Dr J. G. Cecatti, Caixa Postal 6081, 13084-881 Campinas, São Paulo, Brazil.
Objective To compare the effectiveness of immediate induction of labour with vaginal misoprostol versus expectant management for 24 hours followed by oxytocin induction in women with premature rupture of membranes at term (term PROM).
Design An open, randomised, controlled trial.
Setting Public university hospital in Campinas City, Brazil.
Population One hundred and fifty pregnancies, half of them allocated to each group.
Methods Statistical analysis used Student's t test, the χ2 test, Fisher's exact test, survival analysis and risk ratio estimates with 95% CI.
Main outcome measures Latency period, recruitment to delivery period, period of hospitalisation, mode of delivery, contractility pattern, fetal wellbeing, labour and delivery complications, neonatal and maternal morbidity.
Results Both groups had similar general characteristics, but the misoprostol group had a significantly shorter latency period (9.4 vs 15.8 hours), a shorter time interval from recruitment to delivery (18.9 vs 27.5 hours), a shorter period of maternal hospitalisation and a slightly higher proportion of alterations of contractility when compared with the expectant group. Caesarean section rates were 20% in the misoprostol group and 30.7% in the other. There were no differences between them regarding fetal wellbeing, complications during labour and delivery and neonatal or postpartum maternal morbidity. Within 24 hours, 44% of women had delivered in the expectant group against 73.3% in the misoprostol group.
Conclusions Immediate labour induction with misoprostol in cases of term PROM shortens the latency period, the total time between recruitment to delivery and the time of maternal hospitalisation, increasing the occurrence of alterations of contractility without any maternal and perinatal outcomes disadvantages.
Premature rupture of membranes (PROM) occurs in approximately 5–10% of all pregnancies, of which approximately 60% occur at term (term PROM).1,2
Several studies on term PROM have shown favourable results for induction of labour with prostaglandins. These studies showed contradictory results with respect to the incidence of chorioamnionitis, rates of caesarean sections and surgically assisted vaginal births, and neonatal infection rates, but there is general agreement that labour may be shorter.2–7 Although lower rates of maternal infection have been reported with immediate induction with oxytocin,5 the majority of these studies used E2 prostaglandin2,5,7 and long periods of expectant management up to four days.3
There is also evidence in the medical literature comparing misoprostol with prostaglandin E2 for cervical ripening and induction of labour in pregnant women at term without ruptured membranes. These studies concluded that misoprostol is at least as good as PGE2 in these circumstances.8,9 Other studies have also confirmed the efficacy of misoprostol administered vaginally or orally, and these include studies in pregnant women with PROM.10–16
At the time the present study was planned, there was an almost general clinical agreement that the most effective way to manage term PROM was through prostaglandins, specially the E1 analogue (misoprostol). However, there were still several doubts regarding the best option for its management when performing a tradeoff between effectiveness and safety. If there was an international trend in recognising the labour induction as the standard procedure, this was not and is not yet really adopted in most countries in practical terms. Perhaps the most important trial published on this topic was that of Hannah et al.,5 which concluded that immediate induction with oxytocin would be the best management regimen for these cases. However, they studied only prostaglandin E2 and an expectant period of up to four days which is no longer easily accepted in the majority of clinical settings.
The frequency of term PROM and the questions that still exist with regard to optimal management of these cases justify the need to carry out a prospective, randomised study to evaluate the results of the two modes of management, the first consisting of expectant management for a period of only 24 hours followed by intravenous induction with oxytocin if necessary, and the second consisting of immediate induction of labour using misoprostol. The comparison of such regimens for term PROM additionally has the justification that they are attractive to women. In one the intravenous infusion is delayed for 24 hours when they might go into labour spontaneously anyway and in the other the drug is administered vaginally and therefore the women are not restricted by an intravenous line and may remain more mobile.
The aim of the study was to evaluate maternal and perinatal outcomes following immediate induction of labour with vaginal misoprostol or expectant management for a period of 24 hours followed by induction with oxytocin in cases of term PROM in pregnant women at 37 or more completed weeks of gestation who are not in labour. The study was conducted between January 2000 and May 2003. A controlled, randomised, open study was carried out in the Department of Obstetrics of the Centre for Integral Care to Woman's Health following prior approval of the project by the IRB of the Faculty of Medical Sciences, State University of Campinas, according to the national rules and adhering to the regulations of the Declaration of Helsinki. All women gave written consent to participation.
Randomisation was carried out by computer prior to initiation of the study, specifying the same number of cases per group. In order to assure concealment, information regarding the assigned intervention was contained on the forms, which were kept inside sealed opaque envelopes, sequentially numbered according to randomisation. Then, each case enrolled in the study had the next sequential numbered envelope assigned and the correspondent intervention was known only after the envelope was opened.
Sample size was calculated using the results of Ray and Garite3 for prostaglandins versus expectant management with reference to the time interval to delivery as the primary outcome. Using the mean time of 21.2 (9.8) hours for expectant management and a minimal detectable desired difference of 4.5 hours, it was estimated that 75 cases per arm would be necessary. Type I error was fixed at 5% and power at 80%.
Diagnosis of PROM was performed based on clinical history, speculum examination and, if necessary, nitrazine and fern test of vaginal fluid, as well as ultrasound. Once the diagnosis of term PROM was made, all women underwent basal cardiotocography (CTG) to evaluate fetal wellbeing, and the following eligibility criteria were analysed: PROM confirmed up to 6 hours after the occurrence; gestational age ≥37 weeks, cephalic presentation and a live fetus showing no signs of fetal compromise as evaluated by CTG.
Exclusion criteria were: past caesarean section or uterine surgery; being in labour at admission as characterised by regular painful uterine contractions (two contractions in 10 minutes and gradually shortening); presence of fetal malformations incompatible with life; twin pregnancy or strongly suspected or confirmed chorioamnionitis.
For the cases assigned to the expectant management group, the woman was sent to the Obstetrical Pathology Ward for monitoring of temperature, fetal heart rate and uterine activity. If labour occurred within the 24-hour expectant management period since recruitment, the woman was admitted to the Delivery Ward and had routine care. If 24 hours had passed since recruitment and the woman had not yet begun labour, she was taken to the Delivery Ward where she received an intravenous infusion of oxytocin administered by infusion pump for induction of labour. In our practice, oxytocin infusion for labour induction consisted of 5 units mixed into 500 mL of lactate Ringer solution, resulting in an oxytocin concentration of 10 mU/mL, starting dose of 6 mU/min and increasing 3 mU/min at 30-minute intervals to a maximum of 42 mU/min or stabilised labour.
In the cases randomised to induction with misoprostol, the woman was taken directly to the Delivery Ward, where a vaginal presentation of misoprostol tablet was administered in the dose of 25 μg (Prostokos) digitally inserted into the posterior fornix at 6-hourly intervals, up to a maximum of four doses (a total of 100 μg). The women who did not respond to induction using misoprostol within a 24-hour period with a cumulative dose of 100 μg were also given treatment with an intravenous infusion of oxytocin at the doses usually administered for the induction of labour.
During labour, women from both groups were clinically monitored and evaluation of fetal wellbeing was electronically monitored at intermittent intervals, with fetal heart rate and uterine tonus measured by external transducers. Alterations of contractility as tachysystoles was clinically defined as more than five uterine contractions in 10 minutes, hypercontractility as uterine contractions lasting more than 90 seconds and hyperstimulation syndrome as tachysystoles or hypercontractility associated with fetal heart rate deceleration.
After delivery, when mother and child were being discharged from the hospital, a form was filled out with respect to the delivery and neonatal condition and, finally, a follow up postpartum appointment to carry out a clinical evaluation of the woman was scheduled for two weeks after delivery.
Initially, the distribution of baseline characteristics was studied to evaluate the comparability of the two groups. The tables demonstrate the relationship of the dependent variables to the independent variable (i.e. main outcomes to management schemes). For the variable ‘time from recruitment to delivery’, accumulated percentages in function of time using survival analysis calculated using the life table method were used. For the principal maternal and perinatal results, risk ratios (RR) and their respective 95% confidence intervals were calculated for induction with misoprostol in relation to expectant management. All analyses were by ‘intention to treat’.
Statistical significance was calculated using χ2 test or Fisher's exact test for categorical variables, and Student's t test for continuous numbers, with significance set at P < 0.05. For survival analysis, the difference between groups as a function of time was evaluated using the Wilcoxon test. The software programmes used for carrying out the statistical analysis procedures were SAS and Epi-Info.
Following randomisation, 75 cases were included in each group, making a total of 150 pregnant women in the study. There were no dropouts and no woman was discontinued for any reason after enrolment to the study. Of the 234 pregnant women initially eligible for admission to the study, 84 were not included: 13 because they refused to participate and 71 for various other reasons (contractions started before randomisation was carried out, diagnosis of abnormalities, fetal distress and suspected amniotic infection, among others) (Fig. 1).
The two groups were similar with regard to control variables (Table 1), and there were no statistically significant differences between the groups with respect to the time between PROM and admission to hospital or the results of the principal diagnostic tests used to confirm the occurrence of PROM.
Table 1. Baseline characteristics of women at randomisation according to type of management in pregnant women with term PROM. Values are presented as n (%) or mean [SD].
The latency period and the total time between recruitment and delivery were significantly shorter in the group that received misoprostol (Table 2). During labour, there were no significant differences between the groups with respect to alterations in fetal and neonatal wellbeing. The occurrence of uterine hypercontractility or tachysystoles was slightly higher although significant in the misoprostol group. Caesarean section was the type of delivery for almost 31% of women in the expectant group versus 20% in the misoprostol group, but this difference was not statistically significant (P= 0.22) as was not the differences among their indications for. Apgar score below 7 in the first minute was similar between both groups and there was no case of low Apgar score in the fifth minute in any group. The use of oxytocin and maternal stay at hospital were more frequent in the expectant management group (Table 3).
Table 2. Timing of events in labour after recruitment, according to type of management in women with term PROM. Values are presented as mean [SD].
Data are missing for three cases in each group who had caesarean section after induction failure without going into labour.
Between recruitment and beginning of contractions (latency period)*
Table 3. Results of the main outcomes regarding fetal wellbeing, labour and type of delivery, according to type of management, in pregnant women with term PROM. Values are presented as n (%).
RR (95% CI)
Presence of meconium
Alterations of contractility
Use of oxytocin
Delivery by caesarean
Apgar 1st minute <7
Newborn small for gestational age or large for gestational age
Neonatal stay >3 days
Woman stay >3 days
Indication for caesarean section
The onset of labour contractions occurred spontaneously in 48% of the expectant management group within 12 hours, and in 72% within 24 hours following membrane rupture. For the misoprostol group, initiation of labour occurred within 12 hours in 80% of the women, and within 24 hours of membrane rupture in 94.7% of women (Table 4). A similar result was found with respect to total time from recruitment until delivery, with the most striking difference being found at 18 hours following recruitment when two-thirds of the women in the misoprostol group had already given birth versus one-third of women in the expectant management group (Table 4, Fig. 2).
Table 4. Accumulated percentage of cases according to latency and total period until delivery and type of management in pregnant women with term PROM.
RR (95% CI)
Three cases in each group failed to go into labour.
Therefore, the estimated risk ratio for the principal variables studied showed that induction of labour with misoprostol was effective and safe in pregnant women with term PROM and that compared with expectant management for 24 hours followed by oxytocin, it was able to reduce the latency period, the time to recruitment until delivery and resulted in a shorter maternal hospitalisation period and a higher proportion of alterations of contractility (Tables 3 and 4). Neonatal results showed similarities between the groups with complications being practically non-existent and with no cases of perinatal death. No newborn was admitted to the neonatal intensive care unit (NICU), none had breathing difficulties, cerebral haemorrhage, sepsis or required treatment with antibiotics. Finally, with regard to puerperal complications, no maternal deaths occurred and there were no serious complications.
The latency period and the time from recruitment until delivery were significantly shorter in the group randomised to immediate induction using misoprostol. In the literature, these findings are in agreement with controlled studies in which prostaglandin E2 administered vaginally was compared with expectant management for a period of 24 hours followed by induction of labour in cases of term PROM.4,6
There was a shortening of the time of clinical events related to parturition and in the maternal hospitalisation period in the group that received misoprostol. These results are in agreement with other studies published in the literature and it has already been established that the hospitalisation period is shorter when active management with prostaglandins or their analogue, misoprostol, is adopted.4
Although the safety of misoprostol in the process of labour induction in cases of intact or ruptured membranes10,11,15 is already known, there was no significant difference with respect to the evaluation of fetal wellbeing between the two groups. The incidence of decelerations during labour, although not statistically significant, was more frequently diagnosed in the expectant management group and the results found in this study once more confirm the safety of misoprostol. We have no explanation for this finding, however, it could possibly be associated to the longer period of labour in a regimen of oligohydramnios.
The occurrence of alterations of uterine contractility (hypercontractility or tachysystoles) showed a statistically significant difference between the two groups, but with just a slightly higher proportion among women of the misoprostol group. Comparing these results with those found in the literature, our results are similar when compared with studies in which the authors used the same doses of misoprostol for induction.11 Publications of studies in which higher doses were used, 50 μg every 4 hours, resulting in cumulative doses of 300 and 600 μg, demonstrated a greater occurrence of tachysystoles10,15 and similar findings have already been published in the literature.9
Caesarean section rates were 20% and 30.7% (P= 0.22), respectively, in the group that received misoprostol compared with the expectant management group, a non-significant difference. The group that received misoprostol had better results with respect to the rate of vaginal delivery as a difference of 10% in these rates cannot be considered negligible. On the contrary, 10% more vaginal deliveries in the women who used misoprostol would appear to be clinically significant. Some international studies have also failed to demonstrate statistical significance with respect to the type of delivery when expectant management was compared with misoprostol, but have also clearly demonstrated better rates of vaginal delivery.10,15 The lack of significant difference in caesarean delivery rates could easily be the result of a type II error and, therefore, it is possible that a compilation of these data in a future meta-analysis may achieve a sufficient number of cases to show that this difference is also statistically significant.
In view of the concern regarding the indexes that reflect condition at birth, which are also related to the process of labour induction and delivery, and the risk of infection in cases of PROM, one of the objectives of this study was to evaluate neonatal results from both groups and these proved to be highly satisfactory. These results are in agreement with the current literature in which perinatal outcomes are normal even in cases of expectant management for long periods, provided care is taken to avoid digital vaginal examination and that there is no prior clinical evidence of chorioamnionitis.15,17 With regard to maternal postpartum follow up, results were also extremely favourable in both groups with minimal rates of puerperal infection, requirement for antibiotic therapy and other complications, and there was no significant difference between the two groups. These results are also in agreement with the literature.10 However, it should be remembered that the sample size estimate was not performed taking these factors into account and therefore the study does not have enough power to definitely conclude on these aspects.
Latency time and time interval between recruitment and delivery, which were both significantly shorter in the group that received misoprostol, as well as the reduction in caesarean section rates in the group randomised to immediate induction, show that induction with misoprostol, both in terms of cost and with regard to benefits, is a safe, inexpensive and efficient option for the induction of labour in cases of term PROM. On the other hand, a further option of choice in the management of cases of term PROM would be to present the options to the woman so that she, herself, could chose which, among the possible management options, she would prefer.18
The results of this trial show that it is perfectly possible to obtain an effective and safe procedure using low doses of vaginal misoprostol (specially labelled for that purpose), obtaining deliveries in shorter time, without any increase of maternal or perinatal side effects, with a shorter period of maternal hospitalisation and perhaps lower rates of caesarean sections. Comparing this with a relatively short period of expectant time, 24 hours, would probably lower the risk of complications associated with long periods waiting for labour. In addition, it should be remembered that currently there is an important pressure by women's groups in order to avoid invasive procedures in obstetric practice. As said before, under this point of view, both options would seem attractive to women.
Therefore, although misoprostol showed to be a more effective option for term PROM, this situation could perhaps be adequately addressed using either vaginal misoprostol or a relatively short period of expectancy (24 hours) followed by induction of labour with oxytocin only if really necessary, considering that the majority of women experience the onset of labour within this period. In practical and clinical terms, this second option would only imply in a relatively longer period of labour and maternal hospital stay, but perhaps with a slightly higher chance of caesarean section.
The study did not find differences in the rates of maternal and neonatal infections and caesarean section. Immediate labour induction with misoprostol in cases of term PROM has a similar performance to that of expectant management for 24 hours followed by labour induction with oxytocin with respect to maternal and perinatal outcomes. However, misoprostol is responsible for shortening the latency period, the total time between recruitment and delivery, and the time of maternal hospitalisation, while slightly increasing the occurrence of alterations of contractility.