分娩前有胎膜破裂孕妇在足月时口服米索前列醇进行引产
Abstract
Objective: To evaluate the efficacy of oral misoprostol for the induction of labor (IOL) in women with prelabor rupture of membranes at term (PROM) and to monitor maternal or fetal complications. Method: This randomized, placebo controlled trial was performed in a secondary referral hospital. The data of 47 patients in the misoprostol — and 49 patients in the placebo group was available for analysis. The former received 100 μg misoprostol orally, repeated once after 6 h if not in active labor, the latter received two doses of vitamin C also after a 6-h interval. The Mann–Whitney U-test was used for analysis. Results: The median treatment to delivery interval in the misoprostol group was 7.5 h and 25 h in the placebo group (P<0.001). No significant differences were found in the incidence of abnormalities on the cardiotocograph, mode of delivery, neonatal outcome, use of antibiotics for the mothers and patient acceptability. Conclusion: Oral misoprostol in the suggested dose is an effective and cheap alternative for IOL in patients with PROM. No adverse effects could be demonstrated.
Keywords
Misoprostol; Prelabor rupture of membranes; Induction of labor
1. Introduction
Prelabor rupture of membranes affects approximately 10% of pregnant women. In 60–80% it will occur after 37 weeks of gestation [1]. Over 60% of patients with prelabor rupture of membranes at term (PROM) will start labor spontaneously within 24 h and an additional 35% will start within 72 h [2]. The main complication of PROM at term is maternal and neonatal infection. The incidence of neonatal infection with PROM is 2–4% but the use of antibiotics is more common (8–14%). Chorioamnionitis after PROM is clinically diagnosed in approximately 10% of patients after 4 days of conservative management, compared to 1% among controls [2] and [3]. To avoid these complications, labor is usually induced once PROM is confirmed. Different views exist regarding the timing and the method of induction of labor (IOL).
Induction of labor in the presence of an unfavorable cervix may result in a more painful labor [4]. With regard to the mode of delivery there has been no advantage demonstrated for either prostaglandins, oxytocin or expectant management in the setting of PROM [5]. However, a vaginal approach may be better avoided: the use of intravenous oxytocin alone for IOL in the presence of PROM has been shown to be associated with a significant reduction in maternal febrile morbidity when compared to vaginal prostaglandin. This study also showed increased patient satisfaction when the vaginal approach was avoided [2].
The cost of treatment is also relevant to the choice of method of IOL. Prompt IOL avoids expensive prolonged hospitalization [6].
Misoprostol is a synthetic prostaglandin El analogue currently registered as a protector of the gastric mucosa. It has been shown to ripen the cervix and induce labor in a number of studies since 1992 [7], [8], [9], [10], [11], [12], [13], [14] and [15]. The doses varied widely from 100 to 25 μg, either as a single dose or at 2–6-h intervals. The vaginal route has been most commonly used [7], [8], [9], [10] and [11].
Despite the efficacy of misoprostol, in common with other prostaglandins, tachysystole, tonic contractions and hyperstimulation syndrome are complications that cause concern. Sanches-Ramos et al. addressed this problem in 1997 in a meta-analysis that included eight studies using vaginal misoprostol for IOL [16]. This analysis found the incidence of tachysystole to be dose related. The lowest rates (17%) occurred with the use of 25 μg doses [16]. None of the studies describing tachysystole showed adverse neonatal outcomes. The meta-analysis also showed a significantly decreased cesarian section rate in the misoprostol group compared to other methods of induction (15% vs. 21.5%).
A Medline electronic database search prior to July 1998 showed only two studies using misoprostol specifically for IOL in PROM. Ngai et al. used a single oral dose of 200 μg [14] and SanchesRamos et al. used 50 μg vaginally in 4-h intervals [15].
Misoprostol costs approximately 1% of the commercially available vaginal prostaglandin preparations and is stable at room temperature.
Although the overall bioavailability of misoprostol is approximately three times less when administered orally compared to the vaginal route, it's biophysical profile may be more favorable, when the oral route is chosen: peak plasma concentrations are achieved within 1 h, fall steeply after 2 h and remain low. Vaginal Misoprostol reaches the peak plasma concentration between 1 and 2 h and then the levels decline slowly and unpredictably [17].
The aim of this study was to examine the efficacy of oral misoprostol as an oxytocic agent in women with PROM and to monitor the incidence of adverse maternal and fetal effects in the treatment arm of the study.
2. Materials and methods
This study was a randomized placebo controlled trial carried out at a secondary referral hospital in Cape Town, South Africa. Patients were either self-referred, (when living in the area) or referred with prolonged rupture of membranes (more than 6 h) by the Peninsula Midwife Obstetric Units.
Women who were more than 37 weeks pregnant were eligible if the leakage of liquor in the absence of labor was confirmed with a positive nitrazine or ferning test on sterile speculum examination. A normal non-stress cardiotocograph (CTG) test was also required.
Patients were excluded from the study if they had a scarred uterus, multiple pregnancy, non-vertex presentation, symptoms and signs of chorioamnionitis, severe gestational proteinuric hypertension or, underlying medical conditions (cardiac disease and diabetes mellitus). Grand Multipara and patients with antepartum hemorrhage were also excluded from recruitment.
The null hypothesis was: in PROM patients the proportion of women undelivered after 12 h is no different when treated with oral misoprostol (two doses of 100 μg) compared to placebo. The sample size was based on the assumption that approximately 40% of women would be undelivered after 24 h of PROM. It was assumed it would be clinically relevant if we could half this figure. With the alpha set at 5% 91 patients were required in each arm of the study to have 80% power to detect the specified difference.
Randomisation occurred by using computer generated numbers. Only the pharmacist was aware which group contained the active medication. The patients drew consecutively numbered opaque envelopes containing either two 100-μg tablets of misoprostol (one 200-μg tablet in half), or two similar halves of a 100-mg vitamin C tablet together with a data collection sheet. The vitamin C tablet was nearly identical in appearance with the misoprostol tablet and has no known effect on labor. The taste of the two preparations was different.
The statistical analysis was performed applying the Student t-test, the Mann–Whitney U-test and the Chi-square test where appropriate. Statistical significance was defined as a P-value less than 0.05.
Approval for this study was obtained from the University of Cape Town Ethics and Research Committee. Recruitment took place from July 1997 to June 1998.
Written consent was obtained from all participants. At the time of recruitment the women received one of the tablets and both groups received again the same drug as before (misoprostol 100 μm or vitamin C, 50 mg) after 6 h if they were not in active labor (defined as three contractions in 10 min, lasting more than 40 s). Intravenous access was avoided.
The monitoring used was identical to routine clinical use in patients undergoing IOL. An initial continuous CTG for 1 h was recorded, followed by intermittent CTG or continuous CTG once in active labor.
Major CTG abnormalities were defined as late and variable decelerations, baseline tachycardia >160 beats per minute with decelerations or reduced variability of <5 beats per minute around the baseline, or a persistent bradycardia of <105 beats per minute.
Patients in active labor had vaginal examinations performed regularly and further management took place according to standard labor ward policies.
In cases of tachysystole (more than five contractions in 10 min) the intravenous administration of 10 μg hexoprenalin was advised, to prevent the hyperstimulation syndrome (severe CTG abnormalities together with tachysystole or hypertonus). In cases of hyperstimulation syndrome 10 μm of hexoprenalin was mandatory, as well as fetal blood sampling and further appropriate management or emergency cesarean section.
If labor did not occur within 12 h of entering the study, further management took place at the discretion of resident staff according to standard protocols. This protocol consisted of two doses of 1 mg prostaglandin E2 vaginal gel applied to the posterior vaginal fornix, 6 h apart, followed by intravenous oxytocin if the progress of labor was not adequate. Cesarean section for failed IOL was usually performed if the patient was not in active labor 12 h after the first vaginal prostaglandin application.
The endpoint studied was the proportion of patients undelivered 12 h after receiving misoprostol or placebo. Other data were also recorded as listed in Section 3.
The data collection sheets were reviewed by the principal investigator, who was not involved in patient management. The randomization code was broken at the time of the first (and final) analysis.
3. Results
In total, 103 patients were recruited, 51 in the misoprostol group and 52 in the placebo group. Seven patients were excluded. The reasons for exclusion were as follows. Misoprostol group: one patient was below the age of consent (she did not receive the drugs after recruitment), one patient erroneously did not receive drugs and two folders were lost. Placebo group: one patient had unconfirmed rupture of membranes and two folders were unobtainable. The data were analyzed after exclusion of these seven cases.
There were no significant differences between the groups with regard to the mode (0) and range of parity (0–4) (see Table 1), and interval from PROM to medication (see Table 2). The cervical status was not assessed.
The proportion of undelivered patients within 12 h of treatment was significantly reduced in the misoprostol group, with a p-value<0.0001 (see Table 3). There was no statistically significant difference in the proportion of patients delivered between 12 and 24 h of medication (P=0.165), but the proportion of patients still undelivered 24 h after medication was much larger in the placebo group with a P-value<0.0001 (see Table 3). The risk of being undelivered 24 and 48 h after PROM was significantly less in patients treated with misoprostol, the P-values are 0.038 and 0.0002. There was no statistically significant difference in the 24–36-h PROM to delivery group (P=0.179). For the odds ratio with confidence intervals of the preceding data please refer to Fig. 1.
The treatment to delivery interval was significantly reduced, the median time being 7.5 h (445 min) in the misoprostol and 25 h (1525 min) in the placebo group, P<0.001 (see Fig. 2).
Consequently, also the PROM to delivery interval was reduced from 45 h (2670 min) in the placebo group to 30 h (1787 min) in the misoprostol group, P<0.0001 (see Fig. 3).
The ranges for the medication-delivery intervals are wide in both groups.
In the misoprostol groups 33 patients (70%) required only one dose and nine patients (17%) were not in active labor after 12 h, compared to 33 patients (68%) in the placebo group. Fifteen patients in the misoprostol group (29%) were delivered within 4 h. Of those, seven gave birth within 2 h. In the placebo group only two patients (4%) were delivered within 4 h.
3.1. Length of stay
The number of days in hospital were significantly reduced in the misoprostol arm of the study, from 5 days (range 2–10 days) in the placebo group to 3 days (range 2–10), the P-value was <0.05.
3.2. Other outcomes
There were no statistically significant differences in the occurrence of major CTG abnormalities (three patients in the misoprostol group and two patients in the placebo group). One case of hyperstimulation syndrome was reported in the misoprostol group, this was also the only patient who developed tachysystole in both groups. This patient did not receive hexoprenaline but had an emergency cesarean section for fetal distress. The baby had 1- and 5-min apgar scores of 9 and 10.
No statistically significant difference was noted in the numbers or indications for cesarean sections (see Table 4), birth weights, babies requiring admission to the neonatal nursery and maternal treatment with antibiotics (see Table 5). There was no difference in the reported incidence of nausea or elevated temperature during the first 12 h after entering the trial or patient acceptability (at discharge the patients were asked to qualify their experience as positive, acceptable or terrible).
There was no difference in the incidence of postpartum hemorrhage (more than 500 ml blood loss). There were no reports of fetal blood sampling or amnioinfusion.
4. Discussion
The null hypothesis was rejected. Oral misoprostol significantly reduced the proportion of women with PROM undelivered within 12 h of treatment. In addition, significantly fewer patients were undelivered after 24 h and the rupture of membranes to delivery interval was significantly reduced. The hospital stay in the misoprostol group was significantly shorter. No adverse effects on mother or baby could be observed.
The trial was discontinued after the interim analysis. This decision was justified by a large and significant difference in the main outcome already before the estimated number of patients had been reached. It must be seen in the context of an economically exhausted hospital budget, were beds and time are precious. By analyzing the data of more patients further information about the safety of misoprostol could have been collected, but to assess the incidence of a relatively rare complication, far more patients are required.
A problem with misoprostol, as with other oxytocics, is that its action cannot be predicted. As a consequence 13% of the patients in the misoprostol group were delivered within 2 h, which is consistent with the diagnosis of precipitate labor. Of those patients one had to undergo a cesarean section for fetal distress. In the placebo group only one patient was delivered within 2 h (she had a normal vaginal delivery). For these neonates no adverse effects could be demonstrated. This study was not designed to exclude possible harmful effects on the baby as a result of rapid labor. Parous patients may be predisposed to precipitate labor; it was an unproven clinical observation that these women were more sensitive to misoprostol and this merits further study. A lower dose might be preferable for parous patients.
The incidence of tachysystole in this study was 2%. This is much lower than that reported in similar studies [14] and [15]. Previous studies were mainly based on the vaginal application, which results in a much higher bioavailability, as well as a longer and more irregular half-life.
Although it did not reach statistical significance, there were fewer than half the number of cesarean sections in the misoprostol group: 7.7% vs. 16% in the placebo group. This correlates well with the findings of Sanchez-Ramos [16] who found an overall decrease in the cesarean section rate (OR 0.67; 95% Cl 0.48, 0.93) in patients induced with misoprostol as opposed to ‘conventional’ IOL.
A non-significant tendency towards decreased use of intravenous antibiotics could be observed in the misoprostol group, though it is not clear if antibiotics were used therapeutically (for developing infection) or prophylactically (because the attending clinician felt the interval to delivery was unduly prolonged). These findings are consistent with other studies which show that early induction of labor (e.g. <24 h) does not result in an increased risk of abdominal delivery and may reduce maternal infectious morbidity if a non-vaginal route for IOL is chosen [2].
Patient acceptability was not adequately tested and may form the basis for further study. Further research should also examine a 4-h instead of a 6-h dosage interval keeping in mind that the serum concentration of oral misoprostol falls steeply after 2 h.
5. Conclusion
Oral misoprostol in the suggested dose is an effective oxytocic, when used for induction of labor in women with PROM. No adverse effects could be demonstrated. However definite statements about the safety can only be made when much larger numbers of patients are recruited, taking into account the relatively uncommon occurrence of adverse effects.
It is also necessary to evaluate the efficacy of a smaller dose, which might decrease the incidence of precipitate labor, especially in relation to the parity of the woman.
