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Sequential Foley Catheter and Misoprostol Versus Misoprostol Alone for Induction of Labor in Postdated Pregnancy: a Randomized Controlled Trial

Introduction: Induction of labor is done with the aim of normal vaginal delivery. There are different methods; mechanical like intra-cervical Foley’s or pharmacological agents like misoprostol or dinoprostone. Objectives: To compare sequential use of Foley’s catheter and vaginal misoprostol in comparison with vaginal misoprostol only. Methods: Patients with period of gestation more than or equal to 41 weeks without any complications were assigned randomly according to computer generated randomization into sequential use of intracervical Foley followed by vaginal misoprostol after 24 hours (sequential group) or vaginal misoprostol only. Primary outcome was rate of normal vaginal delivery. Secondary outcomes were induction to delivery interval, maternal and fetal morbidity. Results: Rate of normal vaginal delivery in sequential group (n= 353) and misoprostol alone group (n= 356) was 71.6% and 53.3% (p < 0.001) but the time to delivery from induction is statistically more in sequential group (30.3 vs. 11.2 hours, p< 0.001). Maternal outcomes like postpartum hemorrhage, hyper-stimulation syndrome, chorioamnitis and neonatal outcomes like low Apgar score, meconium stained baby and stillbirth are similar in both the groups. Conclusions: The priming of cervix using intracervical Foley catheter before giving vaginal misoprostol was beneficial in increasing the rate of normal vaginal delivery but it increased the induction to delivery interval.


Introduction
Different methods are used for labor induction with the aim of normal vaginal delivery. Intracervical Foley's catheter acts by either direct distension or release of endogenous prostaglandins. 1 It is as effective as prostaglandins with less adverse effects 2 but with potential risk of infections not seen in randomized trials. [3][4][5] Misoprostol either vaginal or oral 6,7 helps in both cervix ripening and uterine contractions by increasing collagenases and proteinases with in the cervix. 8 Different studies comparing safety and effectiveness of different methods are not consistent. 1 So, the optimal method is unclear. 9 Some have shown that they have synergistic effect when used in combination 10,11 while some show they have similar effects. 12,13 Different methods of induction are used in different centers. In BPKIHS, either misoprostol alone or Foleys catheter alone is being used for induction of labor.
This study was designed to compare the efficacy of the sequential use of Foley catheter and vaginal misoprostol; with vaginal misoprostol alone for normal vaginal delivery so that there will be option for induction of labor.

Methods
This is an open-label randomized controlled trial, which was conducted in B. P Koirala Institute of Health Sciences (BPKIHS). Women with period of gestation (POG) ≥ 41 weeks without exclusion criteria requiring induction of labor were recruited. Period of gestation was calculated by last menstrual period and confirmed with early ultrasound. Postdated patients with hypertension, diabetes, ruptured membranes, intrauterine death and any other conditions like multiple pregnancy, previous cesarean section and non-cephalic presentations were excluded. Patients who had irregular menstrual cycles and didn't have 1 st trimester ultrasound were also excluded. Study was conducted after ethical clearance from Institutional Review Committee of BPKIHS. The participants were given written information about the trial, and for those who agreed to participate, informed written consent was obtained prior to recruitment. Computer generated randomization sequence was used. They were allocated to either sequential induction group or misoprostol alone group with 1:1 allocation. To decrease the information bias patient were recruited only after patients were counseled regarding risk and benefits of both the methods of induction and they gave informed consent. After random allocation, Bishop Score was assessed by resident doctor and proceeded for induction, if score < 6. In sequential induction group, Foley's catheter 16 FG was inserted with aseptic precautions and balloon inflated intra-cervically with 40-60 ml of distilled water. External end of catheter was fixed on thigh without traction. Foleys catheter was removed after 24 hours if it did not expel itself. If it expelled out, it was not reinserted and the woman was observed for 24 hours from Foleys insertion. It was removed if woman requested to and excluded from the study. If patient went to labor she was shifted to labor room and managed accordingly. If patient didn't go to labor, after 24 hours of Foleys insertion, 25 µg of misoprostol was inserted per vaginally in posterior fornix and repeated in 4 and 8 hours with maximum 3 doses. If patient didn't go to labor even after 4 hours of third dose, she was termed as failed induction and patient was taken for lower segment caesarean section (LSCS). If she went to labor, she was taken to labor room and managed accordingly.
In the group assigned for misoprostol alone; 25 µg of misoprostol was inserted per vaginally in posterior fornix and repeated in 4 and 8 hours with maximum 3 doses. If patient didn't go to labor even after 4 hours of third dose, she was termed as failed induction and patient was taken for lower segment caesarean section (LSCS). If she went to labor, she was taken to labor room and managed accordingly.
The primary outcome was taken as rate of normal vaginal delivery (NVD) and secondary outcome were induction to delivery interval, and maternal complications like maternal infection, postpartum hemorrhage (PPH) and neonatal outcomes meconium stained liquor (MSL), Apgar score at 5 minutes and stillbirth. For intrapartum infection, any two of the criteria should be present: maternal fever (≥ 38 °C) during labor, fetal tachycardia (≥ 160 bpm), uterine tenderness, purulent amniotic fluid or vaginal discharge and total white cell count > 20,000/mm. 3 Antibiotics were prescribed for them.
Sample size was calculated using previous studies. Previous study 14 shows success rate of normal vaginal delivery in sequential group of about 67% and with misoprostol alone was about 59%. Taking this into account sample size of 344 in each group would be required with α= 0.05 and β = 0.20. OpenEpi data software was used to calculate the sample size. All data were collected prospectively with the use of structured Proforma and were recorded. The data were entered in MS excel and were analyzed using SPSS version 11.5. P value of ≤ 0.05 was considered statistically significant.

Results
During the study period, 1020 patients were eligible for the study. Among them, 720 patients gave informed consent for the trial. The flow diagram of the study is given in Figure 1. 360 patients were randomized in each group. Of 360 who were randomly assigned to the sequential group, four patients were excluded because of high Bishop score ≥ 6; three were excluded because of inability to insert the Foley catheter and two were excluded due to removal of Foley on request by the woman. In misoprostol only group, four patients were excluded because of high Bishop score ≥ 6. In the end, 353 patients in the sequential group and 356 patients in the misoprostol only group were included. The baseline characteristics of both the group were similar (   Induction to delivery interval in sequential group was 30.3 hours and 11.2 hours in misoprostol only group, which was statistically significant (p= 0.001). The most common cause of cesarean in both the cases were non-reassuring non-stress test but there was significantly higher number of failed induction in vaginal misoprostol group than in sequential group (p= 0.017). Other maternal and neonatal outcomes are shown in Table 3 and 4. Only three patients had intrapartum infection with maternal fever and fetal tachycardia in sequential group. There were no cases of maternal fever in misoprostol only group. There were two still births in the sequential group and only one still birth in misoprostol only group.  The rate of normal vaginal delivery was significant even when the patients were compared according to parity but the rate of cesarean section was statistically significant in nulliparas but not in parous women (Table 5). Induction with Foley catheter has been reported to be a method that is well accepted by women 16 but this study showed that cervical priming with Foleys still results in unfavorable cervix. The common sequential use was with oxytocin rather than misoprostol. 17 Different studies have shown the beneficial effect of misoprostol in comparison to oxytocin. 6 There are very few studies that compared sequential Foley followed by vaginal misoprostol but there are numerous studies that have concurrent use of Foley and vaginal misoprostol which has beneficial effects on normal vaginal delivery and decreased cesarean section rate. 18,19 Although there has been concern about increased risk of infection associated with use of Foleys catheter; 12 this has not been demonstrated in randomized controlled trials [13][14][15] which is also consistent with our study. Study by Barrilleaux PS et al 12 showed infection rate with Foley's catheter insertion was about 3% which was higher than in our study which had intra-partum infection rate of about 0.84% only. Neonatal outcomes like meconium stained liquor, low Apgar score and stillbirth were comparable in both the groups; which are also similar in other studies. 14,15 Future investigations about mechanical methods for induction should also focus on the possibility of out-patient priming of cervix with these methods and also the immediate use of vaginal misoprostol after Foley expulsion to decrease the induction to delivery interval in sequential group.

Conclusions
The use of intra-cervical Foley catheter for priming of cervix before inducing the patient with vaginal misoprostol was beneficial to increase the chance of normal vaginal delivery although it caused prolonged induction to delivery interval.