Induction of labor is carried out for maternal and fetal indications. One of the most common indications is prolonged pregnancy 1. Recent studies have suggested that pregnancy beyond 41 weeks leads to a statistically significantly higher rate of perinatal morbidity and mortality, as well as an increased risk to the mother 2,3. Thus, there is a growing body of evidence suggesting the elective induction of labor at 41 weeks of gestation instead of expectant management 3,4.
In the presence of an unfavorable cervix, cervical ripening is recommended to increase the likelihood of successful induction and decrease the risk of a Cesarean delivery 5.
The search for the ideal agent, timing, and dosage interval to convert an unfavorable cervix to one receptive to delivery is an ongoing process. Attention has been focused on prostaglandins as effective pharmacological adjuncts to induction. Misoprostol, a synthetic analogue of prostaglandin E1, has been widely studied in a variety of dosages and routes of administration as an alternative to oxytocin. Misoprostol offers the advantage of promoting both cervical ripening and myometrial contractility 6.
Vaginal misoprostol appears to be more effective than the equivalent dosage administered orally but is associated with a higher risk of uterine hyperstimulation, both without and with fetal heart rate (FHR) changes 7–9. The likely explanation for the high efficacy of vaginal administration could be determined by avoidance of the first-pass effects of the gastrointestinal and hepatic enzymes and its direct effect on the cervix and uterus 10,11.
Oral and sublingual misoprostol have a rapid onset of action. Sublingual and vaginal routes have prolonged activity and possess the greatest bioavailability 12. Benefits of the sublingual route might include less frequent need for vaginal examinations, greater freedom of position in the labor bed, and ease of administration 13.
In this study, we aimed to evaluate the effectiveness of sublingual versus vaginal misoprostol (50 µg) given every 6 h for a maximum of 24 h for labor induction in primigravid women with a viable fetus.
Patients and methods
This prospective randomized clinical study was carried out at the Emergency Unit of the Department of Obstetrics and Gynecology of Kasr El Aini Teaching University Hospital, Egypt from 1 June 2012 to 1 December 2012.
Patients with medical or obstetrical indications for labor induction were enrolled in the study. A total of 72 primigravidae were assessed for eligibility for inclusion into the study. Twelve patients were excluded; therefore, 50 primigravid women were included in the study. All women had a singleton living cephalic fetus with a gestational age of 37 weeks or higher, as determined by the last menstrual period and confirmed by ultrasonographic examination.
Indications for the induction of labor included postdate pregnancies (>41 weeks), chronic, gestational hypertension or mild pre-eclampsia (blood pressure >140/90 and <160/110 mmHg and proteinuria >30 mg/dl), and diabetes mellitus. Other inclusion criteria included the absence of active labor, normal FHR tracing, an amniotic fluid index of more than 5 cm, and an unfavorable cervix (Bishop score ≤4).
The exclusion criteria included the presence of a uterine scar, ultrasonographically estimated oligohydramnios (amniotic fluid index <5 cm), polyhydramnios, fetal macrosomia (>4000 g), fetal anomalies, intrauterine growth restriction, premature rupture of the membranes, noncephalic presentation of the fetus, cephalopelvic disproportion, or other contraindications for vaginal delivery. Patients with known hypersensitivity or contraindications to the use of prostaglandins (e.g. asthma) were also excluded from the study.
Patients meeting the above inclusion criteria were counseled about the study and a written informed consent was obtained.
Clinical workup included: history taking, physical examination, ultrasonographic evaluation with a biophysical profile, a nonstress test, and a vaginal examination to assess the cervix and estimate the Bishop score.
Before the initiation of the study, a computerized randomization was performed. A series of consecutively numbered opaque envelopes, with each envelope containing an even or odd number, was generated. Even numbers indicated sublingual treatment, and odd numbers indicated vaginal administration. The sealed envelopes, indicating sublingual or vaginal treatment, were made available to the attending physician at the labor and delivery unit and opened. Patients in the sublingual group were initially given 50 μg of misoprostol sublingually and those in the vaginal group received 50 μg of misoprostol placed at the posterior fornix using a gel as a lubricant.
The 50 µg dose was prepared by dividing the 200 µg misoprostol tablet (Cytotec; Pharmacia, Kent, UK) into four quadrants. We planned to repeat the dose every 6 h for a maximum of 24 h. The dose was withheld in the presence of active labor (≥3 cm cervical dilatation with regular uterine contractions) or when three or more uterine contractions of 45-s duration over 10 min or the maximum of four doses (200 µg) was reached. After insertion of the first dose of misoprostol, the FHR was continuously monitored. As soon as the patient was in active labor and cervical dilatation permitted, amniotomy was performed, followed by oxytocin augmentation if the frequency of contractions was less than three per 10 min. Oxytocin was administered not less than 6 h after the last misoprostol dose. After delivery, complete neonatal examination and resuscitation were performed.
Tachysystole was defined as at least six contractions per 10 min for at least 20 min. Hypertonus was defined as a single uterine contraction lasting for 2 min or more. Hyperstimulation was defined as the presence of tachysystole or hypertonus with a nonreassuring FHR pattern (fetal tachycardia, late deceleration, severe variable deceleration, or loss of FHR variability) 14; in this case, intrauterine resuscitation was performed immediately in the form of maternal reposition (left lateral position), an oxygen mask, and intravenous hydration. In the sublingual group, the woman was asked to spit the tablet and wash her mouth; in case of vaginal misoprostol, the doctor tried to remove the tablet if possible. The oxytocin infusion (if given) was stopped immediately. If hyperstimulation persisted, an intravenous injection of meperidine (50 mg, diluted) was administered. If the FHR did not return to normal, a Cesarean section (CS) was performed to avoid fetal distress. Labor induction was considered a failure if a woman did not enter the active phase of labor after the four doses of misoprostol, in which case a CS was performed.
The primary outcome measure was the frequency of successful induction, defined as a vaginal delivery within 24 h from the start of induction. The secondary outcomes included the rate of CS due to fetal distress, the induction-to-delivery interval, the number of misoprostol doses needed, the need for oxytocin augmentation, the mode of delivery, and the uterine hyperstimulation rates. The neonatal outcomes included: intrapartum meconium passage, an Apgar score at 1 and 5 min, and the need for neonatal ICU (NICU) admission.
The Statistic Package for Social Sciences (SPSS v 15.0 for Windows; SPSS Inc., Chicago, Illinois, USA) software was used for data analysis. The statistical significance was assessed using the Student t-test and χ2 test as the appropriate data were log-transformed to correct for skewness before the statistical analysis, and the values in the two groups were compared using the Mann–Whitney U-test. Significance was interpreted as a P-value of less than 0.05. All data were presented as mean±SD.
A total of 50 pregnant women were included in the study. They were divided into two equal groups: group 1 received 50 µg of misoprostol sublingually and group 2 received 50 µg of misoprostol vaginally.
The baseline criteria were similar in both groups (Table 1). There was no statistically significant difference in the mean age between both groups (27.1±4.96 for the sublingual group and 27.04±4.6 for the vaginal group). Moreover, the BMI did not show significant differences between both groups (25.01±2.09 for the sublingual group and 24.5±1.85 for the vaginal group). The postdate was the main indication for induction of labor (68% for both groups). In addition, the mean preinduction Bishop score for the sublingual group was 3.5±0.5, which was very similar to that of the vaginal group (3.4±0.8).
More women in the sublingual group (76%) achieved vaginal delivery within 24 h compared with those in the vaginal group (72%); however, this difference was statistically nonsignificant (P=0.747).
The mean duration from the start of induction to delivery was 10.47±7.83 h for the sublingual group and 12.04±7.88 h for the vaginal group (P=0.481).
The mean number of misoprostol doses used in the sublingual group was lower than that needed in the vaginal group (2.2±1.1 vs. 2.48±1.08, respectively, P=0.373).
Three out of 19 (15.7%) women in the sublingual group delivered vaginally by a single dose of misoprostol, whereas two out of 18 (11.11%) women achieved vaginal delivery in the vaginal group (P=0.47).
No statistically significant difference was found between both groups as regards the need for oxytocin augmentation (P=0.771).
Less number of patients in the sublingual group delivered by CS compared with the vaginal group (six vs. seven); however, the difference was statistically nonsignificant (P=0.747).
The main indication for CS in both groups was fetal distress followed by the failure of labor induction (Table 2).
None of the patients in the vaginal group developed tachysystole compared with two patients who developed this condition in the sublingual group (P=0.13). Three patients in the sublingual group developed hypertonus compared with four patients in the vaginal group (P=0.22). Hyperstimulation occurred in three patients in the sublingual group who were delivered by emergency CS because of fetal distress, in which the FHR did not return to normal after intrauterine resuscitation, and four patients in the vaginal group developed hyperstimulation (P=0.22) and were delivered by CS for the same reason. One of the three babies in the sublingual group and two in the vaginal group who were delivered by CS to avoid fetal distress needed resuscitation but all fared well thereafter, and the other four babies did not need resuscitation after birth.
Three babies in the sublingual group (12%) and four in the vaginal group (16%) showed a meconium-stained liquor (P=0.68).
One baby in each group had an Apgar score of less than 7 at 5 min; these babies were referred to the NICU because of neonatal respiratory distress (Table 3).
Although the use of oral misoprostol for cervical ripening and labor induction is growing, its sublingual use is still limited 14–21.
Our results showed that 50 µg of sublingual misoprostol resulted in a higher, although nonsignificant, rate of successful vaginal deliveries when compared with the same dose given vaginally (76 vs. 72%, P=0.747). Moreover, the sublingual group showed a slightly lower induction-to-delivery interval and slightly higher number of patients who delivered by a single dose of misoprostol when compared with the vaginal group.
Gattás et al.21 reported successful vaginal delivery in 60% of their patients, but they used a low dose of sublingual misoprostol (12.5 µg).
The results in our study were similar to those of a study carried out in 2009 on 480 women in which 50 μg of sublingual misoprostol was compared with 50 μg of vaginal misoprostol. In their study, 71% of the patients in the sublingual group achieved successful vaginal delivery compared with 66.7% in the vaginal group. The previous study also reported a slightly shorter induction-to-delivery interval in the sublingual group 22.
In our study, tachysystole occurred in the sublingual group but not in the vaginal group; however, the occurrence of hypertonus and hyperstimulation syndrome was higher in the vaginal group. These results are similar to those reached by many authors 14,15; however, Nassar et al.17 and Feitosa et al.18 mentioned that both the sublingual and vaginal routes have similar levels of safety.
The sublingual route has been shown to produce significantly higher serum peak concentrations of misoprostol compared with either oral or vaginal administration. In addition, the area under the curve for plasma levels over 4 and 6 h was significantly greater after sublingual administration compared with either oral or vaginal administration 10,23,24. This may explain the higher incidence of tachysystole and the higher successful vaginal deliveries in the sublingual group.
In our study, the most frequent indication for CS in both groups was fetal distress (50 and 57.14% in the sublingual and vaginal groups, respectively). These results are supported by those of other studies 14,17,22.
The neonatal outcome was almost similar in both groups in our study. No significant difference was found between both groups as regards the Apgar score at 5 min, meconium passage, and the need for NICU admission. The same results were reached by many authors who compared sublingual with vaginal misoprostol 14,17,22.
From the above results, we can conclude that both the sublingual and the vaginal routes of administration of misoprostol have similar efficacy in inducing labor in primigravidas; however, the sublingual route may be preferred by the patients. Larger studies are needed to comment on the safety of both the techniques.
E.A.M.E.K.: Share in the collection of cases, writing the manuscript, and publishing; G.A.F.A.M.: Share in the collection of cases and writing the manuscript; A.R.A.A.R.: Share in resuscitation and observation of the neonates.
Conflicts of interest
There are no conflicts of interest.
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