About 20% of all pregnancies will need to be induced at a certain time during the gestation for a particular indication [1], postdate being the commonest indication for induction. There are many methods described and used to induce labor [2, 3]: these include, but are not limited to, Misoprostol, Oxytocin, membrane sweeping or stripping, balloon catheter, nipple stimulation, intercourse and herbal remedies. However, vaginal prostaglandin E2 (Dinoprostone, Prostin®) [4, 5] has been used extensively as the preferred way for induction by most specialized institutions and is considered to be the safest option for the mother and neonate as well as the most effective one to induce vaginal delivery within 24 hours for women with an unfavorable cervix [6-11]. However, there is no full agreement on the ideal dosage of PGE2 that should be used to achieve the optimal outcome [12-14]. Moreover, there is much debate concerning the frequency of PGE2 use, whether there are different regimens for multiparous women [15], and at what point induction of labor has failed and that a cesarean section should be the exclusive and definitive mode of delivery. These issues of uncertainty have been addressed by the Royal College of Obstetricians and Gynaecologists (RCOG) and the National Institute for Health and Clinical Excellence (NICE) guidelines in 2001 and 2008; subsequently, a limited number of studies have briefly explored this area but with contradictory results [16].

The current definition of failed induction by NICE (2008) is a failure to establish labor after one cycle of treatment consisting of the insertion of two vaginal PGE2 tablets (3 mg) or gel (1-2 mg) at 6-hourly intervals, or one PGE2 controlled-release pessary (10 mg) over 24 hours. In this situation, NICE recommends counseling the patient about either continuing the induction process by inserting additional doses of vaginal PGE2 or by performing a cesarean section. The paucity of reassuring data about maternal and neonatal safety and the limited information about the success rate of giving birth after exceeding the recommended dose of vaginal PGE2 make this counseling significantly deficient: the final decision still remains extremely difficult. Hence, this dilemma has attracted numerous researchers, including our group, keen to fill this knowledge gap [16-18].

We conducted this study to evaluate the association between repeated doses of vaginal PGE2 and maternal and neonatal outcomes for primigravid and multiparous women. The results can be applied worldwide, especially where there is intention to reduce the alarmingly high rates of cesarean section. The use of additional doses of vaginal PGE2 may be a beneficial way of limiting the steady rise of global cesarean section rates without compromising the wellbeing of mothers and neonates.

We reviewed the medical literature in the PubMed database, searching for similar published studies that examine the correlation between exceeded doses of PGE2 for the induction of labor and maternal and neonatal outcomes. The most recent similar study was a retrospective one conducted at Aberdeen Maternity Hospital in the UK in October 2013. It showed that additional doses of vaginal PGE2 for nulliparous women with singleton pregnancies who were induced for being postdate were not associated with higher rates of adverse neonatal or maternal outcomes; nearly half of the women delivered vaginally [16]. An older randomized controlled study, conducted at Singapore General Hospital in 1999, also showed that using vaginal PGE2 three times over 24 hours, 6 hours apart, was more effective for the induction of labor in primigravid women with singleton pregnancies than for a second group taking one tablet of PGE2 over the same duration. However, there was no difference in the cesarean section rates or instrumental deliveries between the two groups. There was also no difference in neonatal outcomes, nor any cases of uterine hyperstimulation requiring treatment [14]. A study carried out in China in 2002 compared the rates of intrapartum cesarean section in (i) women who had a favorable Bishop score and for whom no prostaglandins had been inserted for the induction of labor with (ii) women who had had one or two doses of Prostaglandin for induction and (iii) women who had received three doses of Prostaglandin for the induction of labor. It was found that the third group had the highest rate of emergency cesarean sections, not to mention the impact on maternal and fetal wellbeing [19].

In addition to the aforementioned studies, a clinical survey of obstetric units conducted in England in 2007 showed that more than 86% of medical practitioners regularly used more than the recommended dose of vaginal PGE2, supporting the clinical claim that repeated doses of vaginal PGE2 is safe for both the mother and the neonate [20]. We also conducted our own electronic survey among Jordanian obstetricians in 2018 and asked them, “Do you think that inserting a third dose of Prostin® (3 mg Dinoprostone) for the induction of labor for primigravid women is safe for the mother and the neonate?” As expected, the results confirmed the general, global consensus among professional practitioners about the safety of repeated doses of vaginal PGE2. The response rate was 70.5% as 55 out of 78 responded to the question with either yes or no. The survey showed that 80% of the respondents, (44 out of 55), said that they used vaginal PGE2 above the doses recommended by the NICE guidelines as they felt it was a perfectly safe practice.

Modern obstetrics should be based on a solid body of evidence rather than on a vague clinical sense of what should be done. The evidence should be carefully examined before any current practice is changed. Our study assessed the relation between repeated doses of PGE2 and maternal and neonatal safety. We evaluated the relationship between repeated doses of PGE2, above the recommended dose, for the induction of labor for different indications, as well as the maternal and neonatal outcomes. The results of our study support the clinical sense that additional doses of vaginal PGE2 above the recommended dosage do not increase maternal or neonatal morbidity. This result gives the study the potential to reduce the rate of cesarean sections, as it encourages all professional medical practitioners caring for women admitted to the labor ward for the induction of labor to continue the process of induction for women with unfavorable cervixes by repeating vaginal PGE2 insertion for a third time.

We believe that adopting this policy will increase the number of vaginal births, which in turn will have a direct beneficial effect on patients, enabling them to avoid major surgery along with its potential complications. There will also be an indirect beneficial effect on national health systems as costs and the need for caesarian specialists will be substantially reduced. This potential benefit will be of great importance not only in Jordan but worldwide for, due to many reasons [21], there has indeed been a universal rise in the number of cesarean sections. Particularly in Jordan, the escalating rate of cesarean deliveries is a major concern. For example, Al Rifai found that cesarean section rates have risen over time from 18.2% in 2002, to 20.1% in 2007, and to 30.3% in 2012 [22].

Our study has shown that repeated doses of vaginal PGE2 insertion for the induction of labor above the current recommendations are not associated with increased maternal or neonatal morbidity for both primigravid and multiparous women. But it has also shown that in primigravid women, the risk of cesarean section will increase for women who have received more than two doses of PGE2. In other words, the study supports the need for counseling primigravid women who have had the recommended doses of PGE2 but have not yet shown a response to it. Our study has demonstrated that such women are in fact less likely to have a vaginal birth if they agree to take a third dose of PGE2. There is, however, a nearly 30% chance for such women to deliver vaginally and avoid a cesarean section if they agree to a third dose. At the same time, they can be reassured that a third dose will have no adverse effect on them or on the neonate. By thus focusing on the positive aspects of a third dose of PGE2 in primigravid women, we anticipate a reasonable reduction in cesarean section rates among those primigravid women who had previously been considered failed to be induced. This could be achieved if the current practice changes such that a third dose of PGE2 is administered to all women scheduled for the induction of labor. We are confident that this can be achieved especially when we are reassured by the fact that there was no single case of uterine hyperstimulation in our study. The adoption of this recommendation will have a tremendous effect in hospitals, such as our labor ward unit, where the cesarean section rate is high. For multiparous women, our study showed no significant change in the risk of having a cesarean section or any significant clinical harm from a third dose of PGE2.

Maternal morbidity was not fully assessed in our study other than in cesarean section rates, uterine hyperstimulation and uterine rupture. In fact, we wanted to include the postpartum hemorrhage rate among women in our study as one of the studied variables, but there were difficulties in assessing the exact amount of bleeding, and post-delivery hemoglobin levels were not done routinely for all patients delivered vaginally. Future studies that include a larger number of women and focus more on maternal morbidity might provide better results.

The authors are thankful to Jordan University of Science and Technology/ King Abdullah University Hospital (IRP number 49/116/2018).

The authors declare no competing interests.