Abstract
Objective
To compare the efficacy and safety of the hourly administration of titrated oral misoprostol solution (OMS) and vaginal dinoprostone for induction of labor.
Methods
Titrated OMS was administrated hourly for induction of labor, starting with a dose of 20 µg and terminating at a dose of 50 µg. The safety and efficacy of OMS were compared with that of vaginal dinoprostone for induction of labor.
Results
From June 2016 to October 2019, 2280 (78.3%) and 2115 (72.9%) women who received titrated OMS and vaginal dinoprostone, respectively, had a vaginal delivery (P = 0.005). Cesarean delivery was performed in 632 (21.7%) and 783 (27.0%) women who received titrated OMS and vaginal dinoprostone, respectively (P = 0.008). Tachysystole with changes in fetal heart rate (FHR) was seen in 104 (3.6%) and 249 (8.6%) women in the OMS and dinoprostone groups, respectively (P = 0.007). The frequency of non‐reassuring FHR was lower in the OMS group compared to the dinoprostone group (P = 0.006).
Conclusion
The titrated OMS has an efficacy comparable to vaginal dinoprostone. Moreover, it causes a lower incidence of cesarean delivery, lower frequency of tachysystole with changes in FHR, and non‐reassuring FHR.
Keywords: dinoprostone, induction of labor, titrated oral misoprostol solution
Synopsis
Titrated oral misoprostol has a similar efficacy to dinoprostone, but with a lower incidence of cesarean delivery and lower frequency of non‐reassuring fetal heart rate.
1. INTRODUCTION
Induction of labor is a common obstetric intervention. An appropriate method of induction of labor plays a crucial role in decreasing maternal and fetal complications without increasing the risks. While safety and efficacy should be important criteria when evaluating the advantages and disadvantages of any method of induction of labor, feasibility, cost, and preference should also be considered.
Misoprostol, a synthetic prostaglandin E1 analog, was initially used for the prophylaxis of peptic ulcers. One of its “side effects” was the induction of uterine contraction during pregnancy and early pregnancy abortion. Thereafter, misoprostol was used for termination of first‐trimester pregnancy. Due to its stability at room temperature, low cost, and ease of oral administration, many clinicians began to study its use for induction of labor in term pregnancy. In 1992, Margulies et al1 published two studies on the use of misoprostol in the posterior vaginal fornix for induction of labor in third‐trimester pregnancy. Since then, several clinical studies have focused on the use of misoprostol by the vaginal route for induction of labor. Used at dose of 50–100 µg at varying frequency, these studies confirmed the efficacy of misoprostol by administration via the vaginal route. However, they also reported hyperstimulation caused by changes in the fetal heart rate (FHR) to be an adverse event associated with its high‐frequency use.2, 3, 4 Based on previous findings, it has been suggested that more attention should be paid to low‐dose misoprostol for induction of labor. Vaginal doses of 25 µg every 3–6 h have been recommended only if the recipients can be kept under constant supervision.5, 6, 7 The oral administration of misoprostol, on the other hand, is easier and has greater acceptability among women, when compared to vaginal administration. In 1996, Ngai et al.8 reported the use of oral misoprostol for pre‐labor rupture of membranes at term. Later, in 2001, Hofmeyr et al.9, 10 reported a new method using a titrated low‐dose oral misoprostol solution (OMS) for induction of labor. Since then, several clinicians have studied the use of titrated OMS for induction of labor, leading to different clinical trials comparing its effects with oxytocin, vaginal misoprostol, Foley catheter, and dinoprostone vaginal insert in different doses and frequencies. Although these studies confirmed the efficacy of titrated OMS for induction of labor, they also highlighted the need for future studies with a large sample size to demonstrate its safety and efficacy.11, 12, 13, 14
The present study is based on the findings of a previous study that compared titrated oral misoprostol with dinoprostone for induction of labor at term pregnancy.15 The aim of the present study was to further compare the safety and efficacy of titrated oral misoprostol with dinoprostone for induction of labor using a large sample size. An in‐depth analysis of the relationship between the rate of cesarean delivery and the cervix Bishop score was also performed.
2. MATERIALS AND METHODS
2.1. Trial design
The present study was a single‐center, randomized, controlled, clinical intervention trial with an open‐label design, comparing titrated OMS with intravaginal dinoprostone for induction of labor in nulliparous women at term pregnancy. The trial was approved by the Medical Ethics Committee of the Xi'an Jiao Tong University Medical Center before enrollment of trial participants. The study was conducted at the affiliated Guangren Hospital of Xi'an Jiao Tong University Medical Center between June 1, 2016, and October 1, 2019. The study hospital accommodates 10 000–14 000 deliveries annually, and labor is induced in approximately 25%–30% of the nulliparous women.
2.2. Inclusion criteria
The inclusion criteria were as follows: nulliparous women with singleton pregnancies; gestational age of 36 weeks or more; cephalic presentation; and unfavorable cervix with Bishop score of 6 or higher. Indications of induction of labor included post‐term pregnancy, premature rupture of membranes, diabetes mellitus (both gestational and pregnancy‐complicated), oligohydramnios, gestational hypertension, pre‐eclampsia, fetal demise, chorioamnionitis, fetal growth restriction, and psychosocial factors. Additionally, other factors such as complications involving renal disease, chronic pulmonary disease, chronic hypertension, antiphospholipid syndrome, maternal medical conditions, and isoimmunization were also considered.
2.3. Exclusion criteria
Pregnant women with severe pre‐eclampsia and eclampsia, placenta previa, transverse fetal lie, umbilical cord prolapse, active genital herpes infection, a previous myomectomy entering the endometrial cavity, and estimated fetal weight above 4000 g were excluded from the study. Women with anaphylaxis to misoprostol, prostaglandins, or any of the drug excipients, as well as complications of glaucoma, asthma, allergic colitis, heart, liver, renal, and adrenal cortex insufficiency, were also excluded from the study.
2.4. Randomized allocation design
All eligible women admitted to the obstetric department were randomized into the titrated OMS or dinoprostone groups at a ratio of 1:1 using computer‐generated numbers. Each participant provided informed consent before the trial. The obstetrician provided all information related to the trial, including the aim of the study, procedure, probability of serious complications, or adverse consequences before initiating induction of labor. All participants were informed that exiting was permitted at any time during the study.
2.5. Methods of administration
Titrated OMS was prepared by dissolving a 200‐µg misoprostol tablet (Zizhu Pharmaceutical Co., Ltd, Beijing, China) in 200 ml of water (final concentration 1.0 µg/ml) and was stored at room temperature for 24 h. Titrated OMS was administered as follows: the initial dose of 20 µg hourly for two doses; in the absence of regular uterine activity, the dose was increased to 30 µg hourly for three doses followed by 40 µg for one dose, at an interval of 1.5 h, and 50 µg for one dose. The total administration procedure took 6.5 h. If the first cycle of administration ended with no signs of regular uterine contraction, a second cycle was started after an interval of 6 h. The indications to withdraw OMS included: regular uterine contractions every 3–5 min, each lasting 60 s or more; dilation of the cervix reached 2.0 cm; emerging membrane rupture; uterine tachysystole; and non‐reassuring FHR.
The 10‐mg dinoprostone vaginal insert (Propess; Pfizer Pharmaceutical Co., Ltd, Glasgow, UK) was administered according to the drug protocol. Dinoprostone was taken from the freezer and immediately inserted into the posterior vaginal fornix using only a small amount of soluble lubricant to aid insertion. The withdrawal tap was left outside the vagina to allow removal. The indications of terminating administration were the same as those for OMS.
2.6. Outcomes measured
The primary outcomes were the efficacy and safety of titrated OMS compared to dinoprostone. The main variables included duration of labor, the incidence of vaginal delivery within 12, 24, or 48 h, vaginal delivery, and the frequency of cesarean delivery. The maternal adverse consequences included uterine tachysystole with or without FHR changes, uterine rupture, preterm membrane rupture, postpartum hemorrhage, and drug side effects such as fever, shivering, nausea and vomiting, and diarrhea. The adverse fetal consequences included non‐reassuring FHR, Apgar scores less than 7 at 1 and 5 min, umbilical vein blood of pH 7 or less, infant death, and admission to the neonatal intensive care unit (NICU). The secondary outcome evaluated was the relationship between the incidence of cesarean delivery and the cervix Bishop score.
Tachysystole was defined as the presence of at least six contractions in 10 min over at least 30 min with or without changes in FHR. Non‐reassuring FHR was defined as the occurrence of successive late deceleration up to three times, severe variable deceleration, prolonged deceleration, tachycardia, or reduced FHR variability requiring intervention by either tocolytics or delivery. Failed induction of labor was defined as one that did not result in effective regular uterine contractions, cervical ripening, and dilation after completion of two cycles of OMS administration or two vaginal inserts of dinoprostone. Uterine rupture was defined by clinical symptoms, including abdominal pain, abnormal FHR pattern, acute loss of contractions, and vaginal blood loss leading to an emergency cesarean delivery. Uterine rupture was confirmed and treated with peripartum hysterectomy or laparotomy after vaginal birth. Maternal infection during labor was defined as fever (temperature ≥37.8°C), fetal tachycardia, and the start of antibiotics, while maternal infection within 1 week postpartum was defined as fever and start of oral or intravenous antibiotics.
2.7. Statistical analysis
Statistical analysis was performed on an intention‐to‐treat basis. All data were analyzed using SPSS 19.0 Statistic Analysis software (IBM Corp., Armonk, NY, USA). The mean and standard deviation was calculated for normally distributed variables, while frequency and percentage were used for categorical variables. The categorical variables, ratio variables, and continuous variables were analyzed using the unpaired t‐test, Pearson χ2 test, or Fisher exact test and Wilcoxon rank‐sum test, respectively. A two‐tailed significance level of P < 0.01 indicated statistical significance.
3. RESULTS
Figure 1 shows the trial profile. A total of 2912 and 2898 women who received titrated OMS and intravaginal dinoprostone, respectively, were enrolled. The baseline characteristics and indications for induction of labor showed no significant difference between the two groups (Table 1).
FIGURE 1.
Study enrollment. Abbreviations: FHR, fetal heart rate; OSM, oral misoprostol solution
TABLE 1.
Baseline characteristicsa
| Variable | OMS (n = 2912) | Dinoprostone (n = 2898) | P value |
|---|---|---|---|
| Age (years) | 27.2 ± 4.1 (18–42) | 27.1 ± 3.7 (18–40) | 0.922b |
| Gestation (weeks) | 39.3 ± 1.6 (36–42) | 39.1 ± 1.2 (36–42) | 0.908b |
| BMI (kg/m2) | 26.1 ± 4.1 (17.1–33.2) | 25.8 ± 4.8 (17.6–33.5) | 0.515b |
| Bishop score | |||
| ≤3 | 1747 (59.9) | 1769 (61.0) | 0.919c |
| 4–6 | 1165 (40.1) | 1129 (39.0) | 0.846c |
| Indications | |||
| Post‐term pregnancy | 869 (29.8) | 883 (32.1) | 0.583c |
| PIH | 353 (12.1) | 327 (11.3) | 0.811c |
| Pre‐eclampsia | 34 (1.2) | 30 (1.0) | 0.667d |
| Gestational hypertension | 232 (7.9) | 216 (7.5) | 0.933c |
| Chronic hypertension | 87 (2.9) | 81 (2.8) | 0.932d |
| Gestational diabetes mellitus | 320 (10.9) | 338 (11.7) | 0.866c |
| Not using insulin | 259 (8.8) | 261 (9.0) | 0.784c |
| Using insulin | 61 (2.1) | 82 (2.8) | 0.442d |
| FGR | 72 (2.5) | 76 (2.6) | 0.622d |
| Oligohydramnios | 151 (5.2) | 123 (4.1) | 0.659c |
| Fetal demise | 8 (0.3) | 6 (0.2) | 0.564d |
| PROM at term | 349 (11.9) | 309 (9.0) | 0.866c |
| Psychosocial indications | 33 (1.1) | 34 (1.2) | 0.882d |
| Othere | 84 (2.9) | 92 (3.2) | 0.690d |
Abbreviations: BMI, body mass index; FGR, fetal growth restriction; OMS, oral misoprostol solution; PIH, pregnancy‐induced hypertension; PROM, premature rupture of membranes; SD, standard deviation.
Values are given as number (percentage) or mean ± SD (range).
Data were analyzed by Wilcoxon rank‐sum test.
Data were analyzed by Pearson χ2 test.
Data were analyzed by Fisher exact test.
Renal disease, chronic pulmonary disease, chronic hypertension, antiphospholipid syndrome, maternal medical conditions, isoimmunization.
To evaluate the efficacy of OMS, the correlative outcomes were compared. The mean interval time from the first treatment to cervix dilation of 2.0 cm was longer in the OMS group compared to the dinoprostone group (12.4 ± 4.6 h vs 8.7 ± 3.5 h, P = 0.008). The mean interval time from the first treatment to vaginal birth was longer in the OMS group compared to the dinoprostone group (20.8 ± 4.7 h vs 14.9 ± 3.4 h, P = 0.003). However, the latent phase interval, the active phase interval, and the total time of labor showed no significant differences between the two groups. These results illustrated that OMS took a longer time compared to dinoprostone to induce effective uterine contractions in the initial stages of induction of labor. The OMS group had an overall higher proportion of vaginal deliveries (P = 0.005), but a lower frequency of vaginal deliveries within 12 h (P = 0.007), compared to the dinoprostone group. However, while the frequency of vaginal deliveries within 24–48 h was higher in the OMS group compared to the dinoprostone group (P = 0.009), that within 12–24 h was comparable between the two groups (P = 0.079).
Among the vaginal deliveries, while the frequency of spontaneous vaginal delivery was higher in the OMS group compared to the dinoprostone group (P = 0.004), that of instrumental vaginal delivery was similar between the two groups (P = 0.067). The incidence of partus precipitatus was lower in the OMS group compared to the dinoprostone group (P = 0.003).
The overall rate of cesarean delivery was significantly lower in the OMS group compared to the dinoprostone group (P = 0.008). Further analysis of the causes of the cesarean delivery, including fetal distress, labor process block, and failed induction, revealed that the frequency of fetal distress was higher in the dinoprostone group compared to the OMS group (P = 0.005). The frequency of requirement for oxytocin augmentation (P = 0.865) and epidural analgesia (P = 0.914) during the labor process was comparable between the two groups (Table 2).
TABLE 2.
Labor outcomesa
| Variable | OMS (n = 2912) | Dinoprostone (n = 2898) | P value |
|---|---|---|---|
| First treatment to cervix dilation 2.0 cm (h) | 12.4 ± 4.6 | 8.7 ± 3.5 | 0.008b |
| Latent phase interval (h) | 8.2 ± 2.4 | 6.9 ± 2.2 | 0.068b |
| Active phase interval (h) | 3.4 ± 1.3 | 3.2 ± 1.5 | 0.826b |
| First treatment to vaginal birth (h) | 20.8 ± 4.7 | 14.9 ± 3.4 | 0.003b |
| Total time of labor (h) | 11.5 ± 3.7 | 9.6 ± 3.8 | 0.134b |
| Delivered vaginally | 2280 (78.3) | 2115 (72.9) | 0.005c |
| ≤12 h | 729 (25.0) | 832 (28.7) | 0.007c |
| 12–24 h | 1345 (46.2) | 1227 (42.3) | 0.079c |
| 24–48 h | 206 (7.1) | 54 (1.8) | 0.009d |
| Vaginal delivery mode | |||
| Spontaneous vaginal delivery | 2004 (68.8) | 1787 (61.7) | 0.004c |
| Instrumental vaginal delivery | 212 (7.3) | 232 (8.0) | 0.067c |
| Partus precipitatus | 54 (1.9) | 96 (3.3) | 0.003d |
| Cesarean delivery | 632 (21.7) | 783 (27.0) | 0.008c |
| Fetal distress | 177 (6.1) | 273 (9.4) | 0.005c |
| Labor process block | 425 (14.6) | 483 (16.7) | 0.039c |
| Failed induction | 30 (1.0) | 27 (0.9) | 0.528d |
| Oxytocin augmentation | 640 (21.9) | 565 (19.5) | 0.865c |
| Epidural analgesia | 2140 (73.5) | 2182 (75.3) | 0.914c |
Abbreviations: OMS, oral misoprostol solution; SD, standard deviation.
Values are given as number (percentage) or mean ± SD.
Data were analyzed by Wilcoxon rank‐sum test.
Data were analyzed by Pearson χ2 test.
Data were analyzed by Fisher exact test.
Based on the cervix Bishop score, patients were classified into two groups: those with a score of 3 or higher or 4–6. The association between the cervix Bishop score and the frequency of vaginal delivery as well as cesarean delivery was then analyzed (Table 3). Among women with a cervix Bishop score of 3 or higher, the OMS group had a higher frequency of vaginal delivery (P = 0.003) and a lower frequency of cesarean delivery (P < 0.001) compared to the dinoprostone group. Analysis of the causes of the cesarean delivery showed that while the OMS group had a lower frequency of fetal distress compared to the dinoprostone group (P = 0.008), the frequency of the labor process block was comparable in the two groups (P = 0.183). There was no significant difference in the rate of failed induction between the two groups (P = 0.729). Among women with a cervix Bishop score of 4–6, the frequency of both vaginal delivery (P = 0.425) and cesarean delivery (P = 0.817) showed no significant difference between the OMS and dinoprostone groups. The causes of the cesarean delivery, including the labor process block and failed induction, were also comparable between the two groups.
TABLE 3.
Correlation between cervix Bishop score and outcome of induction of labora
| Variable | Cervix Bishop score | |||||
|---|---|---|---|---|---|---|
| ≤3 | 4–6 | |||||
| OMS (n = 1724) | Dinoprostone (n = 1769) | P value | OMS (n = 1188) | Dinoprostone (n = 1129) | P value | |
| Vaginal delivery | 1456 (84.5) | 1286 (72.7) | 0.006b | 824 (70.7) | 830 (73.5) | 0.425b |
| Cesarean delivery | 268 (15.5) | 403 (27.3) | <0.001b | 364 (31.2) | 379 (26.5) | 0.817b |
| Fetal distress | 97 (5.6) | 188 (10.6) | 0.008b | 80 (6.7) | 84 (7.4) | 0.213b |
| Labor process block | 151 (8.8) | 196 (11.1) | 0.183b | 274 (23.1) | 287 (25.4) | 0.192b |
| Failed induction | 20 (1.2) | 19 (1.1) | 0.729c | 10 (0.8) | 8 (0.7) | 0.381c |
Abbreviation: OMS, oral misoprostol solution.
Values are given as number (percentage).
Data were analyzed by Wilcoxon rank‐sum test.
Data were analyzed by Pearson χ2 test.
The incidence of maternal and neonatal adverse events is a crucial criterion when evaluating the safety of clinical intervention for induction of labor. Therefore, the correlative maternal and neonate adverse events during the process of induction of labor were analyzed (Table 4). Tachysystole, one of the most common adverse events, is categorized as with and without changes in FHR, according to the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin.5 While the frequency of tachysystole without changes in FHR was similar between the two groups (P = 0.659), that with changes in FHR was higher in the dinoprostone group compared to the OMS group (P = 0.007). The usage of tocolytics was higher in the dinoprostone group than in the OMS group (P = 0.005). The incidence of rupture of membranes showed no significant difference between the two groups (P = 0.623). One woman who was treated with dinoprostone had a complicated uterine rupture and underwent an emergency cesarean delivery and uterine repair because of placental accreta in the uterine horn. The mother and infant had recovered well after 1 month. The frequency of other adverse events, including postpartum hemorrhage, third‐ or fourth‐degree tear of the perineum, chorioamnionitis, and use of intravenous antibiotics, showed no significant differences between the two groups. The incidence of side effects of misoprostol and dinoprostone, including fever, shivering, nausea and vomiting, and diarrhea, showed no difference between the two groups.
TABLE 4.
Maternal and neonatal adverse eventsa
| Variable | OMS (n = 2912) | Dinoprostone (n = 2898) | P value |
|---|---|---|---|
| Maternal adverse events | |||
| Tachystole without FHR changes | 223 (7.6) | 264 (10.1) | 0.657b |
| Tachystole with FHR changes | 104 (3.6) | 249 (8.6) | 0.007b |
| Tocolytics | 248 (8.5) | 463 (15.9) | 0.005b |
| Membrane rupture | 267 (9.2) | 232 (8.0) | 0.623b |
| Postpartum hemorrhage (ml) | 193 (6.6) | 2088 (7.2) | 0.826b |
| ≥500 | 158 (5.4) | 168 (5.8) | 0.941b |
| ≥1000 | 35 (1.2) | 40 (1.4) | 0.834c |
| Third‐ or fourth‐degree tear | 9 (0.3) | 138 (0.4) | 0.697c |
| Uterine rupture | 0 | 1 | |
| Chorioamnionitis | 76 (2.6) | 89 (3.1) | 0.711c |
| Intravenous antibiotics | 2472 (8.5) | 268 (9.2) | 0.881b |
| Fever | 219 (7.5) | 283 (9.7) | 0.169b |
| Shivering | 78 (2.7) | 67 (2.3) | 0.778c |
| Nausea and vomiting | 90 (3.1) | 95 (3.3) | 0.934c |
| Diarrhea | 372 (1.3) | 31 (1.1) | 0.706c |
| Neonatal adverse events | |||
| Non‐reassuring fetal heart rate | 2592 (8.9) | 4458 (15.4) | 0.006b |
| Meconium‐stained liquor | 280 (9.6) | 2898 (9.9) | 0.772b |
| Apgar score | |||
| ≤7 at 1 min | 822 (2.8) | 91 (3.1) | 0.409c |
| ≤7 at 5 min | 8 (0.3) | 12 (0.4) | 0.744c |
| Umbilical vein blood pH ≤7.0 | 2 | 3 | |
| Admission to NICU | 16 (0.5) | 22 (0.7) | 0.792c |
| Infant death | 1 | 1 | |
Abbreviations: FHR, fetal heart rate; NICU, neonatal intensive care unit; OMS, oral misoprostol solution.
Values are given as number (percentage).
Data were analyzed by Wilcoxon rank‐sum test.
Data were analyzed by Pearson χ2 test.
An analysis of the adverse events in neonates showed that the frequency of non‐reassuring FHR in the OMS group was significantly lower than that in the dinoprostone group (P = 0.006). Other adverse events, including meconium‐stained liquor, Apgar score of 7 or less at 1 minute and 5 minutes, and admission to the NICU, showed no significant difference between the two groups. Two neonates in the OMS group and three in the dinoprostone group with umbilical vein blood of pH 7.0 or less required an initial emergency resuscitation and continuous comprehensive treatment but recovered without any complications. One infant in the OMS group died from multiple organ failure induced by hematosepsis, and another in the dinoprostone group died due to neonatal spontaneous cerebral hemorrhage.
4. DISCUSSION
In 2009, the ACOG Practice Bulletin on induction of labor recommended misoprostol for cervical ripening and inducing labor. It suggested administration of 25 μg of misoprostol intravaginally or orally, at a frequency of not more than every 3–6 h.5 In 2011, WHO recommended the use of misoprostol at a low dose (25 μg) either vaginally (every 6 h) or orally (every 2 h) for induction of labor at term.16 In 2012, the International Federation of Gynecology and Obstetrics (FIGO) recommended an oral dose of 25 μg of misoprostol solution every 2 h to induce labor.17 Although different committees have recommended oral misoprostol for induction of labor, its optimal dose and frequency of administration in solution should be studied further in a large clinical controlled trial.
Based on previous findings on titrated OMS for induction of labor, which showed a higher frequency of tachysystole or uterine hyperstimulation at doses greater than 50 μg,6, 16 it was decided not to administer the dose of 60 μg. In the present study, the total duration of labor was longer with OMS than with dinoprostone, though the difference was not significant. The causes were further analyzed because of the long latent phase interval of OMS. The number of women having a vaginal birth in the OMS group (78.3%) was a little higher than that in the dinoprostone group (72.9%). Five trials (681 women) comparing oral misoprostol with intracervical dinoprostone found that the former was associated with a lower rate of failure in achieving vaginal birth within 24 h, but a higher rate of uterine hyperstimulation with changes in FHR.18 While there was also some evidence that oral misoprostol resulted in slower induction, there were no other statistically significant differences. Therefore, OMS for cervical ripening and inducing labor is as effective as dinoprostone.
For the evaluation of the adverse effects of oral misoprostol on induction of labor, the rate of cesarean delivery, tachysystole with or without changes in FHR, and neonatal adverse events were evaluated. The rate of cesarean delivery with OMS was lower than that with dinoprostone. An in‐depth analysis of the causes of the cesarean delivery showed that the incidence of non‐reassuring FHR was higher with dinoprostone than with OMS. Further stratification based on the cervical Bishop score showed that a score of 3 or less resulted in a higher rate of cesarean delivery in the dinoprostone group. The results of the present study were consistent with other studies, showing a correlation between the rate of cesarean delivery and the cervical Bishop score.19, 20, 21 In 12 trials comparing oral misoprostol with vaginal dinoprostone (3859 women), women given oral misoprostol were less likely to need a cesarean delivery.18 Neri et al.19 reported a comparable rate of cesarean delivery between oral misoprostol and vaginal dinoprostone groups. As for the frequency of tachysystole, the present study shows that the rate of tachysystole with changes in FHR was lower with OMS than with dinoprostone. Tachysystole can lead to poor uteroplacental perfusion with a subsequent decrease in fetal oxygenation and may result in poor neonatal outcomes. At least one episode of tachysystole was observed in 10% of the cases during spontaneous labor and in 15% of the cases after induction of labor with oxytocin or prostaglandin E1 or E2, and more cesarean deliveries were performed for non‐reassuring FHR changes.22 In contrast to the previous finding of a higher incidence of rupture of membranes with OMS, the present study found no significant difference between the OMS and dinoprostone groups.
The present study has some limitations. It is a single‐center, randomized study, and therefore, a certain degree of bias cannot be ruled out. In the future, a multicenter, randomized, and controlled trial with a larger sample size would be needed to evaluate the efficacy and safety of OMS for cervical ripening and labor induction.
In conclusion, compared with vaginal dinoprostone, OMS for induction of labor results in a higher rate of vaginal delivery, lower incidence of cesarean delivery, but takes a longer time for induction of labor. Oral misoprostol resulted in a lower frequency of tachysystole with changes in FHR. In short, the use of OMS is an effective, safe, and feasible method for cervical ripening and induction of labor. The present study will provide a good reference for clinicians in choosing a method of induction of labor.
CONFLICTS OF INTEREST
The authors have no conflicts of interest.
AUTHOR CONTRIBUTIONS
XW: protocol development and writing of the manuscript; CZ: data collection, management, and writing of the manuscript; LX: data analysis and revision of the manuscript; HQ: data collection, management, and writing of the manuscript; QL: data collection and revision of the manuscript; JL: data collection, management, and writing of the manuscript; LZ: data collection and draft writing.
ACKNOWLEDGMENTS
This trial was funded by the Xi'an Science and Technology Project, no. 20160525SF/YX08(2).
REFERENCES
- 1.Margulies M, Campos Pérez G, Voto LS. Misoprostol to induce labour. Lancet. 1992;139(8784):64. 10.1016/0140-6736(92)90194-8 [DOI] [PubMed] [Google Scholar]
- 2.Bugalho A, Bique C, Machungo F, et al. Low‐dose vaginal misoprostol for induction of labor with a live fetus. Int J Gynaecol Obstet. 1995;49(2):149–155. [DOI] [PubMed] [Google Scholar]
- 3.Farah LA, Sanchez‐Ramos L, Rosa C, et al. Randomized trial of two doses of the prostaglandin E1 analog misoprostol for labor induction. Am J Obstet Gynecol. 1997;177(2):364–369. [DOI] [PubMed] [Google Scholar]
- 4.Vogel JP, West HM, Dowswell T. Titrated oral misoprostol for augmenting labour to improve maternal and neonatal outcomes. Cochrane Database Syst Rev. 2013;9:CD010648: 10.1002/14651858.CD010648.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.ACOG Practice Bulletin No.107 . Induction of labor. Obstet Gynecol. 2009;114(2 Pt 1):386–397. [DOI] [PubMed] [Google Scholar]
- 6.McMaster K, Sanchez‐Ramos L, Kaunitz AM. Balancing the efficacy and safety of misoprostol: a meta‐analysis comparing 25 versus 50 micrograms of intravaginal misoprostol for the induction of labour. BJOG. 2015;122(4):468–476. 10.1111/1471-0528.12935 [DOI] [PubMed] [Google Scholar]
- 7.Tsakiridis I, Mamopoulos A, Athanasiadis A, et al. Induction of labor: an overview of guidelines. Obstet Gynecol Surv. 2020;75(1):61–72. 10.1097/OGX.000000000000075 [DOI] [PubMed] [Google Scholar]
- 8.Ngai SW, To WK, Lao T, et al. Cervical priming with oral misoprostol in pre‐labor rupture of membranes at term. Obstet Gynecol. 1996;87(6):923–926. [DOI] [PubMed] [Google Scholar]
- 9.Hofmeyr GJ, Matonhodze BB, Alfirevic Z, et al. Titrated oral misoprostol solution–a new method of labour induction. S Afr Med J. 2001;91(9):775–776. [PubMed] [Google Scholar]
- 10.Hofmeyr GJ, Alfirevic Z, Matonhodze B, et al. Titrated oral misoprostol solution for induction of labour: a multi‐centre, randomised trial. BJOG. 2001;108(9):952–959. [DOI] [PubMed] [Google Scholar]
- 11.Aalami‐Harandi R, Karamali M, Moeini A. Induction of labor with titrated oral misoprostol solution versus oxytocin in term pregnancy: randomized controlled trial. Rev Bras Ginecol Obstet. 2013;35(2):60–65. [DOI] [PubMed] [Google Scholar]
- 12.Rouzi AA, Alsahly N, Alamoudi R, et al. Randomized clinical trial between hourly titrated and 2 hourly static oral misoprostol solution for induction of labor. Am J Obstet Gynecol. 2017;216(4):405.e1–405.e6. [DOI] [PubMed] [Google Scholar]
- 13.Kashanian M, Bahasadri S, Nejat Dehkordy A, et al. A comparison between induction of labor with 3 methods of titrated oral misoprostol, constant dose of oral misoprostol and Foley catheter with extra amniotic saline infusion (EASI), in women with unfavorable cervix. Med J Islam Repub Iran. 2019;28(33):115–120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Thaisomboon A, Russameecharoen K, Wanitpongpan P, et al. Comparison of the efficacy and safety of titrated oral misoprostol and a conventional oral regimen for cervical ripening and labor induction. Int J Gynaecol Obstet. 2012;116(1):13–16. [DOI] [PubMed] [Google Scholar]
- 15.Wang X, Yang A, Ma Q, et al. Comparative study of titrated oral misoprostol solution and vaginal dinoprostone for labor induction at term pregnancy. Arch Gynecol Obstet. 2016;294(3):495–503. 10.1007/s00404-015-4000-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.World Health Organization . WHO rRecommendations for induction of labour. 2011. http://apps.who.int/iris/bitstream/handle/10665/44531/9789241501156
- 17.FIGO Working Group on Prevention of Unsafe Abortion and its Consequences, International Federation of Gynecology and Obstetrics . The combination of mifepristone and misoprostol for the termination of pregnancy. Int J Gynaecol Obstet. 2011;115(1):1–4. 10.1016/j.ijgo.2011.07.013 [DOI] [PubMed] [Google Scholar]
- 18.Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induction of labour. Cochrane Database Syst Rev. 2014; 10.1002/14651858.CD001338.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Eleje GU, Ezugwu EC, Ugwu EO, et al. Premaquick© versus modified Bishop score for preinduction cervical assessment at term: a double‐blind randomized trial. J Obstet Gynaecol Res. 2018;44(8):1404–1414. 10.1111/jog.13691 [DOI] [PubMed] [Google Scholar]
- 20.Branger B, Dochez V, Gervier S, et al. Cesarean after labor induction: risk factors and prediction score. Gynecol Obstet Fertil Senol. 2018;46(5):458–465. 10.1016/j.gofs.2018.03.008 [DOI] [PubMed] [Google Scholar]
- 21.McCoy J, Downes KL, Srinivas SK, et al. Postdates induction with an unfavorable cervix and risk of cesarean. J Matern Fetal Neonatal Med. 2019;32(17):2874–2878. 10.1080/14767058.2018.1450861 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ahmed AI, Zhu L, Aldhaheri S, et al. Uterine tachysystole in spontaneous labor at term. J Matern Fetal Neonatal Med. 2016;29(20):3335–3339. 10.3109/14767058.2015.1125463 [DOI] [PubMed] [Google Scholar]