The induction of full-term labor in women with a live fetus remains a major challenge in modern obstetrics 1. The main indication for induction of labor is post-term pregnancy because in such cases, the risk of intrauterine and postnatal death is increased from 2.4/1000 pregnancies at 40 weeks to 5.8/1000 at 43 weeks. In the management of post-term pregnancies, induction of labor reduces perinatal mortality when compared with expectant management 2.
Primiparity has been identified as the only maternal variable that has a significant association with prolonged pregnancies of greater than or equal to 294 days 3.
A variety of techniques have been developed to quantify cervical ripening in order to predict the timing of labor. This quantification is useful for patients at risk for preterm labor and for helping predict which patients will respond to induction of labor for medical reasons or for postdate pregnancy. The most commonly used methodology to evaluate cervical ripening is the Bishop score 4.
Misoprostol, a synthetic prostaglandin E1 analogue, has gained widespread acceptance for cervical ripening after several randomized trials confirmed its effectiveness in women with viable pregnancies 5–7.
Misoprostol can be administered orally, sublingually, vaginally, or rectally. The route of administration is decided on the basis of the preference of the patient and the clinical situation 8.
The tablet, however, is coated with a cellulose matrix to confer the drug with stability at room temperature 9, and this may result in delayed 10 or varying absorption 11 and a cumulative effect 10,11 when placed directly in the vagina. Also, misoprostol tablet is quite small and can fall off the examiner’s finger, especially when divided into pieces, or may be pulled out accidentally during subsequent vaginal examinations.
In this study, we attempted to compare the efficacy of 50 µg of misoprostol tablets with the same dose of misoprostol prepared gel, both applied every 6 h for a maximum of 24 h in induction of labor in post-term primigravidas.
Patients and methods
One hundred patients were enrolled in this study. The patients were recruited from the emergency obstetrics department of Kasr El Aini Hospital in the period from July 2011 to September 2012.
All women included in the study were primigravidas, 17–30 years old, who were sure of their last menstrual period, with gestational age 40–42 weeks, with living, singleton cephalic presentation, amniotic fluid index (AFI) more than 5 cm, intact membranes, and a Bishop score 4 or less. Patients with medical disorders (diabetes mellitus, pre-eclampsia, or chronic hypertension), those with anomalous fetus, a macrosomic fetus (>4000 g), patients with a nonreassuring fetal heart rate (FHR), and patients with active labor (cervical dilatation>3 cm with ≥3 uterine contractions per 10 min each lasting 45 s or longer) as well as women with any condition that contraindicated vaginal delivery (e.g. cephalopelvic disproportion, placenta previa, or a previous uterine scar) were excluded from the study. Patients with known hypersensitivity to prostaglandins or with contraindication to prostaglandins (e.g. asthma) were also excluded from the study.
Written consent was obtained from the patients after explaining the procedure to them.
All patients were subjected to full assessment of history, with a special focus on the calculation of gestational age from the last menstrual period, complete examination, measurements of weight and height, and digital vaginal examination to assess the condition of the cervix (to calculate the Bishop score), to evaluate the pelvis, and to confirm adherence to the inclusion criteria. A nonstress test is done to ensure reactive fetus with no fetal distress (FHR).
Transabdominal ultrasound was performed to confirm gestational age, presentation, amniotic fluid index, estimate fetal weight, and to exclude congenital anomalies.
Patients were randomized (computer randomization performed by a member not involved in patient care using a series of sealed opaque numbered envelopes) to receive 50 µg of misoprostol (Cytotec, 200 µg tablets; Pharmacia, Walton-on-the-Hill, UK), either a vaginal tablet or a vaginal gel.
A total of 50 µg of misoprostol tablet was prepared by dividing the 200 µg tablet into four quadrants; 1/4 of the tablet was then moistened with 1 ml of saline and then inserted deep in the posterior fornix.
Vaginal gel was prepared by the house residents in the antepartum unit immediately before use by dissolving 1/4 of a tablet in 1 ml of normal saline (in an empty plastic blood sample tube) and mixing it with 4 ml of KY gel (Johnson and Johnson Co., New Jersey, USA). Misoprostol gel was then applied into the vagina using a 5-ml plastic sterile syringe guided by fingers.
The patients were then observed for the occurrence of uterine activity. Misoprostol (either tablet or gel) was repeated every 6 h for a maximum of 24 h. No application was made if the patient had a contraction of more than three times per 10 min with efficient intensity as judged by the obstetrician. When uterine activity was established, continuous fetal monitoring was carried out using cardiotocography. When cervical dilatation permitted, amniotomy was performed, followed by oxytocin augmentation if the frequency of contractions was less than three per 10 min. Oxytocin, if used, was administered not less than 6 h after the last dose of misoprostol. Tachysystole was defined as at least 6 contractions per 10 min for at least 20 min. Hypertonus was defined as a single uterine contraction lasting for 2 min or more. Hyperstimulation syndrome was defined as the presence of tachysystole or hypertonus associated with a nonreassuring FHR pattern (fetal tachycardia, late deceleration, severe variable deceleration, or loss of FHR variability) 12. In this case, intrauterine resuscitation was performed immediately by placing the patient in the left lateral position, providing a oxygen mask, discontinuing oxytocin (if administered), and intravenous hydration. If FHR did not return to normal, cesarean section (CS) was performed for fetal distress. Patients who did not enter the active phase of labor after a maximum of four doses were considered as having failed induction and CS was offered to them.
The primary outcome was the occurrence of vaginal delivery within 24 h from the start of induction. Secondary outcomes included induction to the start of contractions interval, induction to delivery interval, CS rate, need for oxytocin, fetal distress rate, and uterine hyperstimulation rate. Neonatal outcomes included Apgar score less than 7 at 5 min, intrapartum meconium passage, and the need for neonatal intensive care unit admission.
Data were statistically described in terms of mean±SD, or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was carried out using the Student t-test for independent samples. For comparison of categorical data, the χ 2-test was carried out. The exact test was used when the expected frequency was less than 5. P values less than 0.05 was considered statistically significant. All statistical calculations were carried out using computer programs statistical package for the social science (SPSS; SPSS Inc., Chicago, Illinois, USA) version 15 for Microsoft Windows.
One hundred patients were enrolled in the study, 50 in the tablet group and 50 in the gel group. Patients in both groups were comparable in terms of the baseline clinical criteria (Table 1). The mean age of the women in the tablet and the gel group was 22.56±3.01 and 23.2±3.14 years, respectively, the BMI was 21.97±1.83 and 22.37±1.78, respectively, the estimated gestational age was 40.87±3.7 and 40.98±3.6 weeks, respectively, and the Bishop score was 3.27±0.73 and 3.29±0.71, respectively.
Thirty-six patients (72%) in the tablet group achieved vaginal delivery within 24 h compared with 32 patients (64%) in the gel group (P=0.179).
The mean duration from the application of the first dose to the start of contractions was 6.27±1.93 h in the tablet group and 5.8±1.94 h in the gel group (P=0.235); however, the induction to delivery interval was significantly different between both groups (15.31±3.48 h for the tablet group and 17.11±3.32 h for the gel group, P=0.009).
Patients in the tablet group required oxytocin less likely than the gel group [26 patients (52%) vs. 28 patients (56%), respectively, P=0.574].
Fourteen patients (28%) in the tablet group and 18 patients (36%) in the gel group were delivered by CS (P=0.179). The indications for CS were mainly fetal distress, followed by failed induction (Table 2).
Six patients (12%) in the tablet group developed tachysystole, whereas four patients (8%) in the gel group developed the same condition (P=0.19). Hypertonus also occurred more frequently in the tablet group compared with the gel group [fie patients (10%) and two patients (4%), respectively, P=0.095]. Hyperstimulation syndrome was observed in eight women (16%) in the tablet group and four women (8%) in the gel group (P=0.086). Of the eight women who developed hyperstimulation in the tablet group, intrauterine resuscitation resulted in an improvement in FHR in three of them, whereas five women continued to have abnormal FHR, who were delivered by emergency CS for fetal distress. Intrauterine resuscitation improved the FHR of two women that developed hyperstimulation in the gel group and the other two were delivered by CS.
Fetal distress was encountered in 11 women (22%) of the tablet group (eight cases associated with hyperstimulation and three cases without) and 10 women (20%) of the gel group (four cases associated with hyperstimulation and six cases without) (P=0.27; Table 3). No cases of uterine rupture or placental abruption were found in the study.
Neonatal outcomes were nonsignificantly different between both groups; meconium-stained liquor was seen in five cases (10%) of the tablet group and four cases (8%) of the gel group (P=0.233). Three babies (6%) in the tablet group and two babies (4%) in the gel group showed Apgar score of less than 7 at 5 min (P=0.314). Those five babies were admitted to the neonatal intensive care unit for further management (Table 4).
Although pharmacokinetic data on the use of the small doses of intravaginal misoprostol tablets are lacking, clinical observations suggest that there may be either a cumulative 11,13 drug effect or a variable 13 or delayed 11 absorption in some patients.
Sometimes, misoprostol tablets are found undissolved in the vagina hours after insertion. Also, it is sometimes difficult to insert such a small tablet into the vagina. This led us to study the efficacy of 50 µg of misoprostol dissolved in saline and mixed with KY gel compared with an equivalent dose of misoprostol tablet in induction of labor.
Our results showed that misoprostol tablets produced a slightly higher percentage of successful vaginal delivery compared with the gel form (72 vs. 64%). Unfortunately, we did not find many trials that studied misoprostol prepared gel. A study was carried out in 1997 on 467 patients randomized to receive 50 µg of either misoprostol vaginal tablet or misoprostol prepared gel every 8 h; the authors have found a higher percentage of successful vaginal deliveries in the tablet group compared with the gel group (65 vs. 48%) 14.
Our percentage of successful vaginal deliveries with misoprostol tablet is almost the same as that obtained in previous clinical trials; Zahran et al. 15 and Nassar et al. 16, reported successful vaginal delivery with 50 µg of misoprostol tablet every 4–6 h of 66.7 and 71.8%, respectively. Oliveira et al. 17, reported successful vaginal deliveries in 50% of cases with misoprostol tablets, but they used a smaller dose for induction (25 µg).
Our results suggested that misoprostol gel is more rapidly absorbed than the tablet form. The period from the first insertion to the start of contractions was, however, nonsignificantly shorter in the gel group than the tablet group (5.8±1.94 vs. 6.2±1.93 h, P=0.235). This is in agreement with Carlan et al. 14, who reported that the mean time from the initial drug administration to first contraction was lower in the gel group (36.5±28.4 min for the gel group vs. 47.9±52.9 min for the tablet group, P=0.18).
Although a higher percentage of successful vaginal deliveries and shorter induction to delivery interval were expected in the gel group, in our study, significantly longer induction to delivery interval was found in the gel group (17.11±3.32 h) compared with 15.31±3.48 h in the tablet group (P=0.009). This is also similar to the findings of Carlan et al. 14, who found that a significantly longer period of time was required by the gel group to deliver (26.5±18.3 h) compared with the tablet group (21.8±14.7 h) (P=0.01). This can be explained by the fact that the syringe containing misoprostol gel still contained a small portion of the dose after application; thus, the entire dose had not been administered to the patient.
The main indication for CS in both groups of our study was fetal distress (57% in the tablet group and 44% in the gel group),;this is comparable with the results of most clinical trials of vaginal misoprostol tablets in induction of labor 12,15,16. However, in a study carried out by Oliveira et al. 17, failed induction was the main indication for CS, which might have been because of the smaller dose used in their study (25 µg).
In this study, a higher incidence of tachysystole, hypertonus, and hyperstimulation syndrome was also expected in the gel group because of the faster absorption of the gel form; yet, tachysystole, hypertonus, and hyperstimulation occurred more in the tablet group, which can be explained by the fact that the gel form was prepared in the antepartum unit by house residents, and even though the technique of preparation was evaluated and monitored by the authors, there may have been variations in preparation, resulting in different concentrations of the total dose applied. Also, the gel form was applied using a syringe and after the application of the dose, some of the drug may have remained in the syringe wall, resulting in the application of a lower dose. A commercially prepared misoprostol gel with an accurately titrated dose, if available, may be better used to compare it with misoprostol tablets.
A measure of 50 µg of misoprostol tablet or gel form every 6 h is similarly effective in inducing labor in post-term primigravidas; however, the tablet form is more easy to use and the gel form is slower in inducing delivery. Larger studies are required to comment on maternal and neonatal safety.
Conflicts of interest
There are no conflicts of interest.
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