Arch Gynecol Obstet DOI 10.1007/s00404-014-3383-5
MATERNAL-FETAL MEDICINE
Comparison of efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membranes after 34 weeks of gestation Nivedita Jha • Haritha Sagili • D. Jayalakshmi Subitha Lakshminarayanan
•
Received: 30 January 2014 / Accepted: 11 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To compare the efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membrane after 34 weeks of gestation. Methods One eighty-eight women having [34 weeks of gestation with PROM, singleton viable fetus and no prior caesarean section were randomized to sublingual misoprostol (50 lg every 4 h and maximum of 3 doses) and intracervical dinoprostone (0.5 mg every 2 h and maximum of 2 doses). Oxytocin augmentation was commenced in those with a satisfactory Bishop score, inadequate contractions and who did not go into spontaneous active labour. Primary outcome measures were induction–delivery interval and the number of women that went into spontaneous labour without oxytocin augmentation. Results There was a significant reduction in induction to delivery interval in sublingual misoprostol group compared to intracervical dinoprostone (8.3 ± 3.6 h vs 12.2 ± 6.6 h; p = 0.000). There was a significant reduction in duration of rupture of membrane to delivery interval (p = 0.015), 1st stage of labour (p = 0.000) in sublingual misoprostol N. Jha (&) H. Sagili D. Jayalakshmi Department of Obstetrics and Gynecology, JIPMER, Puducherry 605005, India e-mail: [email protected] H. Sagili e-mail: [email protected] D. Jayalakshmi e-mail: [email protected] S. Lakshminarayanan Department of Preventive and Social Medicine, JIPMER, Puducherry, India e-mail: [email protected]
group as compared to the intravaginal dinoprostone group. There was no difference observed in spontaneous vaginal delivery between the groups (0.919). Oxytocin requirement was significantly higher in the dinoprostone group p = 0.006). There were more maternal adverse effects of sublingual misoprostol (p = 0.026). However, maternal and neonatal safety profiles were comparable. Conclusions Sublingual misoprostol and intracervical dinoprostone at the dose studied are equally efficacious in achieving spontaneous vaginal delivery, reduction in induction–delivery interval and in reducing the need for oxytocin, in women after 34 weeks gestation with rupture of membranes. Keywords Dinoprostone Misoprostol Premature prelabour rupture of membranes
Introduction Premature/prelabour rupture of membranes (PROM), which is defined as rupture of membranes before the onset of labour, complicates 3–10 % of pregnancies and approximately 60 % occur at term [1]. PROM typically is associated with variable latency between membrane rupture and delivery, increased potential for perinatal infection and in utero umbilical cord compression. The literature is replete with contradictions over the optimal approaches to clinical assessment and treatment of women with term and preterm PROM. The current obstetric management of PROM after 34 weeks includes expectant management or immediate delivery. Management hinges on knowledge of gestational age and evaluation of the relative risks of preterm birth versus intrauterine infection, abruptio placenta and cord
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accident that could occur with expectant management [2– 4]. Active management shortens the interval from prelabour rupture of membranes to delivery thus reducing maternal and foetal complications. The condition of the cervix is important for the success of labour induction, which is evaluated by Bishop Score. A Bishop score of 9 predicts the likelihood of successful induction, whereas a Bishop score of B4 identifies an unfavourable cervix [5]. Prostaglandins have been shown to be an effective method of ripening of unfavourable cervix in preterm and term patients with PROM. There are a number of studies comparing Dinoprostone gel (PGE2) with Misoprostol (PGE2) in PROM, mostly at term [6–10] and a few between 34 and 37 weeks of gestation [11–13]. PGE2 gel administered vaginally or intracervically is costly, unstable at room temperature and carries the risk of ascending infections. PGE1 is cheap, stable at room temperature and can be administered through oral/sublingual and vaginal routes in varying doses and time intervals. Non vaginal route of PGE1 has additional possible advantages when compared to PGE2 gel which can be given only through the vaginal route. These include fewer vaginal examinations, lower risk of sepsis in mother and fetus/neonate, greater freedom of movement for the mother which might facilitate progress of labour, less chance of hyperstimulation and potentially better efficacy because a vaginally administered drug such as PGE2 could partly flow out with the draining fluid. The sublingual route has been shown to lead to rapid onset of contractions with prolonged effect and greatest bioavailability. Data are scarce regarding the use of sublingual route of PGE1 in women with PROM. There is only study comparing sublingual misoprostol with vaginal PGE2 in PROM which found a shorter induction to labour time and less need for a second dose of induction agent or oxytocin infusion with sublingual PGE1. Till now, there is no study comparing sublingual PGE1 with intracervical PGE2 in women with prelabour rupture of membranes after 34 weeks of gestation. The purpose of the present study was to compare the efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membranes after 34 weeks of gestation.
Methods This study, a randomized controlled trial, was conducted in a tertiary care hospital. Institute ethics body approval and written informed consent were obtained before enrolling the patients in the study. One eighty-eight women with rupture of membranes (confirmed on sterile speculum examination) after 34 weeks of gestation with Bishop score \6 having a singleton, live fetus with cephalic presentation
123
were asked to participate. Women who had a history of prior caesarean section, antepartum hemorrhage, active genital infection, chorioamnionitis and prostaglandin sensitivity were excluded from the study. Grand multiparous women were also excluded from the study. The time of spontaneous rupture of membranes was noted. Bishop’s scoring was calculated. Participants were randomized into two groups using computer-generated random numbers. The routes of administration and drug dosage were not blinded. If the foetal heart rate was normal and if the contractions were not present, the woman was randomly allotted to either the group undergoing immediate cervical ripening with sublingual PGE1 (Group 1) or with intracervical PGE2 gel (Group 2). Prophylactic antibiotic (penicillin or cephalosporin) was given to all women. Women assigned to Group 1 were treated with a 50-lg PGE1 tablet sublingually every 4th hour for up to a maximum of three doses. Women in Group 2 were given 0.5 mg PGE2 gel instilled intracervically every 6th hour, for up to a maximum of two doses. Bishop score was evaluated before and after administration of each dose of drug in both the groups. The medications were administered by the trainee residents and application of the ripening agents was stopped if the woman was found to be in the active phase of labour (cervical dilatation C3 cm, uterine contractions 3/10 min), if hyperstimulation occurred and if the Bishop score was C6. Oxytocin induction and augmentation were commenced in those with satisfactory Bishop Score, inadequate contractions and who did not enter spontaneous active labour, so that three contractions were obtained in 10 min or a maximum dose of oxytocin (32 mIU/min) was achieved. Oxytocin infusion was not started until 4 h after the last dose of PGE1 and 6 h after PGE2. The women were carefully monitored every half hour for side effects. Vaginal examination was performed every 4 h to assess the progress of labour and the findings were plotted on a partogram. Primary outcome measures such as changes in the Bishop score, ripening–induction–delivery interval, the incidence of spontaneous labour, oxytocin requirement, mode of delivery and uterine hyperstimulation/tachysystole were recorded. Secondary outcome measures included maternal side effects (pyrexia, vomiting, diarrhoea, shivering, antepartum haemorrhage, maternal injuries), foetal adverse effects (meconium staining, foetal heart rate abnormalities) and neonatal outcome [(APGAR score, birth trauma, neonatal intensive care unit (NICU) admission, sepsis)]. Statistical analysis The sample size was calculated to be 94 in each group in order to estimate a difference of 2.5 h in induction–
Arch Gynecol Obstet
delivery interval in between both groups based on previous studies. Calculations were done using Openepi software, assuming 80 % power and 95 % confidence interval. Descriptive and inferential statistics were used to analyse the data. The subjects’ baseline characteristics were analysed by descriptive statistics. Categorical data were described using frequencies and percentages. The normality of the continuous data was assessed by Kolmogrov Smirnov test. Univariate analysis was carried out to assess the factors influencing the outcome. Student’s t test was used to compare the continuous variables between the two groups. Chi-square test was used to compare the proportions between different groups. All statistical analyses were carried out at 5 % level of significance and the p value \0.05 was considered significant. Statistical analyses were done using SPSS version 20.
Fig. 1 Comparison of pre-ripening and post-ripening Bishop Score in PGE1 (sublingual misoprostol) and PGE2 (intracervical dinoprostone) groups
Results The baseline characteristics such as age, period of gestation and duration of leaking and pre-induction Bishop Score were comparable in both the groups (Table 1). There were more primigravidae in the PGE1 group (53.2 %) while there was more multigravidae in the PGE2 group (61.7 %). However, there was no significant difference between the groups. Liquor was clear in 77.7 % both in PGE1 and PGE2 groups. Meconium stained liquor was found in 22.3 % of women in PGE1 and PGE2 groups. There were no significant differences among the groups with regard to the colour of the liquor.
(h) of oxytocin requirement was higher in the dinoprostone group (6.2 ± 4.2 vs 4.2 ± 3.6) (p = 0.128). Rupture of membrane to delivery intervals and modes of delivery have been summarized in Tables 2 and 3. The percentage of women who required instrumental vaginal delivery for foetal distress and prolonged 2nd stage were 12.8 and 6.4 % in the PGE1 group 10.6 and 8.5 % in the PGE2 group, respectively. However, the observed difference in Table 2 Primary outcome measures—ripening to delivery intervals Characteristics of labour
Significance
PGE1 Mean ± SD
PGE2 Mean ± SD
p value
Duration (ROMdelivery) (h)
22 ± 12.9
27.8 ± 18.5
0.015
Duration (ripeningdelivery) (h)
8.3 ± 3.6
12.2 ± 6.6
0.000
Primary outcome measures The mean post ripening Bishop Score was 8 ± 0.9 in the PGE1 group while it was 7.9 ± 1 in the PGE2 group (p = 0.254) (Fig. 1). The mean change in Bishop Score was 4.09 ± 1.27 in the PGE1 group while it was 4.06 ± 1.33 in the PGE2 group (p = 0.839). 16 % of women required oxytocin after initial ripening with PGE1 while 33 % of women required oxytocin after initial administration of PGE2. The observed difference in additional method used was statistically significant (p = 0.006). The mean duration
Drugs
6.4 ± 2.6
12.4 ± 11.3
0.000
2nd stage of labour (min)
1st stage of labour (h)
30.8 ± 17
29.1 ± 18.7
0.512
3rd stage of labour (min)
10.6 ± 6.5
11.3 ± 5.4
0.441
Data are expressed as mean ± SD; p \ 0.05 considered significant
Table 3 Modes of delivery Table 1 Demographic Characteristics
Outcomes
PGE1 N (%)
PGE2 N (%)
p value
0.74
Spontaneous vaginal delivery
65 (69.1)
66 (70.2)
0.919
Demographic parameters
PGE1
PGE2
p value
Age (years)
24.6 ± 4.2
23.4 ± 4.5
Period of gestation (weeks)
38.2 ± 2.5
Duration of leaking (h) Pre-Induction Bishop Score
14 ± 11.1 3.95 ± 1
38.3 ± 3
0.79
Instrumental delivery
18 (19.1)
16 (17)
17.8 ± 18.5
0.08
Caesarean section
11 (11.7)
12 (12.8)
3.84 ± 0.9
0.34
Data are expressed as mean ± SD, p \ 0.05 considered significant
N (%) number of patients (percent) p \ 0.05 considered as significant
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instrumental vaginal delivery for foetal distress (p = 0.650) and prolonged 2nd stage (p = 0.578) was non-significant. Fetal distress was the most common reason for LSCS (8.5 %) in women in the PGE1 group. In the PGE2 group foetal distress was the most common reason (5.3 %) for LSCS followed by chorioamnionitis (3.2 %) (p = 0.838) (Fig. 2). Nine women developed tachysystole in the misoprostol group compared to one woman in the dinoprostone group (p = 0.003). The cost of sublingual dose of misoprostol was significantly lower when compared to intracervical dinoprostone (p = 0.000). Secondary outcome measures Twenty-nine (30.9 %) women experienced side effects in PGE1 (sublingual) while 16 (17 %) women experienced side effects in PGE2 (intracervical) and this was statistically significant (p = 0.026) (Fig. 3). There were 15 (16 %) cases of foetal distress in PGE1 group and 14(15 %) of cases of foetal distress in PGE2 group (p = 0.76). The mean APGAR score in the newborn at 1 and 5 min was higher in the PGE1 group compared with the PGE2 group (7.2 ± 1.5 vs 7 ± 1.6) and (8.3 ± 2.4 vs 8.1 ± 1.6), respectively, but the difference
Fig. 2 Number of women who underwent lower segment caesarean section due to different reasans in PGE1 and PGE2 groups. FD feetal distress, CPD NP nonprogress of labour, HS hyperstimulation, CA chorioamnionitis
Fig. 3 No. of women developed different side effects of sublingual PGE1 (misoprostol) and PGE2 (intracervical dinoprostone)
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was not significant (p = 0.487 at 1 min) (p = 0.315 at 5 min). 12 (12.8 %) neonates required NICU admission in the PGE1 group while 22 (23.4 %) required NICU admission in PGE2 group (p = 0.05). The most common indication for NICU admission in PGE1 and PGE2 group was respiratory distress accounting for 6.4 % and 12.8 % of neonates, respectively. Meconium aspiration syndrome and prematurity mostly lead to NICU admission in PGE2 group accounting for 6.4 and 4.3 %, respectively. All babies were normal at discharge and there were no history of any seizure and no perinatal mortality. The incidence of respiratory distress was higher in the PGE2 group, but this was not statistically significant (p = 0.137). There was no birth trauma in any of neonates born by any of the three modes of deliveries. In none of the babies septic screen was positive.
Discussion We demonstrated a significant reduction in rupture of membranes to delivery interval, ripening to delivery interval and the 1st stage of labour in the group which received sublingual misoprostol for prelabour rupture of
Arch Gynecol Obstet
membranes after 34 weeks of gestation. The mean change in Bishop Score was not statistically significant in our study similar to a randomized trial by Nagpal et al. [8]. In our study, the ripening to delivery interval was 8 h 20 min in the sublingual misoprostol group compared to 12 h 10 min in dinoprostone group (p = 0.000). However, we did not observe significant differences in the 2nd and 3rd stages of labour. The previous study, which used sublingual misoprostol, observed similar and significant reduction in induction to delivery interval in sublingual misoprostol group in term rupture of membranes, but this was in comparison to intravaginal dinoprostone, whereas in our study dinoprostone was used intracervically [6]. Induction to delivery interval has been shown to be either significantly reduced or comparable to with PGE2 in women with term PROM [7, 9, 11, 13]. Oral misoprostol for active management of PROM at term led to a significantly shorter induction to delivery interval and resulted in more women going into labour and delivering within 24 h of PROM [8, 10]. Oxytocin was required in 16 and 33 % of women in the sublingual misoprostol and intracervical dinoprostone group, respectively, and the difference was statistically significant. The mean duration of oxytocin requirement was higher in the dinoprostone group. Several other studies have also shown a significant reduction in oxytocin requirement with use of misoprostol in women with prelabour rupture of membranes [6, 8, 9, 12, 13]. There were no differences in the incidence of operative vaginal delivery or caesarean delivery between the sublingual PGE1 and intracervical PGE2 groups in our trial, which is in agreement with the other studies [6, 8–13] comparing the two prostaglandins in women with PROM. There were nine cases of tachysystole in the misoprostol group and one in the dinoprostone group (p = 0.003) and this was statistically significant. This is consistent with other study using sublingual misoprostol [6]. Hyperstimulation (2–9 %), tachysystole (20 %) and hypertonus (2.8 %) have also been shown with the use of vaginal misoprostol in women with PROM [9, 12]. The cost of sublingual dose of misoprostol was significantly lower when compared to intracervical dinoprostone (p = 0.000). Twenty-nine (30.9 %) women experienced side effects in PGE1 (sublingual) while 16 (17 %) women experienced side effects in PGE2 (intracervical) and this was statistically significant. Although we noticed more adverse effects overall in the misoprostol group, they were self-limiting and no woman abandoned misoprostol due to adverse effects. The incidence of vomiting was higher in PGE1 group (10.6 % compared to 3.2 % in PGE2 group) and this was statistically significant. The incidence of Pyrexia and diarrhoea were observed more in the PGE2 group (10.6 and
3.2 %, respectively), but this was not statistically significant. However, the incidence of shivering was higher in the PGE1 group (4.3 %). We noticed a comparable APGAR score at 1 and 5 min in both the groups which is in agreement with other studies using PG1 in women with PROM. Maternal and neonatal outcomes were comparable in our studies and are in agreement with several other studies [6–13]. The most common indication for NICU admission in PGE1 and PGE2 group was respiratory distress accounting for 6.4 and 12.8 % of neonates, respectively. Meconium aspiration syndrome and prematurity mostly lead to NICU admission in PGE2 group accounting for 6.4 and 4.3 % respectively. All babies were normal at discharge and there were no history of any seizure and no perinatal mortality. The incidence of respiratory distress was higher in the PGE2 group, but this was not statistically significant (p = 0.137). Data regarding the use of sublingual misoprostol in women with PROM are scarce. Most of the previous studies have used it in women with intact membranes. Sublingual misoprostol has been compared with oral or vaginal misoprostol for induction of labour and the authors have found contradictions in outcomes related to the superiority of one route over another [14–18]. Sublingual misoprostol appears to be at least as effective as when the same dose is administered orally. There are inadequate data to comment on the relative complications and side-effects. Recent meta-analysis has found no statistically significant difference between the sublingual and the vaginal misoprostol groups with respect to the rate of vaginal delivery (OR 1.27, 95 % CI 0.87–1.84), uterine hyperstimulation syndrome (OR 1.20, 95 % CI 0.61–2.33) or caesarean section (OR 1.33, 95 % CI 0.96–1.85) [19]. However, sublingual route of administration offers some attractive advantages such as greater ease of use compared with vaginal administration. In certain clinical contexts, such as when premature rupture of the membranes occurs, it is possible that the sublingual route of administration would be preferable to the vaginal route, with the potential benefit of avoiding digital vaginal examination and reducing infection rates. The sublingual (buccal) route could thus be expected to be as effective as vaginal misoprostol and, avoiding a direct effect on the cervix, might reduce the risk of uterine hyperstimulation and be safer. Blinding of the subjects with respect to drugs administered was not possible in the study. However, the use of randomization at study enrollment and strict labour and delivery protocols should have minimized the bias. Furthermore, we did not evaluate women’s and caregivers’ views and satisfaction with the different methods of induction.
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Conclusion Sublingual misoprostol and intracervical dinoprostone at the dose studied are equally efficacious in achieving spontaneous vaginal delivery, reduction in inductiondelivery interval and in reducing the need for oxytocin, in women after 34 weeks of gestation with rupture of membranes. There was no difference in the mode of delivery between both the groups. There were more side effects in the misoprostol group, though no woman in that group did abandon the study or the intake of misoprostol. The foetal and neonatal outcomes were comparable. Conflict of interest
None.
References
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1. Duff P (1996) Premature rupture of membranes at term. N Engl J Med 20:401–408 2. (2013) ACOG practice bulletin No.139: premature rupture of membranes. Obstet Gynecol 122:918–930 3. Royal College of Obstetricians and Gynaecologists (2006) Preterm prelabour rupture of membranes. Guideline No. 44 4. Buchanan SL, Crowther CA, Levett KM, Middleton P, Morris J (2010) Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks’ gestation for improving pregnancy outcome. Cochrane Database Syst Rev 3:CD004735 5. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ (2010) Labour induction. In: Williams obstetrics. 23rd Ed, McGraw Hill, pp 500–509 6. Parisaei M, Erskine KJ (2008) Is expensive always better? Comparison of two induction agents for term rupture of membranes. J Obstet Gynaecol 28:290–293 7. Chaudhuri S, Mitra SN, Banerjee PK et al (2011) Comparison of vaginal misoprostol tablets and prostaglandin E2 gel for the induction of labor in premature rupture of membranes at term: a
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randomized comparative trial. J Obstet Gynaecol Res 37:1564–1571 Nagpal MB, Raghunandan C, Saili A (2009) Oral misoprostol versus intracervical prostaglandin E2 gel for active management of premature rupture of membranes at term. Int J Gynaecol Obstet 106:23–26 Frohn WE, Simmons S, Carlan SJ (2002) Prostaglandin E2 gel versus misoprostol for cervical ripening in patients with premature rupture of membranes after 34 weeks. Obstet Gynecol 99:206–210 Shetty A, Stewart K, Stewart G, Rice P, Danielian P, Templeton A (2002) Active management of term prelabour rupture of membranes with oral misoprostol. BJOG 109:1354–1358 Abraham C, Meirowitz N, Kohn N (2014) Labor induction for premature rupture of membranes using vaginal misoprostol versus the dinoprostone vaginal insert. Am J Perinatol 31:181–186 Bricker L, Peden H, Tomlinson AJ et al (2008) Titrated low-dose vaginal and/or oral misoprostol to induce labour for prelabour membrane rupture: a randomised trial. BJOG 115:1503–1511 Ayad IA (2002) Vaginal misoprostol in managing premature rupture of membranes. East Mediterr Health J 8:515–520 Feitosa FE, Sampaio ZS, Alencar CA Jr, Amorim MM, Passini R Jr (2006) Sublingual vs. vaginal misoprostol for induction of labour. Int J Gynaecol Obstet 94:91–95 Elhassan EM, NasrAM AdamI (2007) Sublingual compared with oral and vaginal misoprostol for labor induction. Int J Gynaecol Obstet 97:153–154 Zahran KM, Shahin AY, Abdellah MS, Elsayh KI (2009) Sublingual versus vaginal misoprostol for induction of labor at term: a randomized prospective placebo-controlled study. J Obstet Gynaecol Res 35:1054–1057 Shetty A, Mackie L, Danielian P, Rice P, Templeton A (2002) Sublingual compared with oral misoprostol in term labour induction: a randomized controlled trial. BJOG 109:645–650 Kwon JS, Davies GA, Mackenzie VP (2001) A comparison of oral and vaginal misoprostol for induction of labor at term: a randomized trial. BJOG 108:23–26 Souza AS, Amorim MM, Feitosa FE (2008) Comparison of sublingual versus vaginal misoprostol for the induction of labor: a systematic review. BJOG 115:1340–1349
MATERNAL-FETAL MEDICINE
Comparison of efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membranes after 34 weeks of gestation Nivedita Jha • Haritha Sagili • D. Jayalakshmi Subitha Lakshminarayanan
•
Received: 30 January 2014 / Accepted: 11 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To compare the efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membrane after 34 weeks of gestation. Methods One eighty-eight women having [34 weeks of gestation with PROM, singleton viable fetus and no prior caesarean section were randomized to sublingual misoprostol (50 lg every 4 h and maximum of 3 doses) and intracervical dinoprostone (0.5 mg every 2 h and maximum of 2 doses). Oxytocin augmentation was commenced in those with a satisfactory Bishop score, inadequate contractions and who did not go into spontaneous active labour. Primary outcome measures were induction–delivery interval and the number of women that went into spontaneous labour without oxytocin augmentation. Results There was a significant reduction in induction to delivery interval in sublingual misoprostol group compared to intracervical dinoprostone (8.3 ± 3.6 h vs 12.2 ± 6.6 h; p = 0.000). There was a significant reduction in duration of rupture of membrane to delivery interval (p = 0.015), 1st stage of labour (p = 0.000) in sublingual misoprostol N. Jha (&) H. Sagili D. Jayalakshmi Department of Obstetrics and Gynecology, JIPMER, Puducherry 605005, India e-mail: [email protected] H. Sagili e-mail: [email protected] D. Jayalakshmi e-mail: [email protected] S. Lakshminarayanan Department of Preventive and Social Medicine, JIPMER, Puducherry, India e-mail: [email protected]
group as compared to the intravaginal dinoprostone group. There was no difference observed in spontaneous vaginal delivery between the groups (0.919). Oxytocin requirement was significantly higher in the dinoprostone group p = 0.006). There were more maternal adverse effects of sublingual misoprostol (p = 0.026). However, maternal and neonatal safety profiles were comparable. Conclusions Sublingual misoprostol and intracervical dinoprostone at the dose studied are equally efficacious in achieving spontaneous vaginal delivery, reduction in induction–delivery interval and in reducing the need for oxytocin, in women after 34 weeks gestation with rupture of membranes. Keywords Dinoprostone Misoprostol Premature prelabour rupture of membranes
Introduction Premature/prelabour rupture of membranes (PROM), which is defined as rupture of membranes before the onset of labour, complicates 3–10 % of pregnancies and approximately 60 % occur at term [1]. PROM typically is associated with variable latency between membrane rupture and delivery, increased potential for perinatal infection and in utero umbilical cord compression. The literature is replete with contradictions over the optimal approaches to clinical assessment and treatment of women with term and preterm PROM. The current obstetric management of PROM after 34 weeks includes expectant management or immediate delivery. Management hinges on knowledge of gestational age and evaluation of the relative risks of preterm birth versus intrauterine infection, abruptio placenta and cord
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accident that could occur with expectant management [2– 4]. Active management shortens the interval from prelabour rupture of membranes to delivery thus reducing maternal and foetal complications. The condition of the cervix is important for the success of labour induction, which is evaluated by Bishop Score. A Bishop score of 9 predicts the likelihood of successful induction, whereas a Bishop score of B4 identifies an unfavourable cervix [5]. Prostaglandins have been shown to be an effective method of ripening of unfavourable cervix in preterm and term patients with PROM. There are a number of studies comparing Dinoprostone gel (PGE2) with Misoprostol (PGE2) in PROM, mostly at term [6–10] and a few between 34 and 37 weeks of gestation [11–13]. PGE2 gel administered vaginally or intracervically is costly, unstable at room temperature and carries the risk of ascending infections. PGE1 is cheap, stable at room temperature and can be administered through oral/sublingual and vaginal routes in varying doses and time intervals. Non vaginal route of PGE1 has additional possible advantages when compared to PGE2 gel which can be given only through the vaginal route. These include fewer vaginal examinations, lower risk of sepsis in mother and fetus/neonate, greater freedom of movement for the mother which might facilitate progress of labour, less chance of hyperstimulation and potentially better efficacy because a vaginally administered drug such as PGE2 could partly flow out with the draining fluid. The sublingual route has been shown to lead to rapid onset of contractions with prolonged effect and greatest bioavailability. Data are scarce regarding the use of sublingual route of PGE1 in women with PROM. There is only study comparing sublingual misoprostol with vaginal PGE2 in PROM which found a shorter induction to labour time and less need for a second dose of induction agent or oxytocin infusion with sublingual PGE1. Till now, there is no study comparing sublingual PGE1 with intracervical PGE2 in women with prelabour rupture of membranes after 34 weeks of gestation. The purpose of the present study was to compare the efficacy and safety of sublingual misoprostol with intracervical dinoprostone gel for cervical ripening in prelabour rupture of membranes after 34 weeks of gestation.
Methods This study, a randomized controlled trial, was conducted in a tertiary care hospital. Institute ethics body approval and written informed consent were obtained before enrolling the patients in the study. One eighty-eight women with rupture of membranes (confirmed on sterile speculum examination) after 34 weeks of gestation with Bishop score \6 having a singleton, live fetus with cephalic presentation
123
were asked to participate. Women who had a history of prior caesarean section, antepartum hemorrhage, active genital infection, chorioamnionitis and prostaglandin sensitivity were excluded from the study. Grand multiparous women were also excluded from the study. The time of spontaneous rupture of membranes was noted. Bishop’s scoring was calculated. Participants were randomized into two groups using computer-generated random numbers. The routes of administration and drug dosage were not blinded. If the foetal heart rate was normal and if the contractions were not present, the woman was randomly allotted to either the group undergoing immediate cervical ripening with sublingual PGE1 (Group 1) or with intracervical PGE2 gel (Group 2). Prophylactic antibiotic (penicillin or cephalosporin) was given to all women. Women assigned to Group 1 were treated with a 50-lg PGE1 tablet sublingually every 4th hour for up to a maximum of three doses. Women in Group 2 were given 0.5 mg PGE2 gel instilled intracervically every 6th hour, for up to a maximum of two doses. Bishop score was evaluated before and after administration of each dose of drug in both the groups. The medications were administered by the trainee residents and application of the ripening agents was stopped if the woman was found to be in the active phase of labour (cervical dilatation C3 cm, uterine contractions 3/10 min), if hyperstimulation occurred and if the Bishop score was C6. Oxytocin induction and augmentation were commenced in those with satisfactory Bishop Score, inadequate contractions and who did not enter spontaneous active labour, so that three contractions were obtained in 10 min or a maximum dose of oxytocin (32 mIU/min) was achieved. Oxytocin infusion was not started until 4 h after the last dose of PGE1 and 6 h after PGE2. The women were carefully monitored every half hour for side effects. Vaginal examination was performed every 4 h to assess the progress of labour and the findings were plotted on a partogram. Primary outcome measures such as changes in the Bishop score, ripening–induction–delivery interval, the incidence of spontaneous labour, oxytocin requirement, mode of delivery and uterine hyperstimulation/tachysystole were recorded. Secondary outcome measures included maternal side effects (pyrexia, vomiting, diarrhoea, shivering, antepartum haemorrhage, maternal injuries), foetal adverse effects (meconium staining, foetal heart rate abnormalities) and neonatal outcome [(APGAR score, birth trauma, neonatal intensive care unit (NICU) admission, sepsis)]. Statistical analysis The sample size was calculated to be 94 in each group in order to estimate a difference of 2.5 h in induction–
Arch Gynecol Obstet
delivery interval in between both groups based on previous studies. Calculations were done using Openepi software, assuming 80 % power and 95 % confidence interval. Descriptive and inferential statistics were used to analyse the data. The subjects’ baseline characteristics were analysed by descriptive statistics. Categorical data were described using frequencies and percentages. The normality of the continuous data was assessed by Kolmogrov Smirnov test. Univariate analysis was carried out to assess the factors influencing the outcome. Student’s t test was used to compare the continuous variables between the two groups. Chi-square test was used to compare the proportions between different groups. All statistical analyses were carried out at 5 % level of significance and the p value \0.05 was considered significant. Statistical analyses were done using SPSS version 20.
Fig. 1 Comparison of pre-ripening and post-ripening Bishop Score in PGE1 (sublingual misoprostol) and PGE2 (intracervical dinoprostone) groups
Results The baseline characteristics such as age, period of gestation and duration of leaking and pre-induction Bishop Score were comparable in both the groups (Table 1). There were more primigravidae in the PGE1 group (53.2 %) while there was more multigravidae in the PGE2 group (61.7 %). However, there was no significant difference between the groups. Liquor was clear in 77.7 % both in PGE1 and PGE2 groups. Meconium stained liquor was found in 22.3 % of women in PGE1 and PGE2 groups. There were no significant differences among the groups with regard to the colour of the liquor.
(h) of oxytocin requirement was higher in the dinoprostone group (6.2 ± 4.2 vs 4.2 ± 3.6) (p = 0.128). Rupture of membrane to delivery intervals and modes of delivery have been summarized in Tables 2 and 3. The percentage of women who required instrumental vaginal delivery for foetal distress and prolonged 2nd stage were 12.8 and 6.4 % in the PGE1 group 10.6 and 8.5 % in the PGE2 group, respectively. However, the observed difference in Table 2 Primary outcome measures—ripening to delivery intervals Characteristics of labour
Significance
PGE1 Mean ± SD
PGE2 Mean ± SD
p value
Duration (ROMdelivery) (h)
22 ± 12.9
27.8 ± 18.5
0.015
Duration (ripeningdelivery) (h)
8.3 ± 3.6
12.2 ± 6.6
0.000
Primary outcome measures The mean post ripening Bishop Score was 8 ± 0.9 in the PGE1 group while it was 7.9 ± 1 in the PGE2 group (p = 0.254) (Fig. 1). The mean change in Bishop Score was 4.09 ± 1.27 in the PGE1 group while it was 4.06 ± 1.33 in the PGE2 group (p = 0.839). 16 % of women required oxytocin after initial ripening with PGE1 while 33 % of women required oxytocin after initial administration of PGE2. The observed difference in additional method used was statistically significant (p = 0.006). The mean duration
Drugs
6.4 ± 2.6
12.4 ± 11.3
0.000
2nd stage of labour (min)
1st stage of labour (h)
30.8 ± 17
29.1 ± 18.7
0.512
3rd stage of labour (min)
10.6 ± 6.5
11.3 ± 5.4
0.441
Data are expressed as mean ± SD; p \ 0.05 considered significant
Table 3 Modes of delivery Table 1 Demographic Characteristics
Outcomes
PGE1 N (%)
PGE2 N (%)
p value
0.74
Spontaneous vaginal delivery
65 (69.1)
66 (70.2)
0.919
Demographic parameters
PGE1
PGE2
p value
Age (years)
24.6 ± 4.2
23.4 ± 4.5
Period of gestation (weeks)
38.2 ± 2.5
Duration of leaking (h) Pre-Induction Bishop Score
14 ± 11.1 3.95 ± 1
38.3 ± 3
0.79
Instrumental delivery
18 (19.1)
16 (17)
17.8 ± 18.5
0.08
Caesarean section
11 (11.7)
12 (12.8)
3.84 ± 0.9
0.34
Data are expressed as mean ± SD, p \ 0.05 considered significant
N (%) number of patients (percent) p \ 0.05 considered as significant
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instrumental vaginal delivery for foetal distress (p = 0.650) and prolonged 2nd stage (p = 0.578) was non-significant. Fetal distress was the most common reason for LSCS (8.5 %) in women in the PGE1 group. In the PGE2 group foetal distress was the most common reason (5.3 %) for LSCS followed by chorioamnionitis (3.2 %) (p = 0.838) (Fig. 2). Nine women developed tachysystole in the misoprostol group compared to one woman in the dinoprostone group (p = 0.003). The cost of sublingual dose of misoprostol was significantly lower when compared to intracervical dinoprostone (p = 0.000). Secondary outcome measures Twenty-nine (30.9 %) women experienced side effects in PGE1 (sublingual) while 16 (17 %) women experienced side effects in PGE2 (intracervical) and this was statistically significant (p = 0.026) (Fig. 3). There were 15 (16 %) cases of foetal distress in PGE1 group and 14(15 %) of cases of foetal distress in PGE2 group (p = 0.76). The mean APGAR score in the newborn at 1 and 5 min was higher in the PGE1 group compared with the PGE2 group (7.2 ± 1.5 vs 7 ± 1.6) and (8.3 ± 2.4 vs 8.1 ± 1.6), respectively, but the difference
Fig. 2 Number of women who underwent lower segment caesarean section due to different reasans in PGE1 and PGE2 groups. FD feetal distress, CPD NP nonprogress of labour, HS hyperstimulation, CA chorioamnionitis
Fig. 3 No. of women developed different side effects of sublingual PGE1 (misoprostol) and PGE2 (intracervical dinoprostone)
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was not significant (p = 0.487 at 1 min) (p = 0.315 at 5 min). 12 (12.8 %) neonates required NICU admission in the PGE1 group while 22 (23.4 %) required NICU admission in PGE2 group (p = 0.05). The most common indication for NICU admission in PGE1 and PGE2 group was respiratory distress accounting for 6.4 % and 12.8 % of neonates, respectively. Meconium aspiration syndrome and prematurity mostly lead to NICU admission in PGE2 group accounting for 6.4 and 4.3 %, respectively. All babies were normal at discharge and there were no history of any seizure and no perinatal mortality. The incidence of respiratory distress was higher in the PGE2 group, but this was not statistically significant (p = 0.137). There was no birth trauma in any of neonates born by any of the three modes of deliveries. In none of the babies septic screen was positive.
Discussion We demonstrated a significant reduction in rupture of membranes to delivery interval, ripening to delivery interval and the 1st stage of labour in the group which received sublingual misoprostol for prelabour rupture of
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membranes after 34 weeks of gestation. The mean change in Bishop Score was not statistically significant in our study similar to a randomized trial by Nagpal et al. [8]. In our study, the ripening to delivery interval was 8 h 20 min in the sublingual misoprostol group compared to 12 h 10 min in dinoprostone group (p = 0.000). However, we did not observe significant differences in the 2nd and 3rd stages of labour. The previous study, which used sublingual misoprostol, observed similar and significant reduction in induction to delivery interval in sublingual misoprostol group in term rupture of membranes, but this was in comparison to intravaginal dinoprostone, whereas in our study dinoprostone was used intracervically [6]. Induction to delivery interval has been shown to be either significantly reduced or comparable to with PGE2 in women with term PROM [7, 9, 11, 13]. Oral misoprostol for active management of PROM at term led to a significantly shorter induction to delivery interval and resulted in more women going into labour and delivering within 24 h of PROM [8, 10]. Oxytocin was required in 16 and 33 % of women in the sublingual misoprostol and intracervical dinoprostone group, respectively, and the difference was statistically significant. The mean duration of oxytocin requirement was higher in the dinoprostone group. Several other studies have also shown a significant reduction in oxytocin requirement with use of misoprostol in women with prelabour rupture of membranes [6, 8, 9, 12, 13]. There were no differences in the incidence of operative vaginal delivery or caesarean delivery between the sublingual PGE1 and intracervical PGE2 groups in our trial, which is in agreement with the other studies [6, 8–13] comparing the two prostaglandins in women with PROM. There were nine cases of tachysystole in the misoprostol group and one in the dinoprostone group (p = 0.003) and this was statistically significant. This is consistent with other study using sublingual misoprostol [6]. Hyperstimulation (2–9 %), tachysystole (20 %) and hypertonus (2.8 %) have also been shown with the use of vaginal misoprostol in women with PROM [9, 12]. The cost of sublingual dose of misoprostol was significantly lower when compared to intracervical dinoprostone (p = 0.000). Twenty-nine (30.9 %) women experienced side effects in PGE1 (sublingual) while 16 (17 %) women experienced side effects in PGE2 (intracervical) and this was statistically significant. Although we noticed more adverse effects overall in the misoprostol group, they were self-limiting and no woman abandoned misoprostol due to adverse effects. The incidence of vomiting was higher in PGE1 group (10.6 % compared to 3.2 % in PGE2 group) and this was statistically significant. The incidence of Pyrexia and diarrhoea were observed more in the PGE2 group (10.6 and
3.2 %, respectively), but this was not statistically significant. However, the incidence of shivering was higher in the PGE1 group (4.3 %). We noticed a comparable APGAR score at 1 and 5 min in both the groups which is in agreement with other studies using PG1 in women with PROM. Maternal and neonatal outcomes were comparable in our studies and are in agreement with several other studies [6–13]. The most common indication for NICU admission in PGE1 and PGE2 group was respiratory distress accounting for 6.4 and 12.8 % of neonates, respectively. Meconium aspiration syndrome and prematurity mostly lead to NICU admission in PGE2 group accounting for 6.4 and 4.3 % respectively. All babies were normal at discharge and there were no history of any seizure and no perinatal mortality. The incidence of respiratory distress was higher in the PGE2 group, but this was not statistically significant (p = 0.137). Data regarding the use of sublingual misoprostol in women with PROM are scarce. Most of the previous studies have used it in women with intact membranes. Sublingual misoprostol has been compared with oral or vaginal misoprostol for induction of labour and the authors have found contradictions in outcomes related to the superiority of one route over another [14–18]. Sublingual misoprostol appears to be at least as effective as when the same dose is administered orally. There are inadequate data to comment on the relative complications and side-effects. Recent meta-analysis has found no statistically significant difference between the sublingual and the vaginal misoprostol groups with respect to the rate of vaginal delivery (OR 1.27, 95 % CI 0.87–1.84), uterine hyperstimulation syndrome (OR 1.20, 95 % CI 0.61–2.33) or caesarean section (OR 1.33, 95 % CI 0.96–1.85) [19]. However, sublingual route of administration offers some attractive advantages such as greater ease of use compared with vaginal administration. In certain clinical contexts, such as when premature rupture of the membranes occurs, it is possible that the sublingual route of administration would be preferable to the vaginal route, with the potential benefit of avoiding digital vaginal examination and reducing infection rates. The sublingual (buccal) route could thus be expected to be as effective as vaginal misoprostol and, avoiding a direct effect on the cervix, might reduce the risk of uterine hyperstimulation and be safer. Blinding of the subjects with respect to drugs administered was not possible in the study. However, the use of randomization at study enrollment and strict labour and delivery protocols should have minimized the bias. Furthermore, we did not evaluate women’s and caregivers’ views and satisfaction with the different methods of induction.
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Conclusion Sublingual misoprostol and intracervical dinoprostone at the dose studied are equally efficacious in achieving spontaneous vaginal delivery, reduction in inductiondelivery interval and in reducing the need for oxytocin, in women after 34 weeks of gestation with rupture of membranes. There was no difference in the mode of delivery between both the groups. There were more side effects in the misoprostol group, though no woman in that group did abandon the study or the intake of misoprostol. The foetal and neonatal outcomes were comparable. Conflict of interest
None.
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