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doi:10.1111/jog.12396
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1527–1533, June 2014
Concurrent use of Foley catheter and misoprostol for induction of labor: A randomized clinical trial of efficacy and safety Sreelakshmi Lanka1, Tarakeswari Surapaneni1 and Praveen K. Nirmalan2 1
Department of Obstetrics, and 2Clinical Research Unit, Fernandez Hospital, Hyderabad, India
Abstract Aim: The aim of this study was to compare the efficacy of combined intracervical Foley catheter and low-dose vaginal misoprostol with low-dose vaginal misoprostol alone for induction of labor. Material and Methods: This prospective non-blinded randomized controlled trial was conducted over a 2-year period in 126 pregnant women planned for induction of labor at a tertiary care centre. Women at ≥28 gestational weeks with a singleton fetus in cephalic presentation, intact membranes and a Bishop score of ≤4 were randomized for labor induction with either a combination of Foley catheter and misoprostol or only misoprostol. The primary outcome variable was the induction-to-delivery interval between the two groups. The secondary outcome variables included rate of vaginal deliveries, uterine hyperstimulation, cesarean section rate, Apgar scores at 1 and 5 min, neonatal intensive care unit admissions and chorioamnionitis. Results: The mean induction-to-delivery interval and rate of vaginal deliveries were not significantly different between the groups (26.52 h in the combination group and 27.64 h in the misoprostol group, P = 0.65; 65.07% and 65.07%, respectively, P = 0.9). Uterine hyperstimulation and meconium-stained liquor were significantly more prevalent in the misoprostol group (P = 0.001). Neonatal outcomes did not differ significantly between the groups. Conclusion: The addition of Foley catheter to misoprostol did not cause any statistically significant benefit in reducing the induction-to-delivery time. However, it reduced the incidence of uterine hyperstimulation and meconium-stained liquor. Key words: combination, Foley catheter, induction, labor, misoprostol.
Introduction Induction of labor, an increasingly common obstetric intervention, aims to artificially initiate uterine contractions leading to progressive effacement and dilation of the cervix and birth of the neonate. Data from the World Health Organization Global Survey on Maternal and Perinatal Health, which included 373 health-care facilities in 24 countries and nearly 300 000 deliveries, showed that 9.6% of the deliveries
involved labor induction. Overall, the survey found that facilities in African countries tended to have lower rates of induction of labor (lowest: Niger, 1.4%) compared with Asian and Latin American countries (highest: Sri Lanka, 35.5%).1 The recommended indications for induction generally include a gestational age of ≥41 completed weeks, pre-labor rupture of amniotic membranes, maternal medical complications, fetal death, fetal growth restriction and chorioamnionitis.2,3
Received: April 8 2013. Accepted: December 31 2013. Reprint request to: Dr Tarakeswari Surapaneni, Department of Obstetrics, Fernandez Hospital, 3-6-282, Opp. Old MLA Quarters, Hyderguda, Hyderabad – 500029 Andhra Pradesh, India. Email: [email protected] Clinical Trial Registered with the Clinical Trial Registry India. Registration Number: CTRI/2012/12/003265
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Mechanical (Foley catheter, laminaria tents) and pharmacological (prostaglandins, oxytocin) agents have been used for the induction of labor. The supra cervical insertion of a Foley catheter acts by overstretching the lower uterine segment and the cervix. This process strips the fetal membranes from the lower uterine segment and causes rupture of the lysosomes in the decidual cells. The lytic enzymes released include phospholipase A, which acts on phospholipids to form arachidonic acid and is converted to prostaglandins.1 Misoprostol (PGE1) is a prostaglandin analogue used to induce labor that is associated with enzymatic collagen degradation, increased water content in the extracellular matrix and stimulation of the myometrium resulting in uterine contractions.1 Misoprostol has several advantages, including the low cost, stability at room temperature and ease of administration.4 Low-dose vaginal misoprostol is associated with lesser uterine hyperstimulation and achieves prolonged serum levels when compared to oral misoprostol.5 Previous trials that assessed various combinations of labor-inducing agents have reported contradictory results for induction to delivery intervals, vaginal deliveries and complications.6–9 This study used a randomized clinical trial design to explore the hypothesis that a synergistic combination of a mechanical agent (Foley catheter) with a pharmacological agent (low-dose intravaginal misoprostol) may be better for induction compared to the use of misoprostol in isolation. The combination was expected to perform better as it would cause cervical ripening and uterine contractions simultaneously facilitating a shorter induction-todelivery interval.
Methods The study protocol was approved by the Institutional Review Board and registered with the Clinical Trials Registry of India (CTRI registration number: CTRI/ 2012/12/003265). This prospective non-blinded randomized controlled trial was conducted over a 2-year period in 126 pregnant women planned for induction of labor at a tertiary care centre. Written informed consent was obtained from participants in the trial prior to enrolment. The study included pregnant women with a gestational age ≥28 weeks and a singleton fetus, intact membranes at enrolment, absence of labor, cephalic presentation, and Bishop score of 4 or less. Eligible women had a baseline non-stress test (NST) before the procedure that was considered reactive if the baseline was 110–160/min with beat–beat
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variability ≥5 b.p.m. and two or more accelerations (≥15 beats above baseline) without decelerations over a 20-min time period. The study excluded pregnant women with multifetal gestation, congenital malformations of the fetus, gravidity ≥ 5, non-reassuring fetal heart rate trace, ruptured membranes, active genital infection, previous uterine surgery (including cesarean section), low-lying placenta, chorioamnionitis, estimated fetal weight > 4000 g, intrauterine fetal death, known allergies to latex or prostaglandins, and women in spontaneous labor. Demographic details, prior medical and obstetric history, the course of labor and indication for induction were documented. Enrolled eligible women were randomized to one of the two intervention groups using a pre-determined computer-generated randomization sequence that used blocks of unequal length. The random allocation was concealed in sealed opaque envelopes arranged sequentially and opened prior to the procedure by a person not related to the trial. A 16-Fr Foley catheter was inserted into the endocervical canal under direct visualization during a sterile speculum examination for pregnant women randomized to the combination group. Every effort was made to avoid contact of the catheter with the vagina or ectocervix. Thirty milliliters of sterile water was injected into the balloon once the catheter passed the internal os. Traction was applied by taping the end of the catheter to the medial side of the knee or thigh. After securing the catheter in place, a 25-μg moistened misoprostol tablet was inserted into the posterior vaginal fornix under aseptic precautions. The Foley catheter was retained in situ till spontaneous expulsion or for a maximum duration of 12 h. The cervix was assessed every 4 h by Bishop score and a 25-μg misoprostol tablet was inserted 4-hourly, up to a maximum of eight doses if the score was ≤6. The Foley catheter was removed if any of the following occurred: (i) non-reassuring fetal heart rate (FHR) mandating membrane rupture; (ii) spontaneous membrane rupture; or (iii) after 12 h of insertion. Women in the other intervention group received only the misoprostol regime without the Foley catheter. A 25-μg misoprostol tablet (moistened with normal saline) was inserted into the posterior vaginal fornix under aseptic precautions. The cervix was assessed every 4 h by Bishop score and a 25-μg misoprostol tablet was inserted 4-hourly, up to a maximum of eight doses if the Bishop score was ≤6.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Induction of labor
The fetal condition and uterine contractions were monitored in both the groups by an NST half an hour prior to each scheduled dose of misoprostol. Subsequent doses were withheld if labor ensued or if uterine tachysystole or non-reassuring FHR occurred. The final Bishop score was noted when the patient was taken into the labor ward. Active management of labor was done with amniotomy followed by low-dose oxytocin augmentation. Oxytocin infusion was started using an infusion pump at the rate of 1 mU/min and escalated every 30 min until regular uterine contractions were achieved or up to a maximum of 20 mU/min. Failed induction of labor was defined as Bishop score ≤ 6 after eight doses of misoprostol and absence of established uterine contractions. The subsequent management of these women was individualized. The primary outcome variables of interest included the induction-to-delivery interval. The secondary outcomes of interest included rate of vaginal deliveries, uterine hyperstimulation (more than five contractions in 10 min associated with FHR changes), incidence of cesarean section, neonatal outcome (birthweight, Apgar scores at 1 and 5 min, neonatal intensive care (NICU) admissions), and chorioamnionitis. Chorioamnionitis was defined as maternal oral temperature equal to or greater than 100.4° F with any two of the three findings of uterine tenderness, fetal/maternal tachycardia and foul-smelling liquor. The sample size for the study was estimated at 126 women based on α of 0.05 and an estimated mean difference of at least 4 h for the primary outcome between the two groups, and an estimated induction-to-delivery time of 17.0 ± 7.8 h with vaginal misoprostol. The induction-to-delivery time and induction-to-active phase interval were found to be non-normally distributed using the Shapiro–Wilk test and were further analyzed using a non-parametric Mann–Whitney U-test. The Student’s t-test was used to compare continuous variables that were normally distributed and Fisher’s exact test was used to compare categorical variables. A P-value < 0.05 was considered statistically significant. Statistical analysis was performed using stata version 9.0.
Results A total of 126 women enrolled in the study between January 2010 and December 2011 were randomized to receive either low-dose vaginal misoprostol alone or a combination of intracervical Foley catheter and low-
dose vaginal misoprostol. The insertion of Foley catheter was not possible in four women as they complained of pain and they subsequently received only misoprostol and were monitored as per protocol. None of these women were excluded, and an intention-to-treat analysis was performed (see Fig. 1). The baseline maternal characteristics of women enrolled in the trial did not differ between the two groups (see Table 1). Most of the women enrolled in the trial were at term and nulliparous and the most common indication for induction was a post-dated pregnancy. The median Bishop score at admission was similar for the two groups (see Table 1). The median number of doses of misoprostol (two and three, respectively) did not differ significantly between the two groups (P = 0.17). The mean induction-to-delivery time and the induction-to-active phase interval did not differ significantly between the groups (P = 0.65 and 0.31, respectively) using the Mann–Whitney U-test (see Table 2). The mode of delivery and the proportion of deliveries within 24 h after induction did not differ significantly between the two groups (see Table 2). The inductionto-delivery time was further examined stratified by the mode of delivery. The mean (SD) induction-to-delivery interval was 20.62 (11.34) h in the combined group compared to 23.95 (13.12) h in the misoprostol group among women who had a spontaneous vaginal delivery; however, this difference was not statistically significant (P = 0.31). Indications for cesarean section did not differ significantly between the two groups (P = 0.62). The most common indication for a cesarean section was presumed fetal compromise for both the combined and misoprostol groups (n = 8). Other indications for cesarean sections included maternal request (n = 1 and 2), failed induction (n = 4 and 2), failure to progress (n = 4 and 5), cephalopelvic disproportion (n = 2 and 5) and suspected abruption (n = 3 and 0) in the combination and misoprostol groups, respectively. The mean induction to delivery time did not differ significantly between the groups stratified by cesarean section (P = 0.63). Thirty-five (55.56%) women in the combined group and 29 (46.03%) women in the misoprostol group required augmentation of labor with oxytocin (P = 0.37). Uterine hyperstimulation (P < 0.001) and meconium-stained liquor (P = 0.001) were significantly more common in the misoprostol group. There were no documented cases of chorioamnionitis. Neonatal outcomes did not differ significantly between the two groups (see Table 3).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Enrollment
Randomized (n = 126)
Allocation Foley + Misoprostol (n = 63) ♦ Received allocated intervention (n = 59)
♦
♦
♦
Allocated to intervention (n = 63) Received allocated intervention (n = 63)
Did not receive allocated intervention (n = 4) –pain during insertion (n = 4)
Did not receive allocated intervention (n = 0)
Follow-up Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysis Analyzed (n = 63) ♦ Excluded from analysis (n = 0)
Analyzed (n = 63) Excluded from analysis (n = 0)
♦
Figure 1 Flow diagram.
Discussion Induction of labor is one of the most commonly performed obstetric procedures. Delivery before the onset of labor is indicated when the maternal/fetal risks associated with continuing the pregnancy are thought to be greater than the maternal/fetal risks associated with early delivery. In the absence of a ripe or favorable cervix, a successful vaginal birth is less likely.1,10 Misoprostol is a pharmacological agent that acts by initiating the uterine contractions.11 Foley catheter, on the other hand causes cervical ripening with little or no
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uterine contractions.11,12 The combination is presumed to cause simultaneous ripening and uterine contractions, which helps in early cervical dilation. The results of this study indicate that the use of combined Foley catheter plus low-dose vaginal misoprostol does not significantly reduce the induction-to-delivery interval compared to low-dose vaginal misoprostol alone. Although the difference was not statistically significant, the mean inductionto-delivery interval was shorter by more than 3 h and clinically relevant in the combined group compared to the misoprostol group in a subgroup analysis that
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Induction of labor
Table 1 Baseline characteristics of women enrolled into the trial Characteristics
Foley + low-dose vaginal misoprostol (n = 63)
Low-dose vaginal misoprostol (n = 63)
Maternal age (years): Mean (SD) Body mass index (kg/m2): Mean (SD) Median Primigravida Nulliparous Mean (SD) GA at delivery (weeks) Mean (SD) Bishop score at admission, median Indications for induction Postdates Diabetes mellitus Hypertension Oligohydramnios Decreased fetal movements Others†
26.40 (3.72) 25.63 (3.91), 25 40 (63.49%) 50 (79.37%) 39.13 (1.48) 1.84 (1.00), 2
25.90 (3.37) 25.57 (3.80), 26 40 (63.49%) 49 (77.77%) 39.29 (1.68) 2.21 (0.99), 2
15 (23.81%) 16 (25.40%) 9 (14.29%) 5 (7.94%) 9 (14.29%) 9 (14.29%)
23 (36.50%) 8 (12.69%) 9 (14.28%) 8 (12.69%) 6 (9.52%) 9 (14.28%)
†Others include cholestasis of pregnancy, fetal growth restriction and social indications. GA, gestational age; SD, standard deviation.
Table 2 Maternal outcomes, labor details and complications Outcome
Foley + low-dose vaginal misoprostol (n = 63)
Low-dose vaginal misoprostol (n = 63)
P-value
Mean (SD) induction-to-delivery time (h) Mean (SD) induction-to-active phase (h) Spontaneous vaginal delivery Assisted vaginal delivery Cesarean section Delivery within 24 h Uterine hyperstimulation Oxytocin requirement Epidural use Meconium stained liquor
26.52 (15.24) 20.01 (12.98) 28 (44.44%) 13 (20.63%) 22 (34.92%) 32 (50.79%) 5 (7.94%) 35 (55.56%) 51 (82.96%) 4 (6.34%)
27.64 (15.63) 21.56 (12.34) 30 (47.61%) 11 (17.46%) 22 (34.92%) 32 (50.79%) 25 (39.68%) 29 (46.03%) 47 (74.60%) 17 (26.98%)
0.65 0.31 0.59 0.65 1.00 1.00 6 25-μg 4-hourly, 8 doses 24-Fr 50 mL for 12 h
Rust et al.6 1999 (n = 81) Chung et al.7 2003 (n = 146) Kashanian et al.8 2005 (n = 300) Carbone et al.9 2013 (n = 123) Present study (n = 126)
Dose of misoprostol Foley catheter and duration Study
Table 4 Comparison of our results with other studies
Mean induction-todelivery interval ± SD (h) in combination group
Mean induction-todelivery interval ± SD (h) in misoprostol group
Rate of vaginal delivery in combination group
Rate of vaginal delivery in misoprostol group
S. Lanka et al.
doses of misoprostol were withheld if there were adequate uterine contractions clinically or on an NST. Studies have reported an increased uterine tachysystole, uterine hyperstimulation and terbutaline use with the use of misoprostol alone for induction.13,14 Chung et al. reported that the hyperstimulation rate was 33.3% in the misoprostol group compared to 16.3% in the combined Foley–misoprostol regimen (P = 0.02) with a consequent increase in the use of terbutaline (18% vs 9.3%, P = 0.05).7 Similar to these reports, we too found that uterine hyperstimulation and meconium-stained liquor were significantly associated with the misoprostol group compared to the combination group. The lack of association with neonatal outcomes is consistent with previous trials; however, these have to be assessed in larger trials. The randomized design is the strength of this study; however, it was not possible to mask or blind the interventions. It is possible that the ‘non-blinded’ nature of the design may influence decisions to deliver and shorten induction-to-delivery interval. However, we found that the time to delivery did not differ significantly among those who had a cesarean section. The lower induction-to-delivery time for spontaneous vaginal deliveries (>3 h difference) in the combined group was not statistically significant. However, this is a significant clinically relevant reduction that suggests benefits from using a combination of Foley catheter plus low-dose vaginal misoprostol for induction compared to the use of vaginal misoprostol alone. Additionally, the significant difference in meconium-stained liquor as well as uterine hyperstimulation and consequent lower terbutaline use (although not statistically significant) also indicate benefits from the use of combined Foley catheter plus low-dose vaginal misoprostol for induction. A major limitation of the study is the lack of power to study significant differences in complications of labor and neonatal outcomes. Ideally, the effectiveness and safety of induction agents have to be assessed comparing these outcomes too. This will require trials with a larger sample size and will possibly have to be multicenter. In conclusion, this study reports no statistically significant reduction in induction-to-delivery interval in those induced with Foley catheter plus low-dose misoprostol compared to induction with low-dose vaginal misoprostol alone. However, there was a statistically significantly lower rate of uterine hyperstimulation and meconium-stained liquor in the combination
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Induction of labor
group, which contributes towards lowering maternal and neonatal morbidity.
Acknowledgments The authors would like to thank patients, labor ward staff and consultants for their contribution through the study period.
Disclosure
7.
8.
9.
The results of this manuscript have not been distorted by research funding or conflicts of interest. 10.
References 1. World Health Organization. WHO Recommendations for Induction of Labor, 2011. 2. Mozurkewich E, Chilimigras J, Koepke E, Keeton K, King VJ. Indications for induction of labor: A best-evidence review. Br J Obstet Gynaecol 2009; 116: 626–636. 3. National Institute for Health and Clinical Excellence – Induction of labour NICE Clinical guideline 70, July 2008. 4. WHO Expert Committee. The selection and use of essential medicines. World Health Organ Tech Rep Ser 2007; 1–162. 5. Deborah A, Wing A. Benefit-risk assessment of misoprostol for cervical ripening and labour induction. Drug Saf 2002; 25: 665–676. 6. Rust OA, Greybush M, Atlas RO, Jones KJ, Balducci J. Preinduction cervical ripening: A randomized trial of intravaginal
11.
12.
13.
14.
misoprostol alone vs. a combination of transcervical Foley balloon and intravaginal misoprostol. J Reprod Med 2001; 46: 899–904. Chung JH, Huang WH, Rumney PJ, Garite TJ, Nageotte MP. A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostolFoley catheter for labor induction. Am J Obstet Gynecol 2003; 189: 1031–1035. Kashanian M, Akbarian AR, Fekrat M. Cervical ripening and induction of labor with intravaginal misoprostol and Foley catheter cervical traction. Int J Gynaecol Obstet 2006; 92: 79–80. Carbone JF, Tuuli MG, Fogertey PJ, Roehl KA, Macones GA. Combination of Foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: A randomized controlled trial. Obstet Gynecol 2013; 121 (2 Pt 1): 247–252. Embrey MP, Mollison BC. The unfavorable cervix and the induction of labor using a cervical balloon. J Obstet Gynaecol Br Commonw 1967; 74: 44–48. Sullivan CA, Benton LW, Roach H, Smith LG Jr, Martin RW, Morrison JC. Combining medical and mechanical methods of cervical ripening. Does it increase the likelihood of successful induction of labor? J Reprod Med 1996; 41: 823–828. Cromi A, Ghezzi F, Agosti M et al. Is transcervical Foley catheter actually slower than prostaglandins in ripening the cervix? Am J Obstet Gynecol 2011; 204: 338; e1–7. Sciscione AC. A randomized comparison of transcervical Foley catheter to intravaginal misoprostol for preinduction cervical ripening. Obstet Gynecol 2001; 97: 603–607. Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labor. Cochrane Database Syst Rev 2003; (1): CD000941; doi: 10.1002/14651858 .CD000941.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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doi:10.1111/jog.12396
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1527–1533, June 2014
Concurrent use of Foley catheter and misoprostol for induction of labor: A randomized clinical trial of efficacy and safety Sreelakshmi Lanka1, Tarakeswari Surapaneni1 and Praveen K. Nirmalan2 1
Department of Obstetrics, and 2Clinical Research Unit, Fernandez Hospital, Hyderabad, India
Abstract Aim: The aim of this study was to compare the efficacy of combined intracervical Foley catheter and low-dose vaginal misoprostol with low-dose vaginal misoprostol alone for induction of labor. Material and Methods: This prospective non-blinded randomized controlled trial was conducted over a 2-year period in 126 pregnant women planned for induction of labor at a tertiary care centre. Women at ≥28 gestational weeks with a singleton fetus in cephalic presentation, intact membranes and a Bishop score of ≤4 were randomized for labor induction with either a combination of Foley catheter and misoprostol or only misoprostol. The primary outcome variable was the induction-to-delivery interval between the two groups. The secondary outcome variables included rate of vaginal deliveries, uterine hyperstimulation, cesarean section rate, Apgar scores at 1 and 5 min, neonatal intensive care unit admissions and chorioamnionitis. Results: The mean induction-to-delivery interval and rate of vaginal deliveries were not significantly different between the groups (26.52 h in the combination group and 27.64 h in the misoprostol group, P = 0.65; 65.07% and 65.07%, respectively, P = 0.9). Uterine hyperstimulation and meconium-stained liquor were significantly more prevalent in the misoprostol group (P = 0.001). Neonatal outcomes did not differ significantly between the groups. Conclusion: The addition of Foley catheter to misoprostol did not cause any statistically significant benefit in reducing the induction-to-delivery time. However, it reduced the incidence of uterine hyperstimulation and meconium-stained liquor. Key words: combination, Foley catheter, induction, labor, misoprostol.
Introduction Induction of labor, an increasingly common obstetric intervention, aims to artificially initiate uterine contractions leading to progressive effacement and dilation of the cervix and birth of the neonate. Data from the World Health Organization Global Survey on Maternal and Perinatal Health, which included 373 health-care facilities in 24 countries and nearly 300 000 deliveries, showed that 9.6% of the deliveries
involved labor induction. Overall, the survey found that facilities in African countries tended to have lower rates of induction of labor (lowest: Niger, 1.4%) compared with Asian and Latin American countries (highest: Sri Lanka, 35.5%).1 The recommended indications for induction generally include a gestational age of ≥41 completed weeks, pre-labor rupture of amniotic membranes, maternal medical complications, fetal death, fetal growth restriction and chorioamnionitis.2,3
Received: April 8 2013. Accepted: December 31 2013. Reprint request to: Dr Tarakeswari Surapaneni, Department of Obstetrics, Fernandez Hospital, 3-6-282, Opp. Old MLA Quarters, Hyderguda, Hyderabad – 500029 Andhra Pradesh, India. Email: [email protected] Clinical Trial Registered with the Clinical Trial Registry India. Registration Number: CTRI/2012/12/003265
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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S. Lanka et al.
Mechanical (Foley catheter, laminaria tents) and pharmacological (prostaglandins, oxytocin) agents have been used for the induction of labor. The supra cervical insertion of a Foley catheter acts by overstretching the lower uterine segment and the cervix. This process strips the fetal membranes from the lower uterine segment and causes rupture of the lysosomes in the decidual cells. The lytic enzymes released include phospholipase A, which acts on phospholipids to form arachidonic acid and is converted to prostaglandins.1 Misoprostol (PGE1) is a prostaglandin analogue used to induce labor that is associated with enzymatic collagen degradation, increased water content in the extracellular matrix and stimulation of the myometrium resulting in uterine contractions.1 Misoprostol has several advantages, including the low cost, stability at room temperature and ease of administration.4 Low-dose vaginal misoprostol is associated with lesser uterine hyperstimulation and achieves prolonged serum levels when compared to oral misoprostol.5 Previous trials that assessed various combinations of labor-inducing agents have reported contradictory results for induction to delivery intervals, vaginal deliveries and complications.6–9 This study used a randomized clinical trial design to explore the hypothesis that a synergistic combination of a mechanical agent (Foley catheter) with a pharmacological agent (low-dose intravaginal misoprostol) may be better for induction compared to the use of misoprostol in isolation. The combination was expected to perform better as it would cause cervical ripening and uterine contractions simultaneously facilitating a shorter induction-todelivery interval.
Methods The study protocol was approved by the Institutional Review Board and registered with the Clinical Trials Registry of India (CTRI registration number: CTRI/ 2012/12/003265). This prospective non-blinded randomized controlled trial was conducted over a 2-year period in 126 pregnant women planned for induction of labor at a tertiary care centre. Written informed consent was obtained from participants in the trial prior to enrolment. The study included pregnant women with a gestational age ≥28 weeks and a singleton fetus, intact membranes at enrolment, absence of labor, cephalic presentation, and Bishop score of 4 or less. Eligible women had a baseline non-stress test (NST) before the procedure that was considered reactive if the baseline was 110–160/min with beat–beat
1528
variability ≥5 b.p.m. and two or more accelerations (≥15 beats above baseline) without decelerations over a 20-min time period. The study excluded pregnant women with multifetal gestation, congenital malformations of the fetus, gravidity ≥ 5, non-reassuring fetal heart rate trace, ruptured membranes, active genital infection, previous uterine surgery (including cesarean section), low-lying placenta, chorioamnionitis, estimated fetal weight > 4000 g, intrauterine fetal death, known allergies to latex or prostaglandins, and women in spontaneous labor. Demographic details, prior medical and obstetric history, the course of labor and indication for induction were documented. Enrolled eligible women were randomized to one of the two intervention groups using a pre-determined computer-generated randomization sequence that used blocks of unequal length. The random allocation was concealed in sealed opaque envelopes arranged sequentially and opened prior to the procedure by a person not related to the trial. A 16-Fr Foley catheter was inserted into the endocervical canal under direct visualization during a sterile speculum examination for pregnant women randomized to the combination group. Every effort was made to avoid contact of the catheter with the vagina or ectocervix. Thirty milliliters of sterile water was injected into the balloon once the catheter passed the internal os. Traction was applied by taping the end of the catheter to the medial side of the knee or thigh. After securing the catheter in place, a 25-μg moistened misoprostol tablet was inserted into the posterior vaginal fornix under aseptic precautions. The Foley catheter was retained in situ till spontaneous expulsion or for a maximum duration of 12 h. The cervix was assessed every 4 h by Bishop score and a 25-μg misoprostol tablet was inserted 4-hourly, up to a maximum of eight doses if the score was ≤6. The Foley catheter was removed if any of the following occurred: (i) non-reassuring fetal heart rate (FHR) mandating membrane rupture; (ii) spontaneous membrane rupture; or (iii) after 12 h of insertion. Women in the other intervention group received only the misoprostol regime without the Foley catheter. A 25-μg misoprostol tablet (moistened with normal saline) was inserted into the posterior vaginal fornix under aseptic precautions. The cervix was assessed every 4 h by Bishop score and a 25-μg misoprostol tablet was inserted 4-hourly, up to a maximum of eight doses if the Bishop score was ≤6.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Induction of labor
The fetal condition and uterine contractions were monitored in both the groups by an NST half an hour prior to each scheduled dose of misoprostol. Subsequent doses were withheld if labor ensued or if uterine tachysystole or non-reassuring FHR occurred. The final Bishop score was noted when the patient was taken into the labor ward. Active management of labor was done with amniotomy followed by low-dose oxytocin augmentation. Oxytocin infusion was started using an infusion pump at the rate of 1 mU/min and escalated every 30 min until regular uterine contractions were achieved or up to a maximum of 20 mU/min. Failed induction of labor was defined as Bishop score ≤ 6 after eight doses of misoprostol and absence of established uterine contractions. The subsequent management of these women was individualized. The primary outcome variables of interest included the induction-to-delivery interval. The secondary outcomes of interest included rate of vaginal deliveries, uterine hyperstimulation (more than five contractions in 10 min associated with FHR changes), incidence of cesarean section, neonatal outcome (birthweight, Apgar scores at 1 and 5 min, neonatal intensive care (NICU) admissions), and chorioamnionitis. Chorioamnionitis was defined as maternal oral temperature equal to or greater than 100.4° F with any two of the three findings of uterine tenderness, fetal/maternal tachycardia and foul-smelling liquor. The sample size for the study was estimated at 126 women based on α of 0.05 and an estimated mean difference of at least 4 h for the primary outcome between the two groups, and an estimated induction-to-delivery time of 17.0 ± 7.8 h with vaginal misoprostol. The induction-to-delivery time and induction-to-active phase interval were found to be non-normally distributed using the Shapiro–Wilk test and were further analyzed using a non-parametric Mann–Whitney U-test. The Student’s t-test was used to compare continuous variables that were normally distributed and Fisher’s exact test was used to compare categorical variables. A P-value < 0.05 was considered statistically significant. Statistical analysis was performed using stata version 9.0.
Results A total of 126 women enrolled in the study between January 2010 and December 2011 were randomized to receive either low-dose vaginal misoprostol alone or a combination of intracervical Foley catheter and low-
dose vaginal misoprostol. The insertion of Foley catheter was not possible in four women as they complained of pain and they subsequently received only misoprostol and were monitored as per protocol. None of these women were excluded, and an intention-to-treat analysis was performed (see Fig. 1). The baseline maternal characteristics of women enrolled in the trial did not differ between the two groups (see Table 1). Most of the women enrolled in the trial were at term and nulliparous and the most common indication for induction was a post-dated pregnancy. The median Bishop score at admission was similar for the two groups (see Table 1). The median number of doses of misoprostol (two and three, respectively) did not differ significantly between the two groups (P = 0.17). The mean induction-to-delivery time and the induction-to-active phase interval did not differ significantly between the groups (P = 0.65 and 0.31, respectively) using the Mann–Whitney U-test (see Table 2). The mode of delivery and the proportion of deliveries within 24 h after induction did not differ significantly between the two groups (see Table 2). The inductionto-delivery time was further examined stratified by the mode of delivery. The mean (SD) induction-to-delivery interval was 20.62 (11.34) h in the combined group compared to 23.95 (13.12) h in the misoprostol group among women who had a spontaneous vaginal delivery; however, this difference was not statistically significant (P = 0.31). Indications for cesarean section did not differ significantly between the two groups (P = 0.62). The most common indication for a cesarean section was presumed fetal compromise for both the combined and misoprostol groups (n = 8). Other indications for cesarean sections included maternal request (n = 1 and 2), failed induction (n = 4 and 2), failure to progress (n = 4 and 5), cephalopelvic disproportion (n = 2 and 5) and suspected abruption (n = 3 and 0) in the combination and misoprostol groups, respectively. The mean induction to delivery time did not differ significantly between the groups stratified by cesarean section (P = 0.63). Thirty-five (55.56%) women in the combined group and 29 (46.03%) women in the misoprostol group required augmentation of labor with oxytocin (P = 0.37). Uterine hyperstimulation (P < 0.001) and meconium-stained liquor (P = 0.001) were significantly more common in the misoprostol group. There were no documented cases of chorioamnionitis. Neonatal outcomes did not differ significantly between the two groups (see Table 3).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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S. Lanka et al.
Enrollment
Randomized (n = 126)
Allocation Foley + Misoprostol (n = 63) ♦ Received allocated intervention (n = 59)
♦
♦
♦
Allocated to intervention (n = 63) Received allocated intervention (n = 63)
Did not receive allocated intervention (n = 4) –pain during insertion (n = 4)
Did not receive allocated intervention (n = 0)
Follow-up Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysis Analyzed (n = 63) ♦ Excluded from analysis (n = 0)
Analyzed (n = 63) Excluded from analysis (n = 0)
♦
Figure 1 Flow diagram.
Discussion Induction of labor is one of the most commonly performed obstetric procedures. Delivery before the onset of labor is indicated when the maternal/fetal risks associated with continuing the pregnancy are thought to be greater than the maternal/fetal risks associated with early delivery. In the absence of a ripe or favorable cervix, a successful vaginal birth is less likely.1,10 Misoprostol is a pharmacological agent that acts by initiating the uterine contractions.11 Foley catheter, on the other hand causes cervical ripening with little or no
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uterine contractions.11,12 The combination is presumed to cause simultaneous ripening and uterine contractions, which helps in early cervical dilation. The results of this study indicate that the use of combined Foley catheter plus low-dose vaginal misoprostol does not significantly reduce the induction-to-delivery interval compared to low-dose vaginal misoprostol alone. Although the difference was not statistically significant, the mean inductionto-delivery interval was shorter by more than 3 h and clinically relevant in the combined group compared to the misoprostol group in a subgroup analysis that
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Table 1 Baseline characteristics of women enrolled into the trial Characteristics
Foley + low-dose vaginal misoprostol (n = 63)
Low-dose vaginal misoprostol (n = 63)
Maternal age (years): Mean (SD) Body mass index (kg/m2): Mean (SD) Median Primigravida Nulliparous Mean (SD) GA at delivery (weeks) Mean (SD) Bishop score at admission, median Indications for induction Postdates Diabetes mellitus Hypertension Oligohydramnios Decreased fetal movements Others†
26.40 (3.72) 25.63 (3.91), 25 40 (63.49%) 50 (79.37%) 39.13 (1.48) 1.84 (1.00), 2
25.90 (3.37) 25.57 (3.80), 26 40 (63.49%) 49 (77.77%) 39.29 (1.68) 2.21 (0.99), 2
15 (23.81%) 16 (25.40%) 9 (14.29%) 5 (7.94%) 9 (14.29%) 9 (14.29%)
23 (36.50%) 8 (12.69%) 9 (14.28%) 8 (12.69%) 6 (9.52%) 9 (14.28%)
†Others include cholestasis of pregnancy, fetal growth restriction and social indications. GA, gestational age; SD, standard deviation.
Table 2 Maternal outcomes, labor details and complications Outcome
Foley + low-dose vaginal misoprostol (n = 63)
Low-dose vaginal misoprostol (n = 63)
P-value
Mean (SD) induction-to-delivery time (h) Mean (SD) induction-to-active phase (h) Spontaneous vaginal delivery Assisted vaginal delivery Cesarean section Delivery within 24 h Uterine hyperstimulation Oxytocin requirement Epidural use Meconium stained liquor
26.52 (15.24) 20.01 (12.98) 28 (44.44%) 13 (20.63%) 22 (34.92%) 32 (50.79%) 5 (7.94%) 35 (55.56%) 51 (82.96%) 4 (6.34%)
27.64 (15.63) 21.56 (12.34) 30 (47.61%) 11 (17.46%) 22 (34.92%) 32 (50.79%) 25 (39.68%) 29 (46.03%) 47 (74.60%) 17 (26.98%)
0.65 0.31 0.59 0.65 1.00 1.00 6 25-μg 4-hourly, 8 doses 24-Fr 50 mL for 12 h
Rust et al.6 1999 (n = 81) Chung et al.7 2003 (n = 146) Kashanian et al.8 2005 (n = 300) Carbone et al.9 2013 (n = 123) Present study (n = 126)
Dose of misoprostol Foley catheter and duration Study
Table 4 Comparison of our results with other studies
Mean induction-todelivery interval ± SD (h) in combination group
Mean induction-todelivery interval ± SD (h) in misoprostol group
Rate of vaginal delivery in combination group
Rate of vaginal delivery in misoprostol group
S. Lanka et al.
doses of misoprostol were withheld if there were adequate uterine contractions clinically or on an NST. Studies have reported an increased uterine tachysystole, uterine hyperstimulation and terbutaline use with the use of misoprostol alone for induction.13,14 Chung et al. reported that the hyperstimulation rate was 33.3% in the misoprostol group compared to 16.3% in the combined Foley–misoprostol regimen (P = 0.02) with a consequent increase in the use of terbutaline (18% vs 9.3%, P = 0.05).7 Similar to these reports, we too found that uterine hyperstimulation and meconium-stained liquor were significantly associated with the misoprostol group compared to the combination group. The lack of association with neonatal outcomes is consistent with previous trials; however, these have to be assessed in larger trials. The randomized design is the strength of this study; however, it was not possible to mask or blind the interventions. It is possible that the ‘non-blinded’ nature of the design may influence decisions to deliver and shorten induction-to-delivery interval. However, we found that the time to delivery did not differ significantly among those who had a cesarean section. The lower induction-to-delivery time for spontaneous vaginal deliveries (>3 h difference) in the combined group was not statistically significant. However, this is a significant clinically relevant reduction that suggests benefits from using a combination of Foley catheter plus low-dose vaginal misoprostol for induction compared to the use of vaginal misoprostol alone. Additionally, the significant difference in meconium-stained liquor as well as uterine hyperstimulation and consequent lower terbutaline use (although not statistically significant) also indicate benefits from the use of combined Foley catheter plus low-dose vaginal misoprostol for induction. A major limitation of the study is the lack of power to study significant differences in complications of labor and neonatal outcomes. Ideally, the effectiveness and safety of induction agents have to be assessed comparing these outcomes too. This will require trials with a larger sample size and will possibly have to be multicenter. In conclusion, this study reports no statistically significant reduction in induction-to-delivery interval in those induced with Foley catheter plus low-dose misoprostol compared to induction with low-dose vaginal misoprostol alone. However, there was a statistically significantly lower rate of uterine hyperstimulation and meconium-stained liquor in the combination
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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group, which contributes towards lowering maternal and neonatal morbidity.
Acknowledgments The authors would like to thank patients, labor ward staff and consultants for their contribution through the study period.
Disclosure
7.
8.
9.
The results of this manuscript have not been distorted by research funding or conflicts of interest. 10.
References 1. World Health Organization. WHO Recommendations for Induction of Labor, 2011. 2. Mozurkewich E, Chilimigras J, Koepke E, Keeton K, King VJ. Indications for induction of labor: A best-evidence review. Br J Obstet Gynaecol 2009; 116: 626–636. 3. National Institute for Health and Clinical Excellence – Induction of labour NICE Clinical guideline 70, July 2008. 4. WHO Expert Committee. The selection and use of essential medicines. World Health Organ Tech Rep Ser 2007; 1–162. 5. Deborah A, Wing A. Benefit-risk assessment of misoprostol for cervical ripening and labour induction. Drug Saf 2002; 25: 665–676. 6. Rust OA, Greybush M, Atlas RO, Jones KJ, Balducci J. Preinduction cervical ripening: A randomized trial of intravaginal
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misoprostol alone vs. a combination of transcervical Foley balloon and intravaginal misoprostol. J Reprod Med 2001; 46: 899–904. Chung JH, Huang WH, Rumney PJ, Garite TJ, Nageotte MP. A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostolFoley catheter for labor induction. Am J Obstet Gynecol 2003; 189: 1031–1035. Kashanian M, Akbarian AR, Fekrat M. Cervical ripening and induction of labor with intravaginal misoprostol and Foley catheter cervical traction. Int J Gynaecol Obstet 2006; 92: 79–80. Carbone JF, Tuuli MG, Fogertey PJ, Roehl KA, Macones GA. Combination of Foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: A randomized controlled trial. Obstet Gynecol 2013; 121 (2 Pt 1): 247–252. Embrey MP, Mollison BC. The unfavorable cervix and the induction of labor using a cervical balloon. J Obstet Gynaecol Br Commonw 1967; 74: 44–48. Sullivan CA, Benton LW, Roach H, Smith LG Jr, Martin RW, Morrison JC. Combining medical and mechanical methods of cervical ripening. Does it increase the likelihood of successful induction of labor? J Reprod Med 1996; 41: 823–828. Cromi A, Ghezzi F, Agosti M et al. Is transcervical Foley catheter actually slower than prostaglandins in ripening the cervix? Am J Obstet Gynecol 2011; 204: 338; e1–7. Sciscione AC. A randomized comparison of transcervical Foley catheter to intravaginal misoprostol for preinduction cervical ripening. Obstet Gynecol 2001; 97: 603–607. Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labor. Cochrane Database Syst Rev 2003; (1): CD000941; doi: 10.1002/14651858 .CD000941.
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