Abstract
Background/Aim: Labor is induced in 1 out of 5 pregnancies. This is why we aimed to compare two different protocols of orally administered misoprostol for the induction of labor (IOL), with special regard to maternal and fetal outcome, delivery mode and duration. Patients and Methods: One hundred and twenty four patients with a medical indication for IOL were divided into two groups: Group A (n=63), which initially received 50 μg misoprostol escalated to 100 and, subsequently, to 200 μg every 4 h with a daily maximum of 600μg, between 11/2007 and 01/2008; and Group B (n=61), which initially received 25 μg misoprostol followed by 100 μg every 4 h with a daily maximum of 300 μg, between 12/2009 and 04/2010. Results: The mean administration-delivery interval was significantly lower in Group A (19.0 h) compared to Group B (27.1 h, p<0.05). Overall caesarean section rate, average birth weight, APGAR score, umbilical cord pH and meconium-stained fluid rates were similar between both groups. Conclusion: A higher dosage protocol of orally administered misoprostol significantly reduces the mean induction-delivery interval without increasing the risk for an adverse maternal or fetal outcome.
Although misoprostol is used in delivery rooms all over the world for many decades, there are still emerging discussions concerning the safety of this agent. In Germany, in the beginning of 2020, a new public debate about the usage of misoprostol for induction of labor (IOL) unsettled many patients (1). Medical professionals experienced growing uncertainty and anxiety in expectant parents when IOL becomes medically necessary.
Misprostol is a prostaglandin E1 analogue used for different indications in perinatal medicine (2). Its way of administration, dosage, risks and benefits, are still under debate. Most common indications are cervical ripening and uterine stimulation (2). As the aim of every medical intervention should be to achieve an optimal outcome for mother and newborn, the primary purpose of IOL is a safe vaginal delivery and the reduction of adverse pregnancy outcomes. It should only be performed in cases where expectant management puts mother and child at a higher risk than a premature delivery.
In Germany, the usage of misoprostol in obstetrics is still off-label. Product license offers limited use in the gastrointestinal system. The original indication of misoprostol is for treating ulcers of the digestive tract (2). The pharmaceutical company Pfizer has never initiated an approval process to extend the indication for its use in perinatal medicine. For this reason, there are neither official obstetric indications and dosage recommendations nor a list of dose-dependent side effects. Despite this, other European countries already have the option to use a labeled drug of a low-dose oral misoprostol for IOL. In fact, Angusta® is on the market since 2013 in the Nordic countries and will probably be in Germany within the next few years. In the literature, there are plenty of different misoprostol dosage schemes and application modes reported. While current recommendations of WHO suggest administering 25 μg oral misoprostol every 2 h (3), most studies published report the use of higher dosages (4-6).
Although being an off-label drug, in 2013, a nationwide survey revealed that oral misoprostol was used by 66% of German obstetric departments for IOL. The most common dosage regime was 50 μg followed by 100 μg every 4 h (7).
In this study, we focused on the comparison between different dosage schemes of orally administered misoprostol to induce labor, with respect to: i) fetal outcome, ii) delivery mode and iii) duration between the application of misoprostol and delivery.
Patients and Methods
We report on 124 patients who had a medical indication for IOL and received different dosage schemes of oral misoprostol. The gestational age was beyond 34+0 weeks of pregnancy in all cases.
In group A (n=63) patients received an initial dose of 50 μg misoprostol. Four hours later, patients received a second dose of 100 μg misoprostol. If no labor emerged, the next dose was 200 μg, repeated every 4 h. The daily maximum dosage was 600 μg. Data from group A were obtained between 11/2007 and 01/2008. Group B (n=61) received an initial dose of 25 μg misoprostol. Four hours later, the next dose was 100 μg, which was repeated every 4 h until labor occurred. The daily maximum dosage of misoprostol in group B was 300 μg. Data from this group were collected between 12/2009 and 04/2010.
Data were acquired retrospectively, based on birth records through the electronic database Viewpoint® (General Electric Healthcare, Chicago, IL, USA). The time interval of monitoring was chosen at random without any special aspects.
Before each IOL we performed an individual risk-benefit analysis. Each patient was seen by a senior physician and had an ultrasound and a vaginal examination. The following criteria were assessed: i) Bishop score, ii) estimated birth weight, based on fetometry, iii) presence of amniotic fluid, iv) flow of the umbilical artery, v) basic blood count, vi) blood clotting and vii) initial cardiotocography (CTG). The Bishop score did not influence the indication modality chosen.
Inclusion criteria were: i) singleton pregnancy with a cephalic presentation and ii) a gestational age beyond 34+0 weeks. Medical indications for IOL were: i) late-term or post-term pregnancies (>41+0 weeks), ii) diabetes mellitus, iii) premature rupture of membranes (PROM), iv) preeclampsia, v) fetal growth restriction and vi) placental insufficiency without fetal centralization. There were also patients undergoing induction of labor because of special maternal conditions (thrombocytopenia, elevated liver enzymes or bile acids, psychosocial stress, lumboischialgia, urinary obstruction and fetal diseases (congenital pulmonary airway malformation, vitium cordis, Cytomegalovirus infection). Other medical reasons were fetal macrosomia, polyhydramnios with unknown genesis, oligohydramnions and abnormal cardiotocography.
Patients with uterine scars due to previous caesarean section as well as patients with any other contraindication for the use of misoprostol, such as myomectomy, Crohn’s disease, ulcerating colitis, severe bronchial asthma, were not included.
Every patient received detailed medical information about the “off-label use” of misoprostol from the doctor in charge. A standardized information sheet had to be signed by both patients and doctors. In both groups, a 30 min CTG was performed before the first application of misoprostol. Following the first dose of orally administered misoprostol CTG was continued for at least 60 min. If CTG was classified as normal, the next CTG was done after 2 h for at least 15 min before the next administration of misoprostol.
The administration of misoprostol was stopped when adequate uterine contractions would be noticed (33 contractions in 10 min). If contractions would become less frequent and the cervix would not dilate IOL was continued following the aforementioned schemes.
Statistical analysis was performed using SPSS 22.0 (IBM, Armonk, NY, USA). The normal distribution of data was proven with the Kolmogorov-Smirnov test. Student t-tests and Mann-Whitney U-tests were performed in order to explore significant differences between the two groups. A p-Value of less than 0.05 was considered significant.
Results
The demographic characteristics of both groups are displayed in Table I. Maternal and gestational age at delivery were similar in both groups. There were, also, no differences between the overall Bishop Score as well as a Bishop Score>6. The indications for IOL as well as the parity rates were also similar. Most women in either group were nulliparous (57.1% in Group A vs. 65.6% in Group B).
List of primer sequences.
Main maternal outcome parameters are shown in Table II. The mean administration-delivery-interval was significantly lower in Group A compared to Group B (19.0 vs. 27.1 h, p<0.05). The interval between administration and recording of effective constant contractions was also lower in Group A compared to Group B but did not achieve statistical significance (14.0 vs. 21.7 h). In nulliparous women, the time from the administration of misoprostol until effective constant contractions was also lower in Group A compared to Group B (14.0 vs. 21.1 h). Nulliparous women in Group A delivered around 8 h earlier compared to women in Group B (19.8 vs. 27.9 h).
Maternal outcome.
Successful induction, defined as spontaneous or operative vaginal delivery, was achieved in 85.7% (Group A) and 85.2% (Group B). The overall Caesarean section rate was 14.5% (14.3% in Group A and 14.7% in Group B). The rate of operative vaginal delivery was similar between the two groups. Around three quarters of women in both groups delivered spontaneously (76.2% in Group A and 78.7% in Group B,). The rate of maternal lacerations was significantly higher in Group B compared to Group A (47.6% vs. 68.9%), although there was no difference in lacerations of higher degree (3rd or more). The rate of episiotomies did not differ between the groups. The total amount of misoprostol administered was 235±181 μg in Group A and 200±222 μg in Group B.
When assessing nulliparous women only, we found no significant difference with respect to the delivery mode. Specifically, 66.7% of patients in group A and 70% in Group B delivered spontaneously. In multiparous women there were more cases of cesarean sections in Group A (11.1%) compared to Group B (4.8%).
The findings of the neonatal outcome are displayed in Table III. The average birthweight was similar between the two groups (Group A: 3,275 g, Group B: 3,416 g). When we analyzed the birthweight beyond 4,000 g separately, we found that Group B had significantly more newborns with higher birthweight >4,000 g compared to Group A. The APGAR score did not differ between the groups. The mean umbilical cord pH was 7.25 in Group A and 7.27 in Group B. We also did not record any differences in the rate of meconium-stained fluid between the two groups (11.1% in Group A and 13.1% in Group B). Base excess was significantly lower in Group A compared to Group B (–9.93 vs. –3.82).
Fetal outcome.
Discussion
Misoprostol is probably the best investigated agent for IOL. Plenty of trials have been performed during the last decades in order to find an appropriate regime for safe IOL (2). Nevertheless, due to its limited product license in Germany in the beginning of 2020, media reports have spread incomplete and unprofessional information, which have led to uncertainty and anxiety in expecting parents. Our study might contribute to reassuring patients concerning the safety of misoprostol. Dosage schemes, like the one administered in this study, seem to be safe, even though they might be higher than usual (2).
IOL is performed when the risks of ongoing pregnancy outweigh the potential maternal and neonatal risks of an earlier delivery. In general, 20-30% of all pregnancies undergo IOL (8).
A recent meta-analysis showed that oral misoprostol had the lowest caesarean section (CS) rate compared to other IOL medication (9). In this study, 85.5% of our patients had a successful vaginal delivery. Our overall CS rate was 14.5%, which seems to be lower than that of previous studies. In the literature, the CS rates following IOL vary between 16.8%, using 50 μg of misoprostol every 4 h (8), 22.7%, using 20 μg on an hourly basis (10), and 26.2%, using 50 μg every 4 h (11).
Only a few studies report on the administration-delivery interval for their dosage protocols of oral misoprostol (11, 12). Moreover, comparing the results between them is complicated due to the unequal parity rates and different dosage schemes. In fact, the administration-delivery interval varies between 24 and 33.7 h in the literature (11, 13), it is, however, suggested that the higher the dosage of oral misoprostol the faster the vaginal delivery. In this study we documented a mean duration of the administration-delivery interval of 19.0 (Group A) and 27.1 h (Group B). To our knowledge, this is the fastest IOL following oral misoprostol that is reported in the literature. The highest oral doses of misoprostol for IOL have been reported by Carlan et al. (13), who achieved a mean administration delivery interval of 24 h after 2’200 μg followed by 300 μg every 6 h.
Shetty et al. (12) have also performed IOL using two different dosage regimes of oral misoprostol (50 μg every 4 h and 100 μg every 4 h). Their induction to delivery intervals did not differ significantly between the two groups and were 33.7 and 26.8 h, respectively.
The same authors stated in another more recent publication (11) that more inductions would fail using lower dosage regimes of oral misoprostol. In their study the CS rate due to failed induction was higher in women who received the lower dosage protocol. Our data does not support this finding as we had similar delivery modes between our higher and lower dose groups. Unfortunately, we did not report on the explicit reason why CS had to be chosen. This information would improve the thesis on the rate of failed inductions.
Although the implications of the meconium-stained fluid for the fetal outcome are still under debate (14), it seems to appear more often after IOL with misoprostol (15, 16). This may be due to the high maturity level of the pregnancies induced. On the other hand, the presence of meconium-stained fluid is also believed to reflect the fetal gastrointestinal stimulation, as a side effect of misoprostol (15). Shetty et al. (11) have found similar rates of meconium-stained fluid in their groups (18.4 in the group which received 50 μg misoprostol every 4 h and 19.8% in the group which received 100 μg every 4 h). Our rates of meconium-stained fluid were lower compared to those by Shetty et al. In addition, they were also similar between the two groups (11.4 and 13.1%). On the other hand, Prager et al. in 2008 noticed 26% meconium-stained fluid after IOL with vaginal 25 μg misoprostol (17). Obviously IOL does not increase the incidence of meconium-stained fluid, which is estimated to occur in 9.2-20.4% of pregnancies (18).
Interestingly, we report a significantly higher rate of maternal lacerations in our lower dosage group. This might be due to the fact that we had significantly more fetuses >4,000 g in Group B compared to Group A, although the mean birth weights were not different. Anyhow, this observation underlines that a shorter duration of labor does not correspond to risking birth injuries.
Our study is limited by its retrospective nature and would have yielded more unbiased results if both groups would have been randomized concerning important aspects, such as parity. The total number of nulliparous women was higher in our low dosage group. In addition, we did not report on either gastrointestinal side effects or on hyperstimulation events. These facts would contribute to a better evaluation of the side effects. Moreover, we did not report on oxytocin being used additionally in cases of secondary insufficient contractions.
Nevertheless, treatment of oral misoprostol with a higher dosage scheme seems to be as safe as the lower dosage scheme and even more effective when compared to it, without increasing any adverse outcomes for either the mother or the child. The main finding of this study is that the mean induction to delivery interval was significantly lower in the higher compared to the lower dosage group, without increasing the CS rate and without deteriorating the neonatal outcome.
These findings underline the thesis of Shetty et al. in 2002, who emphasized that there are no safety issues concerning the use of higher misoprostol doses (11). Moreover, they stated that both dosage schemes they used have a “reasonably safe profile” and suggested that a higher dose could decrease the rate of failed inductions without increasing the perinatal risks.
Due to its off-label use in Germany, obstetrics practioners have no official dosage recommendations to rely on. WHO recommends a regime of just 25 μg oral misoprostol every 3-6 h because they expect higher dosages to hyperstimulate and lead to decelerations in fetal heart rate (3). Although our data could not support this evidence, it seems that due to legal issues, many colleagues hesitate to use misoprostol while there are alternative effective licensed drugs available (19). Lately, the most common dosage regime in Germany for oral misoprostol is an initial dosage of 50 μg followed by 100 μg every 4 h (7).
Expecting parents should be reassured that there is no better investigated drug for IOL than oral misoprostol. Another important aspect of counselling patients is to emphasize that there are no long-term health impairment issues after intrapartum exposure of misoprostol in the absence of fetal distress during delivery (20).
In conclusion, the time interval from administration of misoprostol until vaginal delivery can be significantly shortened if higher dosages of misoprostol are used, without increasing an adverse outcome for either the mother or the neonate.
Footnotes
Authors’ Contributions
OR was involved with manuscript writing, data collection, statistical analysis; DR was on project development and manuscript writing; ADL and AKE performed manuscript editing and data collection; MRM, BG and PM edited the manuscript; EG performed the statistical analysis. JSA was involved with the development of the project, writing and editing of the manuscript.
Conflicts of Interest
The Authors declare that there are no conflicts of interest.
- Received January 7, 2022.
- Revision received February 20, 2022.
- Accepted March 8, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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