In this prospective cohort study, we assessed the safety and efficacy of misoprostol for induction of labour in nulliparous women, with two different routes of administration; 25 mcg oral tablets and 200 mcg slow release vaginal-insert in a total of 288 women. We found no significant difference in women achieving vaginal delivery. For safety aspects, this study found a significantly increased risk of tachysystole for the vaginal administration route; 28.4% compared with 2.3% (RR 12.2; CI 4.5–34). However, there were no events of serious neonatal asphyxia in this group. The time from induction to delivery was significantly shorter for the vaginal administration route, where more than half the women had delivered within 24 h, compared with 16.8% in the oral administration group, leading to smaller risk of prolonged rupture of membranes and pyrexia, although not significant. The efficacy of vaginal insert of misoprostol also led to a significantly decreased use of additional augmentation methods such as artificial rupture of membranes, balloon-catheter and use of oxytocin. The number of failed inductions leading to CS was also decreased. We found a tendency of increased risk of developing pyrexia in the women who received oral tablets. Nevertheless, the difference was not statistically significant probably due to the size of our material. Pyrexia has previously been reported as a side effect to misoprostol when used in higher doses for prevention of post-partum hemorrhage [13,14,15], but it may also be attributed to the increased risk of prolonged rupture of membranes that was observed in this study.
The present study was subject to methodological limitations as it was neither randomised nor blinded and set in two different hospitals. However, apart from inclusion of women with gestational diabetes the two populations were comparable and a subanalysis excluding the women with gestational diabetes did not change the results (Additional file 1: Table S1 and S2). Another limitation of the study was the in- vs out-patient regimen for the induction, where tachysystole could be thoroughly observed in the in-patient group (vaginal insert), and may have been underestimated in the out-patient setting (oral tablets).
Further limitations of the present study were a lack of data on all neonatal morbidity (i.e. admission to a neonatal department, proven bacterial infection, cooling and seizures etc.) due to restricted permissions for accessing the children’s medical records. Therefore, neonatal asphyxia is the only reported item on neonatal morbidity.
Since the study was not blinded the healthcare professionals might have contributed to inadvertent bias. Healthcare professionals were aware of the risk of tachysystole prior to the present trial and may have been prone to act outside of the guidelines for the regimen. The midwives may have been affected by this in choosing induction method (artificial rupture of membranes or medical induction), and this could subsequently be reflected in the slightly lower Bishop score for the women induced with vaginal misoprostol had.
Unfortunately, the desired number of women included in this study was not reached due to logistical matters resulting in a weaker statistical power.
No previous studies have compared misoprostol vaginal slow-release insert with oral misoprostol. The present study included only nulliparous women at term with intact membranes leading to two relatively homogenous study-groups.
Women’s experiences on a fast vs a slow delivery have not previously been investigated, which will be reported for the women included in this study in a separate publication.
Previous studies on nulliparous women with doses of oral misoprostol between 25 and 50 mcg found that delivery within 24 h occurred in 15 and 36% respectively; which is similar to our results [16, 17]. Rates of CS were reported as 13.6–32% in the same studies.
The misoprostol slow-release vaginal insert has been assessed in five previous studies, also including multiparous women, that found consistent results compared with ours. Time from induction to delivery has been reported between 14.5–26.6 h and rates for CS was 7.5–40.1 [17,18,19,20,21,22,23]. Frequency of hyperstimulation was reported between 4.0 and 48.1%, leading to a higher CS rate and negative effects on neonatal outcomes. In the present study, the women induced with vaginal insert were hospitalised from the time of induction and therefore monitored thoroughly. When tachysystole occurred, health care professionals were able to take relevant measurements and we did not observe any adverse outcomes in CS rates and serious neonatal asphyxia.
With the observed risk of tachysystole for vaginal insert, it is of essence that the woman and healthcare professionals are informed of the risks and induction is commenced in an in-patient setting to ensure patient safety, where there are means to take appropriate action if tachysystole occurs. Vaginal insert with misoprostol has some advantages compared with oral misoprostol tablets and there may be some individuals who could benefit from this method of induction, for instance where induction of labour is expected to be particularly difficult and/or prolonged. In a subgroup analysis on women with BMI > 30 or immature cervical conditions (Bishop score ≤ 4), the results were consistent with the whole groups, and these subgroups of women does not seem to benefit from one method of induction over the other (Additional file 1: Table S3).
A Cochrane analysis in 2014 stated, “Any proposed dose regimen includes a trade-off between rapid birth and uterine hyperstimulation” . This seems evident in the present study where not only the risk of tachysystole is a matter of safety, but also the length of an induction and consequently the risk of prolonged rupture of membranes, antibiotics, pyrexia and failure of induction is a matter of safety both for the woman and her child.
Besides safety being the major concern for labour induction, there are also a number of practical implications to consider in choosing a method of induction. In this study, oral misoprostol appeared to be safe in an outpatient setting, whereas the vaginal insert only could be recommended to use when the patient is hospitalised and monitored thoroughly. From an economical perspective, induction of labour is costly, in both medication/devise expenses and staff-time. The average price for induction of labour varies between countries and the local sett-up at the hospital, and have therefore not been calculated in the present study. However, the additional number of medications and devises (i.e. oxytocin stimulation, double balloon catheter, epidural and antibiotics) were significantly higher the oral misoprostol group of women. The average staff time spent on labour inductions is seemingly higher for the women induced with oral misoprostol, although the majority of the women in this group was induced in an outpatient setting and the time from induction to delivery is not a reasonable estimate for the staff-time spent on the induction.