Active management of term prelabour rupture of membranes with oral misoprostol

Authors


*Correspondence: Dr A. Shetty, Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK.

Abstract

Objective To compare the active management of term prelabour rupture of membranes with oral misoprostol with conservative management for 24 hours followed by induction with oxytocin or prostaglandin E2 (PGE2) gel.

Design A non-blinded randomised controlled trial.

Setting Induction and labour wards, Aberdeen Maternity Hospital.

Population Sixty-one women with confirmed prelabour rupture of the membranes at ≥36 weeks of gestation.

Methods The women were randomised to 50 μg of oral misoprostol repeated every 4 hours, if required, to a maximum of five doses (active group), or to induction of labour with PGE2 gel or oxytocin only if not in spontaneous labour 24 hours after prelabour rupture of membranes (conservative group).

Main outcome measures Number of women in active labour within 24 hours of the prelabour rupture of membranes, preference of women for any one particular method of management in any subsequent pregnancy with prelabour rupture of membranes.

Results 93.3% of the active group and 54.8% of the conservative group were in spontaneous labour within 24 hours of the prelabour rupture of membranes (RR 1.7, 95% CI 1.2 to 2.4). Of those achieving a vaginal delivery, 72% of the active group did so within 24 hours of the prelabour rupture of membranes as compared with 26.9% of the conservative group (RR 2.7, 95% CI 1.4 to 5.3, P= 0.002). There were no significant differences in the neonatal or maternal outcomes. In the active group, 78% felt they would have the same method of induction as compared with 40% in the conservative group (RR 1.9, 95% CI 1.1 to 3.3, P= 0.03).

Conclusions Active management with oral misoprostol resulted in more women going into labour and delivering within 24 hours of the prelabour rupture of membranes with no increase in maternal or neonatal complications. Women tended to view active management of prelabour rupture of membranes more positively. Oral misoprostol might be an option to consider in those wishing active management.

Introduction

The management of prelabour rupture of membranes at term is still a matter of debate, and varies from centre to centre. While active induction of labour soon after prelabour rupture of membranes has resulted in a lower risk of maternal and fetal sepsis in some studies1–5, it has also been associated with a higher caesarean section rate in others6–8. The largest randomised controlled trial on prelabour rupture of membranes to date9 found that active labour induction with oxytocin or vaginal prostaglandin E2 (PGE2) gel, and expectant treatment resulted in similar rates of caesarean sections and neonatal infections, although the risk of maternal infection was lower with oxytocin induction. This reduction in maternal infections was not seen with vaginal PGE2, and was probably due to a greater number of vaginal examinations in this group. Women with active management had shorter prelabour rupture of membranes to delivery intervals as compared with the expectant group and tended to prefer active management.

Misoprostol, a PGE1 analogue has been used effectively both orally and vaginally for labour induction with prelabour rupture of membranes10–14. The advantage of misoprostol orally, with particular reference to prelabour rupture of membranes, might be that repeated vaginal examinations could be avoided thus resulting in less risk of sepsis for mother and baby. Oral PGE2 preparations have been tried in other studies, and although found to be effective for labour induction, have been associated with significant gastrointestinal side effects, with quoted incidences of 10–50%15,16. They are therefore not used routinely. The risk of hyperstimulation with misoprostol seems to be related both to the dosage and route of administration. With oral preparations at doses of 100 mg or less, this risk is small10–14.

The routine protocol at our centre for managing prelabour rupture of membranes at term includes conservative management for 24 hours, followed by induction with PGE2 gel if cervical Bishop's score is ≤6 or less, or with oxytocin if cervical score is ≥7. Our aim in this randomised controlled trial was to see if active management with oral misoprostol resulted in significantly more women going into labour within 24 hours of the prelabour rupture of membranes, and to assess patient preferences for management. We also wished to look at other outcome measures like the prelabour rupture of membranes to vaginal delivery intervals, operative delivery rates and the neonatal and maternal outcomes.

Methods

The study was carried out at the Aberdeen Maternity Hospital between July 1999 and January 2001. Full ethical approval to proceed with the study was obtained from the local ethics committee and permission to use oral misoprostol in labour induction was obtained from the Medicines Control Agency, London.

The eligibility criteria for recruitment into the trial included a gestation ≥36 weeks, singleton pregnancy in a cephalic presentation, rupture of membranes confirmed by seeing a pool of amniotic fluid on a sterile speculum examination and a reassuring fetal heart tracing. Exclusion criteria included signs of labour, signs and symptoms suggestive of chorioamnionitis, meconium, significant fetal or maternal concerns (e.g. vaginal bleeding in pregnancy, significant proteinuric hypertension, intrauterine growth retardation), a previous caesarean section, parity over 5 and gram-positive cocci suggestive of group B haemolytic streptococci in the high vaginal swab.

Patients were initially seen on the labour ward when presenting with a history of leaking amniotic fluid. A fixed presenting part was confirmed by abdominal examination. Uterine contractility, if any, was noted. The rupture of membranes was confirmed by seeing amniotic fluid on a speculum examination. High vaginal swabs were taken for Gram's staining for gram-positive cocci and for culture. Digital vaginal examination was avoided. A fetal cardiotocographic (CTG) trace to confirm fetal wellbeing was performed. If all of the inclusion criteria for the study were fulfilled, the patient was randomised to the active or to the conservative arm after full informed written consent. The randomisation was blind and was done by opening sequentially numbered opaque envelopes containing cards stating the type of treatment. These cards were based on a computer-generated randomisation table. After randomisation, neither the patients nor the staff were blinded to the mode of management as one of the aims was to assess patient preference.

Women randomised to the active arm received 50 μg of oral misoprostol, which was prepared by halving a 100-μg tablet (Cytotec, Searle Pharmaceuticals, Ontario, Canada). The dose could be repeated after 4 hours if there was no uterine activity or if the uterine contractions were less than two mild contractions in 10 minutes with the patient being comfortable, to a maximum of five doses. Before every dose, a fetal CTG was done to confirm fetal wellbeing. When uterine activity suggested the onset of labour, a vaginal assessment was performed and the woman moved to the labour ward. The management on the labour ward, including oxytocin augmentation, was according to our normal protocols. If at the end of five doses of misoprostol, labour had not set in, induction with oxytocin could be started, after an interval of at least 4 hours after the last dose of misoprostol.

In those women randomised to the conservative arm, if labour had not set in by 24 hours of the prelabour rupture of membranes, a vaginal examination was performed to evaluate the cervical score (modified Bishop's score). If cervical score was less than 7, PGE2 vaginal gel (Prostin gel) was administered into the posterior fornix. In primiparous women, the starting dose could be 2 mg (if cervical score <4), while in parous women this was 1 mg. PGE2 could be repeated in 1 mg doses for both nulliparous and multiparous women every 6 hours for a maximum of three doses, after a normal fetal CTG before every dose. If the cervical score was 7 or more, then oxytocin infusion was started. Labour management was according to normal labour ward protocols. Postnatally, before discharge home, the women were requested to complete questionnaires, which included ‘tick box’ type questions.

Uterine hyperstimulation was defined as tachysystole (six or more contractions in 10 minutes) or strong contractions lasting over 2 minutes with associated fetal heart changes necessitating delivery or administration of salbutamol. Maternal sepsis was taken to be a recorded aural temperature of 38°C, with antibiotics being administered anytime from the prelabour rupture of membranes to discharge home (usually the third postnatal day). Administration of antibiotics to the neonate with clinical signs of infection and confirmed sepsis or presumed sepsis was recorded and was determined from the neonatal notes.

The baseline demographic maternal characteristics in the two groups including parity and gestational age were compared.

Assuming that 68% in the conservative group would be in active labour within 24 hours of the prelabour rupture of membranes17, our sample size of 30 patients in each group was based on finding a 30% increase in this number in the actively managed misoprostol group (power 80%, α= 0.05, β= 0.2). Statistical analysis included relative risks with 95% confidence intervals for discrete data and mean difference with 95% of the confidence intervals of the mean difference for continuous data, using GraphPad Instat Version 3.01 (GraphPad Software, San Diego, California, USA) and SPSS for Windows Version 10.0 (SPSS, Chicago, USA). All tests were two sided with a 0.05 significance value.

Results

Thirty women were randomised to the active group, and 31 to the conservative group. There were no differences in the maternal demographic characteristics between the two groups, with 66.7% in the active group and 67.7% in the conservative group being primiparous (Table 1).

Table 1.  Maternal demographic characteristics. Values are given as mean [SD], n {%}, or median (range).
 Active group (n= 30)Conservative group (n= 31)RR/Mean difference (95% CI)P
  1. a Unpaired t test.

  2. b Fisher's test.

Age (years)29.2 [5]29.2 [5.8]0 (−2.78 to +2.8)1.0a
Height (cm)164 [7]163 [6.4]−1 (4.4 to 2.4)0.6a
Weight (kg)66.9 [13.5]68.3 [13.9]1.4 (5.6 to 8.4)0.7a
Gestational age (days)274 [11]273 [12]−1 (−6.9 to 4.9)0.7a
Parity0 (0–3)0 (0–2)  
No. of primiparous women20 {66.7}21 {67.7}0.98 (0.7 to 1.4)1.0b

Twenty-eight women (93.3%) in the active group were in labour within 24 hours of the prelabour rupture of membranes as compared with 17 (54.8%) in the conservative group (RR 1.7, 95% CI 1.2 to 2.4, Table 2). There were no significant differences in the modes of delivery in the two groups. Twenty-five women (83.3%) in the active group had a vaginal delivery as compared with 26 (83.8%) in the conservative group. Seventy-two percent of these women who delivered vaginally did so within 24 hours of the prelabour rupture of membranes in the active group as compared with 26.9% in the conservative group (RR 2.7, 95% CI 1.4 to 5.3, Table 3). The rupture of membranes to delivery time was significantly shorter in the active group (20.5 hours [SD 12] vs 35.5 hours [SD 15], mean difference 15 hours, 95% CI 7.2 to 22.8).

Table 2.  Delivery outcomes. Values are given as n (%) or n.
 Active group (n= 30)Conservative group (n= 31)RR (95% CI)P
  1. a Fisher's test.

No. in active labour ≤24 hours of the prelabour rupture of membranes28 (93.3)17 (54.8)1.7 (1.2 to 2.4)0.001a
Spontaneous vaginal delivery14 (46.6)17 (54.8)0.9 (0.5 to 1.4)0.6a
Ventouse delivery6 (20)8 (25.8)0.8 (0.3 to 1.9)0.8a
Forceps delivery5 (16.7)1 (3.2)5.2 (0.6 to 42)0.1a
LSCS5 (16.7)5 (16.2)1.0 (0.3 to 3.2)1.0a
 Prolonged labour32  
 Fetal concerns01  
 Failed instrumental delivery22  
Hyperstimulation00  
Tachysystole3 (10)2 (6.5)1.6 (0.3 to 8.6)0.7a
Nausea and vomiting4 (13)6 (19)0.7 (0.2 to 2.2)0.7a
Pyrexia3 (10)3 (9.6)1.0 (0.2 to 4.7)1.0a
FBS done in labour6 (20)5 (16)1.2 (0.4 to 3.6)0.8a
Table 3.  Outcomes in women delivering vaginally. Values are given as mean [SD] or n {%}.
 Active group (n= 25)Conservative group (n= 26)Mean difference/RR (95% CI)P
  1. aFisher's test.

  2. b Unpaired t test.

No. delivered vaginally ≤24 hours18 {72}7 {26.9}2.7 (1.4 to 5.3)0.002a
Rupture of membrane to delivery time (hours)20.5 [12]35.5 [15]15 (7.2 to 22.8)0.0003b

Of the 31 women in the conservative group, nine (29%) had a cervical score of >6 at 24 hours after the rupture of membranes and were given oxytocin only, while five women (16.2%) were given PGE2 gel as they had cervical scores of ≤6, the rest (54.8%) being in spontaneous labour within 24 hours of the prelabour rupture of membranes. Of the five given PGE2 vaginal gel, two women required only one dose while the others were given two doses. In the misoprostol group, 22 women (73.3%) required only one dose of misoprostol, with 16.7% and 6.7% requiring two and three doses, respectively. Oxytocin augmentation was given in 11 women in the active group (36.7%) and in 14 women (nine who went into spontaneous labour, and all the five who received PGE2 gel) in the conservative group. There were no differences in the mean number of vaginal examinations between the two groups [median of 4 (range 2–8) in the active group, and 5 (range 2–9) in the conservative group]. On more detailed analysis of the case notes, it was found that all women who had repeat doses of misoprostol had vaginal examinations prior to its administration, despite there being no significant uterine activity. This could reflect hesitation in administering an inducing agent without prior vaginal evaluation.

There were no cases of uterine hyperstimulation in either group. Two women in either group had tachysystole while on oxytocin infusions (Table 2). There were no differences in the gastrointestinal side effects between the two groups. Three women in either group had pyrexia of 38°C noted in active labour and received prophylactic antibiotic cover. Four of these women had epidural analgesia. There was one patient with post-operative pyrexia secondary to a caesarean section wound infection.

There were no differences in the neonatal outcomes. No baby had an Apgar score of less than 7 at 5 minutes or a cord pH of less than 7.10. One baby in the active group was admitted to the neonatal unit with suspected sepsis, but all cultures done were subsequently negative for infection (Table 4).

Table 4.  Neonatal outcomes. Values are given as mean [SD], n {%} or median (range).
 Active group (n= 30)Conservative group (n= 31)RR/mean difference (95% CI)P
  1. a Unpaired t test.

  2. b Fisher's test.

Birthweight (g)3439 [358]3407 [562]−32 (−274 to +210)0.8a
No. of FBS done in labour6 {20}5 {16}1.2 (0.4 to 3.6)0.7b
Apgar at 5 minutes9 (7–10)9 (9–10)  
pH7.31 [0.15]7.33 [0.13]0.02 (−0.05 to +0.09)0.6a
Base deficit−6.1 [2.8]−5.3 [2.2]0.8 (−0.5 to 2.1)0.2a
NNU admission103.2 (0.1 to 8.2)0.5b

Eighteen women in the misoprostol group (60%) and 25 women (80.6%) in the conservative group returned completed questionnaires (RR 0.7 95% CI 0.5 to 1.1, P= 0.1). The satisfaction rates in the two groups were not significantly different (83% in the active group vs 76% in the conservative group, Table 5). Of those who returned questionnaires, 78% in the active group felt they would prefer active treatment again if they were to have prelabour rupture of membranes in a subsequent pregnancy, while the rest felt they would prefer to wait for at least 24 hours before intervention were to be considered. In the conservative group, 44% felt they would prefer active treatment in any subsequent prelabour rupture of membranes, with 40% preferring to wait for 24 hours. The rest (16%) were unsure if they had any particular preferences.

Table 5.  Questionnaire returns. Values are given as n (%).
 Active (n= 18)Conservative (n= 25)RR (95% CI)P
  1. a Fisher's test.

Satisfied15 (83)19 (76)1.1 (0.8 to 1.5)0.8a
Preference for management in any subsequent prelabour rupture of membranes
Active management14 (78)11 (44)  
Conservative4 (22)10 (40)  
Not sure04 (16)  

Discussion

This study compared active treatment with oral misoprostol with our routine protocol of managing prelabour rupture of membranes at term with expectant management for 24 hours followed by oxytocin/vaginal PGE2 induction. Our results suggest that active treatment does result in shorter prelabour rupture of membranes to delivery times with significantly more patients going into labour and delivering within 24 hours of the prelabour rupture of membranes. There were no differences in the modes of delivery or in the neonatal and maternal outcomes, although our sample size was not large enough to address these issues adequately. Fewer questionnaires were returned in the active group as compared with the conservative group, but it does seem that women tend to view active induction more positively. Rather than efficacy, this might be an important issue while considering the management of prelabour rupture of membranes at term18.

The large randomised controlled trial by Hannah et al.9 on the management of prelabour rupture of membranes at term showed that although active induction of labour with oxytocin or PGE2 vaginal gel resulted in shorter prelabour rupture of membranes to delivery times, it did not result in a decrease in the rates of neonatal infection or operative delivery rates as compared with expectant management (up to four days). However, the rate of maternal infection in the active oxytocin induction group was significantly lower than both the vaginal prostaglandin and the expectant management groups, and this was thought to be due to the larger number of internal examinations in these groups. Again women in the active group were less likely to say they liked ‘nothing’ about their treatment than those in the expectant management groups.

Our study did not show a reduction in the number of vaginal examinations in the oral misoprostol group. However, with more experience of using this agent, we might be able to administer repeat doses of the drug without prior evaluation of cervical status, based on uterine contractility alone. In conclusion, oral misoprostol might be an option to consider in those women wishing to be actively managed following prelabour rupture of membranes at term.

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