Isosorbide mononitrate for preinduction cervical ripening at or post-term pregnancy: randomised placebo-controlled clinical trial

Introduction

Induction of labour (IOL) is a common practice in modern obstetrics, aimed at initiating uterine contractions before spontaneous labour begins, with or without the rupture of membranes.1 The condition of the cervix plays a crucial role in determining the success of labour induction. For primigravida women, the average time from induction to delivery is approximately 27 hours, with around 18 hours required for cervical softening before labour commences. Cervical ripening, which involves the preparation of cervical tissue for childbirth, is essential to reduce the risk of caesarean delivery and failed induction.2 An ideal cervical ripening agent should soften the cervix without causing uterine contractions, hypertonicity or necessitating fetal monitoring, while minimising adverse effects on both the mother and fetus. Prostaglandins, commonly used for this purpose, often induce uterine contractions due to their effects on the myometrium, sometimes requiring tocolytic therapy.3 Nitric oxide, a natural substance produced by the cervix, has been proposed as a key mediator of cervical softening before the onset of labour.3 Unlike prostaglandins, nitric oxide donors, which increase nitric oxide levels in the body, are becoming increasingly popular for cervical ripening because of their minimal impact on uterine contractions.2 This study aimed to evaluate the safety and effectiveness of isosorbide mononitrate (ISMN) as a cervical ripening agent in pregnant women at term or post-term.

Materials and methods

From December 2023 to June 2024, we conducted a prospective, double-blind, randomised, placebo-controlled clinical trial at a maternity hospital. We included pregnant women at or beyond term with an unfavourable cervix (Bishop score<6). The trial was designed and conducted in compliance with the Enhancing the QUAlity and Transparency ofHealth Research network guidelines, specifically adhering to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomised clinical trials.4 Following approval from the scientific and ethical commission, 40 women were excluded due to meeting the exclusion criteria or opting out of participation. We informed 160 women about the trial, obtained written informed consent and recruited them after discussing other delivery options, including caesarean section. Eligible participants were primigravida women aged 20–35 with a prepregnancy body mass index (BMI)<30 kg/m² and indications for labour induction. Inclusion criteria included single cephalic term or post-term pregnancies, a Bishop score of less than 6, fetal weight between 2.9 and 3.7 kg and an appropriate pelvic diameter. Exclusion criteria included regular uterine contractions, previous uterine scars, fetal distress, non-reassuring Cardiotocography, malpresentation, multiple gestations, indications for caesarean section (eg, severe cephalopelvic disproportion or fetal macrosomia), placenta previa, vasa previa, active genital herpes, severe maternal illnesses and premature rupture of membranes with signs of chorioamnionitis. Participants underwent vaginal and abdominal examinations, regular obstetric ultrasounds and prenatal evaluations. They were randomly assigned to the ISMN or placebo group using the SPSS Random Number Generator (IBM, Chicago, Illinois, USA) in a 1:1 ratio. The hospital pharmacy prepared sequentially numbered envelopes containing ISMN or placebo, ensuring the blinding of the physicians, nurses and participants. On admission, a senior resident assessed the modified Bishop score, evaluating cervical dilation, length, position, consistency and station. In the ISMN group, a single intravaginal ISMN tablet (Effox 40 mg; Mina Pharm, Egypt) was inserted into the posterior fornix every 4 hours, up to four times. Cervical evaluations continued until labour onset, with a partogram used to monitor cervical dilation after it reached 4 cm. If the Bishop score remained <6 after ISMN doses, a second ripening agent (PGE2 pill) was administered intracervically, with up to two doses given 6 hours apart. Participants with a favourable cervix (Bishop score≥6) underwent amniotomy and oxytocin augmentation (Syntocinon 5 IU/mL: Novartis, Egypt). The oxytocin infusion was started at 4 mIU/min and was increased every 30 min up to 16 mIU/min, with labour management following hospital protocols. Induction failure was defined as the absence of labour despite two doses of PGE2 and maximum oxytocin stimulation. Monitoring included fetal cardiotocography, maternal pulse and blood pressure checks 30 min before medication administration, as well as 1 and 6 hours afterwards. Intrapartum monitoring followed American College of Obstetricians and Gynecologists guidelines. The placebo group received an intravaginal pyridoxine placebo tablet every 4 hours, up to four doses. If labour did not commence, an oxytocin infusion was provided in the same manner as the ISMN group. Failure to induce labour after four ISMN doses, amniotomy and oxytocin infusion resulted in caesarean section in both groups. The primary outcome was the effectiveness of vaginal ISMN for cervical ripening, measured by the time from labour induction to delivery. Secondary outcomes included maternal complications, the need for oxytocin augmentation, fetal outcomes, delivery method and caesarean section rates. For those undergoing caesarean section, the time was measured until the decision for surgery was made. According to findings from a prior publication,5 the time span between induction and the active phase of delivery with vaginal isosorbide mononitrate was approximately 387.6±215 min, compared with approximately 520±201 min in the placebo group. Subsequently, our calculation determined that a minimum sample size of 39 participants in each group was necessary to reject the null hypothesis with 80% power at an α=0.05 level, using a t-test for independent samples. This sample size calculation was conducted using MedCalc Statistical Software V.19.5.3 (MedCalc Software, Ostend, Belgium; https://www.medcalc.org; 2020). Data were analysed using SPSS V.26.0. Categorical data were reported as percentages and compared using the χ² or Fisher’s exact test. The Kolmogorov-Smirnov test was used to assess the normality of continuous data, which were reported as mean±SD. Group comparisons were performed using an unpaired t-test for parametric data or a Mann-Whitney U test for nonparametric data, with p<0.05 considered statistically significant.

Results

A total of 160 women were randomly assigned to either the ISMN group or the placebo group, with 80 participants in each group (see figure 1). After the trial began, seven participants in the ISMN group and four in the placebo group withdrew voluntarily. Table 1 shows that there were no statistically significant differences in demographic characteristics between the two groups, including age, BMI, gestational age, initial Bishop score and indications for labour induction. Table 2 shows significant differences in labour and delivery characteristics in the ISMN group, including Bishop score after the full dose, changes in Bishop score, the number of Bishop scores≥6, the need for additional ripening agents and the use of oxytocin to support labour. However, there were no significant differences between the groups in terms of mode of delivery or reasons for caesarean section. Significant differences were observed between the groups in terms of time from induction to delivery (as shown in table 3), except for the duration of the active phase, second stage of labour and third stage of labour. Table 4 shows maternal outcomes, with significant differences in the incidence of headaches, palpitations and flushing. There were no significant differences in the frequencies of tachysystole, uterine hypertonus, meconium-stained amniotic fluid, postpartum haemorrhage, nausea, fever, shivering, hypotension or tachycardia. Finally, table 5 shows that there were no statistically significant differences in fetal outcomes between the groups, including Apgar scores at 1 and 5 min, transient tachypnea of the newborn, acute respiratory distress syndrome, neonatal intensive care unit (NICU) admissions, neonatal infection or birth weight.

Discussion

The study found that the ISMN group experienced a significant increase in Bishop score after receiving the full dose of ISMN. The mean change in Bishop score was significantly higher in the ISMN group compared with the placebo group, leading to a reduced need for additional ripening agents and faster labour progression after amniotomy and oxytocin augmentation. These consistent findings align with previous studies demonstrating the effectiveness of ISMN in improving Bishop scores and expediting delivery.6 7 Furthermore, our study did not find a significant reduction in caesarean section rates between the two groups, which is consistent with previous studies that reported stable caesarean rates across different studies.8–11 However, some studies have reported varying results. Despite showing clinical benefits in shortening labour duration, one study did not find an increase in mean Bishop score following ISMN administration.11 Another study found no significant difference in mean Bishop score between groups, possibly due to differences in dosage and sample size.2 Regarding ripening agents, our study observed a non-significantly lower need for additional ripening agents in the ISMN group, which is in line with previous studies.2 In contrast, other studies have reported significant differences in the need for additional ripening agents,8–10 likely due to variations in sample size. Our study also noted significant labour progress in the ISMN group following oxytocin augmentation, consistent with earlier findings.9 Conversely, some studies have reported a significant increase in oxytocin use in the placebo group to assist labour progression,6 8 possibly due to the inclusion of multiparous women. However, several studies have found no significant differences in oxytocin requirements between groups,2 5 10 which may be attributed to differences in sample size and dosing. Our study found no significant differences in adverse maternal and neonatal outcomes between the two groups, except for a higher incidence of headaches, palpitations, and flushing in the ISMN group. These findings are consistent with previous research.9 10 12

In our study, we excluded pregnant women with intrauterine growth restriction (IUGR), obesity, hypertension and diabetes mellitus due to the high-risk nature of these conditions. Managing these pregnancies involves intensive monitoring—such as frequent Doppler studies for IUGR or regular glucose checks and ultrasounds for diabetic and obese patients—to address complications such as macrosomia, birth trauma, eclampsia and placental abruption. This level of specialised care may not be feasible in all healthcare settings, particularly those with limited resources. By excluding these high-risk groups, our study focused on a population with a more consistent risk profile, allowing for a clearer assessment of the intervention’s effectiveness without the confounding effects of these complex conditions. Nonetheless, research indicates that IOL in cases of IUGR, obesity with diabetes and pre-eclampsia can be beneficial. For example, IOL at 37 weeks in IUGR cases is linked to reduced neonatal morbidity and does not significantly increase caesarean section rates compared with expectant management, provided the fetus is stable.13–16 In obese diabetic women, IOL at 39 weeks helps reduce risks such as shoulder dystocia and other neonatal complications, despite a higher likelihood of caesarean delivery.17–21 For pre-eclampsia, IOL at 37 weeks decreases severe maternal and neonatal complications, though it may slightly increase the risk of caesarean section.22–25 Guidelines from ACOG and NICE suggest that induction in these high-risk cases at specific gestational ages can improve maternal and neonatal outcomes, carefully balancing the risks of continuing pregnancy with the potential for caesarean delivery.15 19–21 24 25

Conclusion

In conclusion, our study suggests that ISMN is an effective and safe agent for cervical ripening, potentially reducing labour duration in primiparous women.