A randomized, double-blind, three-arm study was performed at two hospitals in Qazvin, Iran, from July 2019 to September 2020. Kosar was a university hospital while Mehregan was a privately owned. Both hospitals' research ethics boards accepted the report. In advance of participating in the study an informed consent form signed by all volunteers. This clinical study was approved in the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT20190415043278N1, date approval 2019-05-27.
Inclusion criteria consisted in Nuliparity, singleton pregnancy, gestational age 37 weeks or greater, cephalic presentation, live fetus, cervical Bishop score ≤ 5, estimated fetal weight < 4000 grams. Women were excluded in case of premature rupture of membranes, Placenta Previa, placenta abruption, fetal malformations, Multiparity, severe preeclampsia, abnormal fetal heart rate tracings or signs of active labor at admission and previous uterine scars. Other exclusion criteria were the presence of contraindications for the use of PG analogues, including glaucoma, asthma, epilepsy, and allergy. The misoprostol used in this study (Cytotec, Searle, England) was an analog of prostaglandin E1 in 200 mg tablets. The tablets were cut into quarters for the application of labor induction, each portion containing 50 mg.
The tablets were packed in the containers of the cervix, sublingual (SL) or vagina (V) and then numbered between 1 and 300. Only the responsible pharmacist had knowledge of the contents of each container. By a computerized randomization sequence, the pouches were numbered. A blocked randomization was made to guarantee that the groups were of equal size(16). Participants underwent obstetric examinations, including Bishop scoring at admission upon entering the delivery room and recorded by one of the midwives, then obtained one of these containers. Due to blindness, 50 mg of misoprostol was applied to the cervical canal, vaginal posterior fornix or sublingual to induce labor by a gynecologist or the second investigator. Also, women were not informed about the treatment that they offered. In order to avoid information bias in the estimation of Bishop Scores, three midwives were responsible for vaginal examination who were unaware of the procedure, and midwifery vaginal examinations were coordinated with each other prior to the outset of the study.
Dosing was repeated every 4 hours until 3 or more uterine contractions lasting 40 s occur within minutes, or when the maximum of 4 doses has been reached. In the absence of active labor 6 hours after the final dosage of misoprostol or if cervical dilation did not advance for 2 hours, it was reckoned a failure to induce labor so that intravenous oxytocin for augmentation or cesarean section was taken. Maternal vital signs and gastrointestinal symptoms were evaluated every 2 hours and samples was monitored for both uterine contraction and fetal heart rate.
The primary outcome was vaginal delivery rate, the time from the first administration of misoprostol to labor initiation and delivery; labor duration; total of doses of misoprostol applied. Secondary outcomes were adverse drug effects during treatment and infant outcomes. Adverse effects included disorders of uterine contractility (Tachysystole and Hyperstimulation syndrome), gastrointestinal symptoms such as nausea, vomiting, hyperthermia, diarrhea, and headache. We adopted the definition of Heuser et al(17) in which uterine tachysystole was defined by any occurrence of five or more contractions within 10 min, averaged over three consecutive 10-min periods, Uterine hyperstimulation syndrome was defined as uterine tachysytole with concurrent foetal heart rate decelerations or bradycardia, hypertonus as a single contraction with duration of at least 2 min. Neonatal outcome consisted of the rates of 5-min Apgar score < 7, umbilical artery/venous pH, presence of meconium and NICU hospitalization. In cases where the Apgar score was less than 7, arterial blood gas cord blood data were collected.
A demographic questionnaire containing information such as age, parity, abortion history and body mass index was initially filled out. Another questionnaire is the primary form of delivery that is available in each delivery room in which labor progress and delivery of the infant was completed during labor and after delivery. Several questions such as dilatation and effacement of the cervix, fetal head station, Bishop Score estimation, status of water bags, side effects of medicines, infant birth weight, Apgar score, and amniotic fluid transparency were collected.
Based on the same study (18) and the average amount of changes in bishop score and considering 10% drop in sample size, 104 people in each group were calculated. Participants were randomly split into three groups. Statistical analysis was processed using SPSS software (version 20), and P < 0.05 was considered significant. Continuous data are described as the mean ± standard deviation (SD), while categorical data are described as the frequency and percentage. Dichotomous variables were compared between the groups using the Chi square test or Pearson, and continuous variables were analyzed using the One-way ANOVA test. The differences in the induction-onset of labor intervals were evaluated by Tukey test. Covariance analysis (ANCOVA) was used to compare the effects of some variable on time to active phase.