administration of misoprostol 25 Ag by the sublingual route was neither more effective nor safer than the same dose administered vaginally. D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
The use of misoprostol for labor induction with a live fetus was first described in 1992, in the pioneering study by Margulies et al. [1]. Since then, decreasing doses have been proposed and labor

* Corresponding author. Address: Rua Batista de Oliveira, 1000 apto. 1401-Bairro Coco , Fortaleza, Ceara , CEP 60176-030, Brazil. E-mail address: edsonlucena@secrel.com.br (F.E.L. Feitosa).

0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2006.04.031

92 induction with misoprostol has been favorably compared with other methods [2,3]. Currently, to reduce the incidence of contractility disturbances and neonatal complications, 25 Ag is the recommended dose of vaginal misoprostol for induction of labor [4]. Recent studies have suggested the possibility of sublingual administration of misoprostol for labor induction [57]. In these studies Cytotec tablets (Searle Pharmaceuticals, Ontario, Canada) were used. Originally manufactured for oral use in 100 or 200 Ag doses, these tablets had to be broken in smaller pieces to achieve the 25 Ag dosage. In Brazil, vaginal tablets containing 25 Ag of misoprostol have been commercially available since 1998. Until recently, using the LILACS, Medline, Scielo, and Cochrane Library data bases, only 2 randomized studies comparing the sublingual and vaginal routes for induction of term labor could be found [8,9]. A recent meta-analysis comparing the effects of different doses of misoprostol (50 Ag or higher) administered orally, vaginally, and sublingually found no statistically significant differences between the effectiveness of these routes, and the authors suggested that double-blind randomized studies should be performed, with sufficient sample sizes to allow for adequate extrapolation of the results [10]. The present study was carried out to test the effectiveness and safety of 25 Ag tablets of misoprostol sublingually every 6 h for the induction of term labor, compared with the same dose administered vaginally.

F.E.L. Feitosa et al. bo were specifically manufactured for the study. They had a pleasant taste and fast dissolution, and they were much smaller than the vaginal tablets. The placebo vaginal tablets had the same appearance as the marketed Prostokos vaginal tablets. The tablets were placed in pouches identified as sublingual (SL) or vaginal (V) and then stored in boxes numbered from 1 to 150. Each box contained one pouch with vaginal misoprostol and another with sublingual placebo, or vice versa. Only the responsible pharmacist had knowledge of the content of each pouch and each box. The boxes were numbered according to previously generated randomization numbers using Epiinfo statistical software, version 6.04 (available from the Centers for Disease Control, Atlanta, GA, USA). A blocked randomization was made to assure that the groups were of equal size [11]. Each participant received 1 sublingual and 1 vaginal tablet, only 1 of them containing misoprostol. The administration was repeated every 6 h until 3 or more uterine contractions of 40 s duration occurred over minutes, or when the maximum of 4 doses (i.e., 100 Ag) was reached. In the absence of active labor 6 h after administration of the last dose of misoprostol, failed induction was reported and cesarean section was performed. Fetal auscultation every 15 min was performed during labor in all patients, before, during, and after contractions. Cardiotocography was performed every 2 h or at shorter intervals at the discretion of the attending obstetrician. The uterine activity was clinically assessed every 30 min. The primary outcome measure was vaginal delivery rate. Demographic characteristics and indications for the induction of labor were analyzed. Secondary outcomes included the time from first misoprostol administration to initiation of labor and to delivery; duration of labor; number of misoprostol doses administered, and need for augmentation of labor with oxytocin. Adverse effects included uterine contractility disturbances (tachysystole and hyperstimulation syndrome), gastrointestinal symptoms such as nausea, vomiting, and diarrhea, and hyperthermia. Perinatal outcomes analyzed were fetal heart rate (FHR) changes during labor, intrapartum meconium passage, intrapartum fetal death, Apgar scores at 1 and 5 min, and newborn admission in the intensive care unit (NICU). Tachysystole was defined by the presence of at least 5 uterine contractions in 2 consecutive 10 min periods. Hyperstimulation syndrome was defined as tachysystole and/or hypertonus on cardiotocography, with fetal heart rate (FHR) alterations such as bradycardia (FHR b 110 bpm), late decelerations,

2. Material and methods

A double-blind randomized clinical trial was conducted in 2 hospitals of the northeast region of Brazil between June 2004 and March 2005. The research ethic boards of both hospitals approved the study. All volunteers signed an informed consent form. Inclusion criteria were the following: singleton pregnancy, gestational age of 37 weeks or greater, live fetus, cephalic presentation, estimated sonographic fetal weight less than 4000 g, amniotic fluid index greater than 5 cm, normal antepartum non-stress test results, and Bishop score of 6 or less. Women were excluded in cases of fetal malformations, intrauterine growth restriction, previous uterine scars, premature rupture of membranes, or any contraindication to vaginal delivery. The tablets for sublingual administration containing 25 Ag of misoprostol (Prostokos; Hebron S/A Ind. Quimicas e Farmace uticas, Caruaru, Brazil) or place-

Sublingual vs. vaginal misoprostol for induction of labor and/or loss of fetal heart beat variability [12]. The occurrence of any of these abnormal events defined fetal distress [13]. The 73.8% vaginal delivery rate with sublingual misoprostol published in a 2002 study by Shetty et al. [6] was used for sample size calculation. With an a error of 5% and 80% power, a sample size of 138 women was needed to detect a 20% difference between the groups [14]. A total of 150 women were randomized. All women underwent the labor induction protocols at the participating hospitals. There were no withdrawals or exclusions post randomization, and all women received the originally assigned treatment. Statistical analysis was performed using the statistical package SAS/STAT, version 8.2 (SAS Institute, Cary, NC, USA). The statistician had access to the groups denomination (A or B) but was unaware of the kind of tablet used in each group. The randomization code was broken only after the results of the analysis were recorded. A significance level of 5% was adopted. Risk ratio (RR) and 95% confidence interval (CI 95%) were calculated to assess the magnitude of the association between outcomes and route of misoprostol administration, and vaginal misoprostol the reference category.

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3. Results
There were no significant differences between groups regarding maternal age, parity, gestational

age, or indication for the induction. Prolonged pregnancy (49% of participants in the sublingual group and 39% in the vaginal group, respectively) and hypertensive syndromes (36% in the sublingual group and 48% in the vaginal group) were the main indications for labor induction. Vaginal delivery was achieved in 57% participants in the sublingual group and in 69% in the vaginal group, but the difference did not reach statistical significance (RR, 0.8; 95% CI, 0.61.1) (Table 1). The number of misoprostol doses used was similar in both groups. About 21% of the women who received misoprostol sublingually and 24% of those who received misoprostol vaginally needed only 1 dose for initiation of labor. There were no significant differences between the 2 groups regarding latency time; time from induction to delivery; number of deliveries achieved in fewer than 12 h, within 12 h, within 24 h, and after 24 h; need for oxytocin augmentation; and failed labor induction (Table 1). The rates of contractility disturbances, such as tachysystole and hyperstimulation, were similar in the 2 groups. The main indications for cesarean section were dystocia and fetal distress in the sublingual group and failed labor induction in the vaginal group. Although the number of cesarean sections for fetal distress was almost 3 times greater in the sublingual group, the difference did not reach statistical significance (Table 1). Maternal adverse effects such as nausea, vomiting, diarrhea, and hyperthermia were similar in the 2 groups. There were also no significant differences between the groups regarding meconium-stained

Table 1
Variable

Doses and routes of misoprostol administration and intrapartum results

Sublingual misoprostol n (%) (21) (20) (16) (43) (32) (49) (19) (57) (35) (13) (9) (4) (15) (15) (13) Vaginal misoprostol n 18 19 10 28 14 27 11 52 26 11 5 1 6 4 11 2 (%) (24) (25) (13) (37) (27) (52) (21) (69) (35) (15) (7) (1) (8) (5) (15) (2) RR (95% CI)

Misoprostol 25 Ag (1 dose) Misoprostol 50 Ag (2 doses) Misoprostol 75 Ag (3 doses) Misoprostol 100 Ag (4 doses) Vaginal delivery b 12 h Vaginal delivery 1224 h Vaginal delivery N 24 h Vaginal delivery Oxytocin use Failed induction Tachysystole Hyperstimulation Indications for CS Dystocia Fetal distress Failed induction Impending eclampsia

16 15 12 32 14 21 8 43 26 10 7 3 11 11 10 0

0.9 (0.51.6)* 1.1 0.9 0.9 0.7 1.0 0.9 1.4 3.0 (0.62.2) (0.61.5) (0.32.0) (0.51.0) (0.61.7) (0.42.0) (0.44.0) (0.328.1)

1.8 (0.74.8) 2.7 (0.98.2) 0.9 (0.42.0) Not estimated

Abbreviations: CI, confidence interval; CS, cesarean section; RR, relative risk. * Calculated for 1 dose and more than 1 dose.

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Table 2
Variable

F.E.L. Feitosa et al.

Misoprostol administration route and maternal side effects and perinatal outcomes
Sublingual misoprostol n % 7 3 1 1 16 13 13 1 Vaginal misoprostol n 6 2 1 1 13 7 11 2 1 % 8 3 1 1 17 9 15 3 1 0.9 1.0 1.0 1.0 (0.41.7) (0.32.7) (0.24.0) (0.34.0) RR (95% CI)

Adverse effect Nausea Vomiting Hyperthermia Diarrhea Perinatal outcome Intrapartum meconium FHR changes Apgar score b 7 at 1 min Apgar score b 7 at 5 min NICU admission

5 2 1 1 12 10 10 0 1

0.9 (0.61.4) 1.2 (0.71.8) 0.9 (0.51.5) Not estimated 1.0 (0.24.0)

Abbreviations: CI, confidence interval; FHR, fetal heart rate; NICU, neonatal intensive care unit; RR, relative risk.

amniotic fluid, FHR changes, Apgar scores less than 7 at 1 and 5 min, or in the need for admissions to NICU (Table 2).

4. Discussion
Because plasma levels of misoprostol and the area under the curve are significantly greater when the same dose is administered sublingually rather than vaginally, the sublingual route could be expected to me more effective. That expectation, however, was not confirmed by the findings, as the proportion of vaginal deliveries within 12 h of administration was only slightly higher in the sublingual group. None of the other indicators of effectiveness were found to be better in the sublingual group. There was a 12% difference in the vaginal delivery rate in favor of the vaginal route. Although this difference did not reach statistical difference, it is not certain that it does not exist, considering that the sample size allowed to distinguish as significant differences of 20% or greater. Studies performed by Caliskan et al. [8] and Moraes-Filho et al. [9] with doses higher than 25 Ag found no differences in rates of vaginal delivery, fetal distress, or successful induction between the vaginal and sublingual groups. The patterns of plasma levels achieved by the 2 routes suggest the possibility of a greater risk of hypercontractility with sublingual administration. This was not observed, however, except for the non-statistically significantyet considerabledifference in the numbers of cesarean sections due to fetal distress. Again, the risk for this event increased 2.7-fold with the use of sublingual misoprostol. This finding does not allow to affirm that the 2 routes of administration have the same effects, although it does not allow claim that the effects are different. Thus, only new randomized

double-blind studies with larger sample sizes can clarify this issue. Nevertheless, the apparent difference in numbers of cesarean section for fetal distress in this study is not consistent with a complete lack of difference in the incidence of hypercontractility, meconium staining of the amniotic fluid, low Apgar score, and NICU admission. Thus, the sublingual route can be considered as safe as the vaginal route for administration of misoprostol for the induction of labor. It is interesting to note that in this study, almost all the difference in vaginal deliveries (in 9 participants) can be explained by the difference in numbers of CS for fetal distress (in 7 participants). Failed labor inductions occurred in both groups (13% in the sublingual and 15% in the vaginal group) but without statistical significance. The failed induction rates were lower in the study by MoraesFilho et al. [9], (10.3% and 4.9% for the sublingual and vaginal groups, respectively), but the authors continued misoprostol administration for 48 h, suggesting that prolonging treatment could improve the success rate. This is the first randomized, double-blind, controlled clinical trial of these 2 routes of administration that used a specially manufactured 25 Ag tablet of misoprostol for sublingual use. The results tend to confirm that the sublingual route represents a valid alternative for induction of labor, as already suggested by other authors [59]. According to 2 studies [15,16] the sublingual route appears to have the advantage of a greater acceptance by women than the vaginal route. It is understandable that it is more comfortable to place a tablet in the mouth than in the vagina, and that acceptance would improve if a specially designed tablet of pleasant taste was used, as was done in this study. Thus, although in this study the sublingual administration of misoprostol 25 Ag was neither more effective nor safer than the same dose

Sublingual vs. vaginal misoprostol for induction of labor administered vaginally, the limited sample size does not allow reaching definitive conclusions. Given the proven feasibility of using the sublingual route and the preference of the women, similar trials with a larger sample size should be carried out in the near future.

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Acknowledgments
The misoprostol tablets used in this clinical trial were donated by the Hebron S/A Ind. Quimicas e Farmace uticas, Caruaru, Brazil.

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