Arch Gynecol Obstet (2015) 291:537–544 DOI 10.1007/s00404-014-3429-8
MATERNAL-FETAL MEDICINE
Oral versus vaginal misoprostol for induction of labor in Enugu, Nigeria: a randomized controlled trial Paschalina Constance Ezechukwu • Emmanuel Onyebuchi Ugwu Samuel Nnamdi Obi • Chibuike Ogwuegbu Chigbu
•
Received: 7 April 2014 / Accepted: 12 August 2014 / Published online: 20 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective The study aimed at comparing the effectiveness and maternal satisfaction of oral misoprostol with vaginal misoprostol for induction of labor at term. Materials and methods A randomized controlled trial of 140 term pregnant women at the University of Nigeria Teaching Hospital Enugu, Nigeria, was conducted from April 2011 to May 2012. The women were equally randomized into two groups (A and B) to receive oral and vaginal misoprostol, respectively. Results The vaginal route reduced the mean induction– vaginal delivery interval by four-and-half hours (20.7 ± 12.1 vs. 16.2 ± 10.4; mean difference: 4.50, 95 % CI 0.63–0.82; p = 0.02). Furthermore, the mean dose of misoprostol required to achieve induction of labor and the mean duration of oxytocin augmentation when indicated were significantly less in the vaginal group than in the oral group (2.5 ± 1.3 vs. 2.0 ± 1.1; mean difference: 0.50, 95 % CI 0.10–0.90; p = 0.02 and 4.6 ± 3.2 vs. 3.4 ± 3.1; mean difference: 1.20, 95 % CI 0.15–0.23; p = 0.03 respectively). However, neonatal complications and maternal satisfaction were similar between the two groups. Conclusion Both routes of administration are effective in the induction of labor at term and have comparable maternal satisfaction. However, the vaginal route has the added advantage of shorter induction–delivery interval among others, and thus should be highly considered when induction of labor is indicated at term.
P. C. Ezechukwu E. O. Ugwu (&) S. N. Obi C. O. Chigbu Department of Obstetrics/Gynaecology, University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, Nigeria e-mail: [email protected]
Keywords Induction of labor Oral misoprostol Vaginal misoprostol Nigeria
Introduction Induction of labor is a challenge to obstetricians, especially those practicing in the developing countries because of lack of facilities for adequate monitoring of labor. This is further compounded in the tropics by the prohibitive cost of prostaglandin E2 preparations in addition to its narrow temperature range of 2–8 °C, which makes them out of reach to most patients in Nigeria and other low-resource countries. The incidence of induction of labor varies widely ranging from 3 to 20 % [1]. Misoprostol, a synthetic prostaglandin E1 analog essentially licensed and marketed for prevention and treatment of non-steroidal anti-inflammatory drugs (NSAID)-related gastric/duodenal ulcers but rapidly gaining grounds as an effective induction agent, appears to hold the key to labor induction in the tropics and low-resource settings. This is in view of its widespread availability, cost-effectiveness, temperature stability with less subjectivity to strict storage rules, and numerous routes of administration among others. Despite the high efficacy of the vaginal route of administration for induction of labor [2–9], there is increasing interest in the oral route because of its potential for higher maternal satisfaction than the vaginal route [10– 16]. This is in view of its advantages of easier administration and less invasiveness, greater freedom of position and movement after administration, avoidance of repeated vaginal examinations, and cost effectiveness due to limited consumption of materials during administration. The cost effectiveness advantage is anticipated to be even more important in low-resource settings [11] like Nigeria where
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payments for maternal health services are almost entirely out of pocket. Currently, there is widespread experience with the use of the vaginal route for induction of labor in our environment [17–20], but experience with the use of the oral route is limited. Furthermore, only few studies in literature have assessed maternal satisfaction following the oral and/or vaginal route of administration for induction of labor. This study therefore aims at comparing the effectiveness of oral administration of misoprostol for induction of labor with that of vaginal route in a low-resource setting. The study also evaluates maternal satisfaction with both routes.
Materials and methods The study was a randomized controlled trial of 140 pregnant women attending the antenatal clinic of the University of Nigeria Teaching Hospital (UNTH) Enugu, Nigeria between 1st April 2011 and 30th May 2012, and requiring induction of labor at term (37–42 completed weeks of gestation). The hospital records an average of 1,000 deliveries annually. Eligible women were randomized equally to either the intervention group (A) or control group (B). The intervention group received oral misoprostol, while the control group received vaginal misoprostol. All uncomplicated singleton pregnancies in cephalic presentations at term, without uterine contractions, were eligible for the study. Exclusion criteria were being unsure of date, pre-conception irregular menstrual cycle, evidence of any contraindication to vaginal delivery, medical diseases in pregnancy, term premature rupture of membranes, known allergy to prostaglandin preparations, and contraindications to receiving prostaglandin including previous cesarean section and history of glaucoma or asthma. Written informed consents were obtained from all eligible women before recruitment. Ethical clearance for the study was obtained from the Institutional Review Board of the UNTH, Enugu. The sample size (n) for each group was calculated to be 70, based on a power of 80, 5 % error margin, and estimated attrition rate of 20 %. Participants’ randomization was adapted from a recent study [21]. Thus, two sets of random numbers (1–140), corresponding to the intervention and control groups were developed by a blinded statistician using a computer-based random sequence generator (RANDOM.ORG). Sealed opaque envelopes were labeled sequentially from 1 to 140; each numbered envelope contained a 5 9 5 cm white paper labeled either ‘‘A’’ for intervention group or ‘‘B’’ for control group, corresponding to the appropriate number set described above. The envelopes were kept by a medical
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intern (third party), blinded to the study’s objectives. Furthermore, serial numbers 1–140 were consecutively assigned to each recruited woman. For each eligible woman recruited, the third party was contacted to open the envelope corresponding to the participant’s serial number; the treatment group concealed inside the envelope was assigned to the woman. Bishop score before the administration of the first dose of misoprostol was documented as well as the time of administration of the first dose. Time of subsequent misoprostol administrations and Bishop scores were also noted. Participants allocated to the vaginal misoprostol group received intermittent doses of 50 lg of misoprostol inserted into the posterior vaginal fornix 6 hourly until active phase of labor was achieved or a maximum of four doses were inserted. Because of the unavailability of the 50-lg tablets commercially in our environment, the 200-lg tablet was cut into fourths (4 parts) by the hospital pharmacist. The maximum dose of misoprostol used for each participant was 200 lg, equivalent to four total doses, over a 24-h period. On the other hand, participants assigned to ‘oral misoprostol group’ were given intermittent doses of 50 lg of misoprostol to swallow 6 hourly until active phase of labor was achieved. The maximum dose of misoprostol used was 200 lg, equivalent to a total of four doses, over a 24-h period. For patients’ monitoring, the fetal heart rate was checked with Sonicaid (SONOBEAT) on admission and prior to administration of each dose of misoprostol. In addition, the uterine contraction pattern and fetal heart rate were monitored hourly from the time of application of the first dose until active phase labor when monitoring became more frequent. The next dose of misoprostol was withheld if the participant got into active labor (three contractions in 10 min, each lasting 40–60 s or cervical dilatation of 4 cm or above) or if there was evidence of fetal distress, tachysystole or hyperstimulation [15]. Whenever indicated, oxytocin infusion was delayed for 6 h from the last dose of misoprostol. The administration of the oxytocin infusion followed a standardized hospital protocol, starting with 4 mIU/min and increasing at interval of 30 min to achieve adequate uterine contraction pattern of 3–5 in 10 min, each lasting 40–60 s. Following the development of active phase labor, routine intrapartum active management of labor was adopted regardless of the study group using standard protocol of the hospital—the fetal heart rate was monitored quarter hourly by intermittent auscultation using Sonicaid. At intervals of 30 min, there was evaluation for uterine contraction pattern and frequency over a 10-min period together with the duration and intensity of each contraction. The maternal vital signs were assessed half hourly. All the monitoring was done by the principal investigator and two research assistants, all of whom were senior
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obstetric registrars of the hospital. The findings were recorded on a prescribed partograph. Abnormalities in labor were managed appropriately in line with standard obstetric intervention(s). Failure to achieve active phase labor after 24 h (four doses) of initiation of treatment in either arm was regarded as ‘method failure’ and necessitated method interchange or emergency cesarean section or a further attempt at induction using oxytocin infusion as was deemed necessary. Participants who developed tachysystole and/or hyperstimulation were treated according to standard protocol of the hospital—immediate discontinuation of oxytocin infusion if in use, infusion of normal saline with a fresh infusion set, maternal positional change (left lateral positioning), and supplementary oxygen through an intranasal catheter. An injection of salbutamol, 10 mg, was added in 1 l of normal saline and titrated against uterine contraction if contractions did not reduce to the desired level. Persistence of tachysystole and/or hyperstimulation, if in the vaginal misoprostol group, was managed with irrigation of the vagina using normal saline via a 50-ml syringe without the needle, and repeating several times until the pill fragments were no longer recovered. In addition, where necessary, 4 g of magnesium sulfate was given by intravenous load over 20 min followed by a 2-g/h infusion as well as close feto-maternal monitoring and other interventions as may be indicated. Participants’ baseline data that were recorded included maternal age, parity, gestational age, and the initial Bishop score. The primary outcome measures included induction– vaginal delivery interval, route of delivery, Apgar score at birth, need for oxytocin augmentation, and maternal satisfaction with the route of administration, while the secondary outcome measures included number of doses of misoprostol required, frequency of tachysystole, hypertonus, hyperstimulation, uterine rupture, and other maternal side effects such as fever, vomiting, diarrhea, abdominal pain, and the cesarean section rate. A structured interviewer-administered questionnaire was given to each of the participants as soon as possible after delivery to assess the acceptance and satisfaction with the received method of induction of labor. To ensure consistency, the questionnaire was administered by the same interviewer throughout the study. Induction–delivery interval was defined as the interval between the time of insertion of an agent and delivery of the baby, tachysystole as development of more than 5 (C6) contractions in 10 min for two consecutive 10-min intervals, hypertonus as development of uterine contraction lasting more than or equal to 2 min (C120 s), and hyperstimulation as tachysytole in the presence of abnormal fetal heart rate [17].
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The definitions of maternal perception and satisfaction with a method of induction of labor were adapted from a previous related study [12]. Thus; maternal perception of a particular method was described as acceptable, not acceptable, or indifferent. A method is said to be acceptable to a participant if the participant is pleased or happy with the method, and vice versa. Maternal satisfaction with a particular method of induction of labor was defined as patient’s expression of preference and willingness to consent to the same method if induction of labor is indicated in any subsequent pregnancies [12]. On the other hand, maternal satisfaction with the obstetrician’s care was defined as her expression of happiness with the way the obstetrician conducted the labor process [12]. Labor pain experience was assessed ‘categorically’ by asking if the woman experienced more pain than expected, less than expected, or as expected [12]. All data collected from the study were recorded on ‘case record forms’ prepared for the study. Statistical Package for Social Sciences (SPSS) computer software version 16 was used for data analyses. Intention to treat was adopted for analysis. Continuous and categorical data were compared using Student’s t test and Fisher’s exact test, respectively. Relationships were expressed using relative risks and confidence intervals. All tests were two sided and statistical significance was considered to be at a probability value of \0.05.
Results Within the 14-month study period, 1,197 deliveries took place out of which 161 were induced. This gave an induction rate of 13.5 %. One hundred and fifty-three women were eligible for the study, but 140 were randomized—70 per group (Fig. 1). All the women enrolled in the study participated to the end. There were no significant differences between the two groups with respect to their baseline characteristics, including the pre-induction Bishop score and the indications for induction of labor (Table 1). Post-datism was the most frequent indication in the two groups, accounting for 45 (64.3 %) in the ‘oral group’ and 50 (71.4 %) in the ‘vaginal group’ (Table 1). The induction–vaginal delivery interval (in h) was significantly higher in the oral group than in the vaginal group (20.7 ± 12.1 vs. 16.2 ± 10.4; mean difference: 4.50, 95 % CI 0.63–0.82; p = 0.02). Similarly, the mean number of doses of misoprostol required to achieve induction of labor was significantly higher in the oral group than in the vaginal group (2.5 ± 1.3 vs. 2.0 ± 1.1; mean difference: 0.50, 95 % CI 0.10–0.90; p = 0.02). The need for oxytocin augmentation in labor was significantly higher in the oral group compared to the vaginal group [39/70 (55.7 %) vs.
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Fig. 1 Study flowchart
25/70 (35.7 %); RR: 1.56; 95 % CI: 1.07–2.28; p = 0.02]. Furthermore, the mean duration (in h) of oxytocin use (when indicated) was significantly longer in the oral group compared to the vaginal group (4.6 ± 3.2 vs. 3.4 ± 3.1; mean difference: 1.20, 95 % CI 0.15–0.23; p = 0.03), respectively (4.6 ± 3.2 vs. 3.4 ± 3.1; p = 0.03). A total of eight (11.4 %) women in the oral group and five (7.1 %) in the vaginal group could not achieve an active phase of labor after 24 h of commencement of the induction process (RR: 1.60; 95 % CI: 0.55–4.65; p = 0.39). All the 13 women (in both groups) who had ‘method failure’ requested for cesarean delivery with favorable outcome. The route of delivery and labor complications were similar between the two groups (Table 2). Likewise, the neonatal outcomes including the 1st and 5th min APGAR scores, birth weight, and the need for admission into newborn special care unit (NBSCU) were similar between the two groups (Table 3). With respect to maternal complications that developed during labor, tachysystole was significantly less in the oral group than in the vaginal group [2/70 (2.85 %) vs. 15/70
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(21.42 %): RR: 0.13; 95 % CI: 0.03–0.56; p = 0.01). Other maternal complications were similar in the two groups (Table 4). There was no recorded case of hypertonus, uterine hyperstimulation, or uterine rupture in either of the two groups. There were no stillbirths or neonatal deaths recorded in both the study groups. However, two babies were noted to have tight cord around the neck during cesarean section and both belonged to the vaginal misoprostol group. With respect to the post-induction survey of the participants, equal number of women: 69 (98.6 %) in each group felt some discomfort with the method of induction used. There was also no significant difference in the women’s perception of the methods used with regard to acceptability of the route of administration of misoprostol [53/70 (75.7 %), oral group vs. 61/70 (87.1 %), vaginal group; p = 0.20). Similarly, there was no significant difference in the likelihood to give consent in future for the same method if labor induction is indicated in subsequent pregnancies (maternal satisfaction) [49/70 (70 %), oral group vs. 50/70 (80 %), vaginal group; p = 0.17]. Furthermore, there was
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Discussion
Table 1 Baseline characteristics of the participants Oral group (n = 70)
Vaginal group (n = 70)
p value
27.24 ± 4.53
28.24 ± 3.66
0.15
Primary education Secondary education
1
2
1.00
22
27
0.72
Tertiary education
37
43
0.39
Age (years) Educational status
Parity
0.77 ± 1.21
0.79 ± 1.17
0.92
Nulliparous
44 (62.9 %)
42 (60.0 %)
0.86
Primiparous
11 (15.7 %)
11 (15.7 %)
1.00
Multiparous
15 (21.4 %)
17 (24.3 %)
0.84
Gestational age (weeks)
40.59 ± 1.48
40.66 ± 1.63
0.79
Pre-induction Bishop score 0–5
43 (61.4)
39 (55.7)
0.57
6–13
27 (38.6)
31 (44.3)
0.56 0.47
Indications for induction of labor Post-datism
45 (64.3 %)
50 (71.4 %)
Pre-eclampsia
7 (10.0 %)
3 (4.3 %)
0.33
Diabetes mellitus
2 (2.9 %)
1 (1.4 %)
1.00
IUGR
12 (17.1 %)
13 (18.6 %)
1.00
Maternal request
4 (5.7 %)
3 (4.3 %)
1.00
t test for continuous variables and Fisher’s exact test for categorical variables IUGR intrauterine growth restriction
Table 2 Route of delivery Route of delivery
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
p value
Vaginal
46 (65.7)
49 (70.0)
0.86
46 (65.7)
48 (68.6)
0.85
Spontaneous Assisted (vacuum) Cesarean section
0 (0)
1 (1.4)
–
24 (34.3)
21 (30.0)
0.72
8 (11.4)
5 (7.1)
0.39
Poor progress in labor
12 (17.1)
11 (15.7)
1.00
Fetal distress
4 (5.7)
5 (7.1)
1.00
Indications for C/S Maternal request
Fisher’s exact test
no significant difference in the labor pain experiences and in the participants’ satisfaction with the obstetrician’s care during labor between the two groups (p [ 0.05). Details are shown in Table 5.
Misoprostol is being increasingly used for induction of labor in low-resource settings because of its low cost and effectiveness. The result of the present study revealed that 50 lg of oral and vaginal misoprostol is effective for induction of labor at term with comparable maternal satisfaction. However, the vaginal route has the added advantage of shorter induction–delivery interval, less number of doses of misoprostol required to achieve induction of labor, and less duration of oxytocin augmentation whenever indicated. The clinical significance of the shorter induction– delivery interval obtained in this study with the vaginal route is that the route may be more suitable in clinical situations where there is need to expedite delivery. Additionally, the shorter induction–delivery interval recorded in the vaginal route could result in shorter hospital stay, lesser family dislocation, and reduced period of anxiety. This resultant social/family harmony together with a reduced economic burden would ultimately lead to a less psychologically traumatized mother with a more fulfilled childbirth experience—a significant goal of modern obstetrics. However, despite these demonstrable advantages of vaginal route over the oral route as evident in this study, there is increasing report in literature that the oral or sublingual route of administration is more preferred by women as the former is thought to be embarrassing or inconveniencing to the women [11–16]. In view of this concern, recent researchers are advocating for consideration of the oral or sublingual route whenever misoprostol induction of labor is indicated [11, 12]. The present study has, however, proven otherwise, as pregnant Nigerian women at least in southeastern Nigeria do not abhor the vaginal route of administration because there was no demonstrable difference in maternal satisfaction or labor pain experiences between the two groups. It therefore means that the vaginal route should be highly considered in our environment whenever misoprostol induction of labor is indicated, since it is more effective than the oral route and has comparable acceptability and maternal satisfaction. Nevertheless, women should also be given the option for the oral route since it is also effective. The significant reduction in the need for oxytocin augmentation when the vaginal route is used for induction of labor as demonstrated in this study may suggest that the risks associated with oxytocin augmentation of labor can be largely obviated when the vaginal route is used. Furthermore, the additional cost of oxytocin augmentation of labor can to some extent be avoided. This is very important in low-resource settings like our environment where payment for maternal and neonatal services is almost entirely out of pocket.
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Table 3 Neonatal outcome
Neonatal variable
Oral group (n = 70)
Vaginal group (n = 70)
p value
Birth weight (kg)
3.44 ± 0.42
3.32 ± 0.51
0.14
\7
11 (15.7 %)
8 (11.4 %)
0.62
C7
59 (84.3 %)
62 (88.6 %)
0.62
\7
2 (2.9 %)
0 (0.0 %)
–
C7
68 (97.1 %)
70 (100 %)
0.50
Supplemental O2 required
13 (18.57 %)
8 (11.43 %)
0.35
Admission to NBSCU
8 (11.43 %)
7 (10.00 %)
1.00
1st min APGAR score
5th min APGAR score
t test for continuous variables and Fisher’s exact test for categorical variables
Table 4 Maternal complications that developed following induction of labor Maternal Complications
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
Tachysystole
2 (2.85)
15 (21.42)
Fever
1 (1.4)
2 (2.9)
p value
Table 5 Comparison of women’s experiences with induction of labor in the two groups
RR (95 % CI)
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
p value
69 (98.6)
69 (98.6)
1.00
0.01
0.13 (0.03–0.56)
Ever felt discomfort in labor
–
–
Level of discomfort felt
Vomiting
2 (2.9)
0 (0.0)
–
–
Mild-moderate
41 (58.0)
38 (53.6)
0.73
Postpartum hemorrhage
1 (1.4)
1 (1.4)
–
–
Severe
29 (42.0)
32 (46.4)
0.73
Maternal perception of the method
Fisher’s exact test
Acceptable
53 (75.71)
61 (87.14)
0.12
RR relative risk, CI confidence interval
Not acceptable
16 (22.9)
8 (11.4)
0.11
1 (1.4)
1 (1.4)
1.00
Indifferent
Although some previous studies have compared the efficacy of oral versus vaginal misoprostol for induction of labor at term, comparing the results of these studies is difficult due to considerable heterogeneity of the studies. Different doses of misoprostol have been used and, even when similar, the interval for vaginal or oral drug administration varied. Again, the gestations at recruitment of the women for the studies varied widely. Nevertheless, the significantly shorter interval to achieve induction of labor in the vaginal route in this study was similar to the findings of other researchers [2–9]. The reason for the greater effectiveness of the vaginal route could be because of the greater bioavailability of the drug following vaginal administration compared to the oral route. Though the oral route of administration has quicker onset of action, first pass effect reduces its bioavailability [22, 23]. In fact, the bioavailability of vaginally administered misoprostol is three times higher than that of orally administered misoprostol [23]. However, the result of the presented study is different from the report by Bano and co-workers [24] who demonstrated that 50 lg of misoprostol through the oral route was as effective as 50 lg through the vaginal route in terms of induction–delivery interval and number of doses of misoprostol required. The dosing interval of 6 hourly used in this report compared to
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Maternal satisfaction with the method Satisfied
49 (70.0)
56 (80.0)
0.17
Not satisfied
21 (30)
14 (20)
0.17
Maternal satisfaction with obstetrician’s care Satisfied 69 (98.6) 65 (92.9) Not satisfied
0.09
1 (1.4)
5 (7.1)
0.09
More than expected
35 (50.0)
44 (62.86)
0.17
Just as expected
29 (41.43)
25 (35.71)
0.60
6 (8.57)
1 (1.43)
0.11
Labor pain experience
Less than expected Fisher’s exact test
the 4-hourly interval used by Bano and co-workers may have contributed to the differences in the results obtained. Another reason for the differences obtained might be the possibilities of racial and environmental differences in individual responses to misoprostol as postulated by previous authors [17, 19]. The increased risk of tachysystole with the vaginal route observed in this report could be explained by the relatively longer half-life of misoprostol and its metabolites in maternal serum after vaginal administration compared to the oral administration [22, 23]. This finding is in
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agreement with previous related studies [2, 3, 6, 7, 10]. The absence of other contractile abnormalities in this study including hypertonus, hyperstimulation, or uterine rupture was similar to previous reports from our environment [17, 19]. The incidence of minimal contractile abnormalities together with the low cesarean section rate obtained in this study might be explained by the low dose of misoprostol (50 lg) used in this study and the strict adherence to the protocol of 6-hourly dosing interval, with non-commencement of oxytocin infusion until 6 h had elapsed after the last dose of intravaginal or oral misoprostol, since the terminal half-lives of misoprostol metabolites averaged 4.5 h for the variety of animals, including the human subjects [22]. These probably minimized the risks of possible cumulative drug effects which could result from a more frequent dosing regimen and the action summation that could result from interaction between misoprostol and oxytocin. This favorable finding further confirms that misoprostol is safe for induction of labor in our environment and that it is rarely associated with contractile abnormalities when used at doses not more than 50 lg and at intervals not less than 6 hourly. This study demonstrated that there was no difference in the rate of cesarean section as well as the route of delivery between the two groups. Similarly, the neonatal outcomes in terms of the APGAR scores and need for admission into the NBSCU were similar in both groups. All these findings are in agreement with previous trials on effectiveness of vaginal and oral misoprostol for induction of labor [2, 25]. The study further revealed that there was no significant difference in maternal satisfaction or labor pain experiences between the two groups with 80 % of the women who received vaginal misoprostol expressing satisfaction with the method. This finding is in contrary with the report by Nassar and co-worker [12] who observed a much lower maternal satisfaction rate of 25 % with the vaginal route. It is however in agreement with a previous related report which did not find any significant difference in the maternal satisfaction rate between the two routes of administration [26]. Despite the randomized design of this trial, there were some limitations. The misoprostol tablets were manually divided into four parts with the assistance of the hospital pharmacist and so we are not sure of the equality of the fourths. Nevertheless, the effect of this possible inequality on the study’s outcome is likely to be minimal and nondirectional. Furthermore, there was inability to mask the attending obstetrician or the women on the method of misoprostol administration assigned, and therefore we could not exclude the possibility that some biases were unavoidable. Cardiotocograph (CTG) was not applied in this study, and thus subtle fetal/contractile CTG abnormalities might have been missed. Measurement of neonatal
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outcome in terms of incidence of birth asphyxia was limited to the use of APGAR scores without any corresponding arterial umbilical cord PH analysis. Also, feeding of the women prior to commencement of labor was not under the control of the attending obstetricians and so the possible effect of food on the metabolism of misoprostol following oral administration could not be controlled. Another important limitation of the study is that the sample size used for the study was not large enough to study for the rarer complications and adverse effects of misoprostol induction of labor such as fever, vomiting, and postpartum hemorrhage. In conclusion, this study has demonstrated that orally and vaginally administered misoprostol is effective for induction of labor at term with comparable maternal satisfaction. However, the vaginal route has the added advantages of shorter induction–delivery interval, fewer doses of misoprostol needed to achieve induction of labor, and reduced need of oxytocin augmentation. It should therefore be highly considered when induction of labor is indicated at term. Conflict of interest
We declare that we have no conflict of interest.
References 1. Orhue AA (1997) Review of induction of labor. Trop J Obstet Gynaecol 14:1–14 2. Rasheed R, Alam AA, Younus S, Raza F (2007) Oral versus vaginal misoprostol for labor induction. J Pak Med Assoc 57(8):404–407 3. Akhtar Z, Tahir Saleem S, Lateef F (2010) Comparison of oral versus vaginal misoprostol for induction of labor at term. JRMC 14(1):104–106 4. Shetty A, Danielian P, Templeton A (2001) A comparison of oral and vaginal misoprostol tablets in induction of labor at term. BJOG 108(3):238–243 5. Ayaz A, Saeed S, Farooq MU, Ahmad I, Ali Bahoo ML, Saeed M (2009) Labor induction with randomized comparison of oral and intravaginal misoprostol in post-date multigravida women. Malays J Med Sci 16(1):34–38 6. Fisher SA, Mackenzie VP, Davies GA (2001) Oral versus vaginal misoprostol for induction of labor at term: a double blind randomised controlled trial. Am J Obstet Gynecol 185(4):906–910 7. Nopdonrattakoon L (2003) A comparison between intravaginal and oral misoprostol for labor induction: a randomised controlled trial. J Obstet Gynaecol Res 29(2):87–91 8. Deshmukh VL, Yelikar KA, Waso V (2013) Comparative study of efficacy and safety of oral versus vaginal misoprostol for induction or labour. J Obstet Gynaecol India 63(5):321–324 9. Mehrotra S, Singh U, Gupta HP (2010) A prospective double blind study using oral versus vaginal misoprostol for labour induction. J Obstet Gynaecol 30(5):461–464 10. Komala K, Reddy M, Quadri IJ, B S, V R (2013) Comparative study of oral and vaginal misoprostol for induction of labor, maternal and fetal outcome. J Clin Diagn Res 7(12):2866–2869 11. Alfirevic Z, Weeks A (2006) Oral misoprostol for induction of labour. Cochrane Database Sys Rev 2:CD001338 (Review)
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544 12. Nassar AH, Awwad J, Khalil AM, Abu-Musa A, Mehio G, Usta IM (2007) A randomised comparison of patient satisfaction with vaginal and sublingual misoprostol for induction of labour at term. BJOG 114(10):1215–1221 13. Cheng S, Ming H, Lee J (2008) Titrated oral compared with vaginal misoprostol for labor induction: a randomised controlled trial. Obstet Gynecol 111(1):119–125 14. Wing DA, Park MR, Paul RH (2000) A randomized comparison of oral and intravaginal misoprostol for labor induction. Obstet Gynecol 95(6):905–908 15. Arvidsson C, Hellborg M, Gemzell-Danielsson K (2005) Preference and acceptability of oral versus vaginal administration of misoprostol in medical abortion with mifepristone. Eur J Obstet Gynecol Reprod Biol 123(1):87–91 16. Oppegaard KS, Qvigstad E, Nesheim BI (2006) Oral versus selfadministered vaginal misoprostol at home before surgical termination of pregnancy: a randomised controlled trial. BJOG 113(1):58–64 17. Ugwu EO, Onah HE, Obi SN, Dim CC, Okezie OA, Chigbu CO, Okoro OS (2013) Effect of the Foley catheter and synchronous low dose misoprostol administration on cervical ripening: a randomised controlled trial. J Obstet Gynaecol 33(6):572–577 18. Ekele BA, Nnadi DC, Gana MA, Shehu CE, Ahmed Y, Nwaobodo EI (2007) Misoprostol use for cervical ripening and induction of labor in a Nigerian Teaching Hospital. Niger J Clin Pract 10(3):234–237 19. Adeniji OA, Oladokun A, Olayemi O, Adeniji OI, Odukogbe AA, Ogunbode A, Aimakhu CO, Omigbodun AO, Ilesanmi AO
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20.
21.
22.
23.
24.
25.
26.
(2005) Pre-induction cervical ripening: trans-cervical Foley catheter versus intravaginal misoprostol. J Obstet Gynaecol 25(2):134–139 Fawole AO, Adegbola O, Adeyemi AS, Oladapo OT, Alao MO (2008) Misoprostol for induction of labour: a survey of attitude and practice in southwestern Nigeria. Arch Gynecol Obstet 278(4):353–358 Ugwu EO, Obi SN, Iferikigwe ES, Dim CC, Ezugwu FO (2014) Membrane stripping to prevent post-term pregnancy in Enugu, Nigeria: a randomized controlled trial. Arch Gynecol Obstet 289(1):29–34 Schoenhard G, Oppermann J, Kohn FE (1985) Metabolism and pharmacokinetic studies of misoprostol. Dig Dis Sci 30:126S– 128S Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD (1997) Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 90(1):88–92 Bano K, Mahjabeen Bhutta SZ (2009) Oral versus vaginal misoprostol for induction of labour at term. J Surg Pak (International) 14(1):38–41 Akter S, Chowdhury SB, Fatema N (2010) A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labour induction. ORION Med J 33(1):710–713 Colo´n I, Clawson K, Hunter K, Druzin ML, Taslimi MM (2005) Prospective randomized clinical trial of inpatient cervical ripening with stepwise oral misoprostol vs vaginal misoprostol. Am J Obstet Gynecol 192(3):747–752
MATERNAL-FETAL MEDICINE
Oral versus vaginal misoprostol for induction of labor in Enugu, Nigeria: a randomized controlled trial Paschalina Constance Ezechukwu • Emmanuel Onyebuchi Ugwu Samuel Nnamdi Obi • Chibuike Ogwuegbu Chigbu
•
Received: 7 April 2014 / Accepted: 12 August 2014 / Published online: 20 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective The study aimed at comparing the effectiveness and maternal satisfaction of oral misoprostol with vaginal misoprostol for induction of labor at term. Materials and methods A randomized controlled trial of 140 term pregnant women at the University of Nigeria Teaching Hospital Enugu, Nigeria, was conducted from April 2011 to May 2012. The women were equally randomized into two groups (A and B) to receive oral and vaginal misoprostol, respectively. Results The vaginal route reduced the mean induction– vaginal delivery interval by four-and-half hours (20.7 ± 12.1 vs. 16.2 ± 10.4; mean difference: 4.50, 95 % CI 0.63–0.82; p = 0.02). Furthermore, the mean dose of misoprostol required to achieve induction of labor and the mean duration of oxytocin augmentation when indicated were significantly less in the vaginal group than in the oral group (2.5 ± 1.3 vs. 2.0 ± 1.1; mean difference: 0.50, 95 % CI 0.10–0.90; p = 0.02 and 4.6 ± 3.2 vs. 3.4 ± 3.1; mean difference: 1.20, 95 % CI 0.15–0.23; p = 0.03 respectively). However, neonatal complications and maternal satisfaction were similar between the two groups. Conclusion Both routes of administration are effective in the induction of labor at term and have comparable maternal satisfaction. However, the vaginal route has the added advantage of shorter induction–delivery interval among others, and thus should be highly considered when induction of labor is indicated at term.
P. C. Ezechukwu E. O. Ugwu (&) S. N. Obi C. O. Chigbu Department of Obstetrics/Gynaecology, University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, Nigeria e-mail: [email protected]
Keywords Induction of labor Oral misoprostol Vaginal misoprostol Nigeria
Introduction Induction of labor is a challenge to obstetricians, especially those practicing in the developing countries because of lack of facilities for adequate monitoring of labor. This is further compounded in the tropics by the prohibitive cost of prostaglandin E2 preparations in addition to its narrow temperature range of 2–8 °C, which makes them out of reach to most patients in Nigeria and other low-resource countries. The incidence of induction of labor varies widely ranging from 3 to 20 % [1]. Misoprostol, a synthetic prostaglandin E1 analog essentially licensed and marketed for prevention and treatment of non-steroidal anti-inflammatory drugs (NSAID)-related gastric/duodenal ulcers but rapidly gaining grounds as an effective induction agent, appears to hold the key to labor induction in the tropics and low-resource settings. This is in view of its widespread availability, cost-effectiveness, temperature stability with less subjectivity to strict storage rules, and numerous routes of administration among others. Despite the high efficacy of the vaginal route of administration for induction of labor [2–9], there is increasing interest in the oral route because of its potential for higher maternal satisfaction than the vaginal route [10– 16]. This is in view of its advantages of easier administration and less invasiveness, greater freedom of position and movement after administration, avoidance of repeated vaginal examinations, and cost effectiveness due to limited consumption of materials during administration. The cost effectiveness advantage is anticipated to be even more important in low-resource settings [11] like Nigeria where
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payments for maternal health services are almost entirely out of pocket. Currently, there is widespread experience with the use of the vaginal route for induction of labor in our environment [17–20], but experience with the use of the oral route is limited. Furthermore, only few studies in literature have assessed maternal satisfaction following the oral and/or vaginal route of administration for induction of labor. This study therefore aims at comparing the effectiveness of oral administration of misoprostol for induction of labor with that of vaginal route in a low-resource setting. The study also evaluates maternal satisfaction with both routes.
Materials and methods The study was a randomized controlled trial of 140 pregnant women attending the antenatal clinic of the University of Nigeria Teaching Hospital (UNTH) Enugu, Nigeria between 1st April 2011 and 30th May 2012, and requiring induction of labor at term (37–42 completed weeks of gestation). The hospital records an average of 1,000 deliveries annually. Eligible women were randomized equally to either the intervention group (A) or control group (B). The intervention group received oral misoprostol, while the control group received vaginal misoprostol. All uncomplicated singleton pregnancies in cephalic presentations at term, without uterine contractions, were eligible for the study. Exclusion criteria were being unsure of date, pre-conception irregular menstrual cycle, evidence of any contraindication to vaginal delivery, medical diseases in pregnancy, term premature rupture of membranes, known allergy to prostaglandin preparations, and contraindications to receiving prostaglandin including previous cesarean section and history of glaucoma or asthma. Written informed consents were obtained from all eligible women before recruitment. Ethical clearance for the study was obtained from the Institutional Review Board of the UNTH, Enugu. The sample size (n) for each group was calculated to be 70, based on a power of 80, 5 % error margin, and estimated attrition rate of 20 %. Participants’ randomization was adapted from a recent study [21]. Thus, two sets of random numbers (1–140), corresponding to the intervention and control groups were developed by a blinded statistician using a computer-based random sequence generator (RANDOM.ORG). Sealed opaque envelopes were labeled sequentially from 1 to 140; each numbered envelope contained a 5 9 5 cm white paper labeled either ‘‘A’’ for intervention group or ‘‘B’’ for control group, corresponding to the appropriate number set described above. The envelopes were kept by a medical
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intern (third party), blinded to the study’s objectives. Furthermore, serial numbers 1–140 were consecutively assigned to each recruited woman. For each eligible woman recruited, the third party was contacted to open the envelope corresponding to the participant’s serial number; the treatment group concealed inside the envelope was assigned to the woman. Bishop score before the administration of the first dose of misoprostol was documented as well as the time of administration of the first dose. Time of subsequent misoprostol administrations and Bishop scores were also noted. Participants allocated to the vaginal misoprostol group received intermittent doses of 50 lg of misoprostol inserted into the posterior vaginal fornix 6 hourly until active phase of labor was achieved or a maximum of four doses were inserted. Because of the unavailability of the 50-lg tablets commercially in our environment, the 200-lg tablet was cut into fourths (4 parts) by the hospital pharmacist. The maximum dose of misoprostol used for each participant was 200 lg, equivalent to four total doses, over a 24-h period. On the other hand, participants assigned to ‘oral misoprostol group’ were given intermittent doses of 50 lg of misoprostol to swallow 6 hourly until active phase of labor was achieved. The maximum dose of misoprostol used was 200 lg, equivalent to a total of four doses, over a 24-h period. For patients’ monitoring, the fetal heart rate was checked with Sonicaid (SONOBEAT) on admission and prior to administration of each dose of misoprostol. In addition, the uterine contraction pattern and fetal heart rate were monitored hourly from the time of application of the first dose until active phase labor when monitoring became more frequent. The next dose of misoprostol was withheld if the participant got into active labor (three contractions in 10 min, each lasting 40–60 s or cervical dilatation of 4 cm or above) or if there was evidence of fetal distress, tachysystole or hyperstimulation [15]. Whenever indicated, oxytocin infusion was delayed for 6 h from the last dose of misoprostol. The administration of the oxytocin infusion followed a standardized hospital protocol, starting with 4 mIU/min and increasing at interval of 30 min to achieve adequate uterine contraction pattern of 3–5 in 10 min, each lasting 40–60 s. Following the development of active phase labor, routine intrapartum active management of labor was adopted regardless of the study group using standard protocol of the hospital—the fetal heart rate was monitored quarter hourly by intermittent auscultation using Sonicaid. At intervals of 30 min, there was evaluation for uterine contraction pattern and frequency over a 10-min period together with the duration and intensity of each contraction. The maternal vital signs were assessed half hourly. All the monitoring was done by the principal investigator and two research assistants, all of whom were senior
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obstetric registrars of the hospital. The findings were recorded on a prescribed partograph. Abnormalities in labor were managed appropriately in line with standard obstetric intervention(s). Failure to achieve active phase labor after 24 h (four doses) of initiation of treatment in either arm was regarded as ‘method failure’ and necessitated method interchange or emergency cesarean section or a further attempt at induction using oxytocin infusion as was deemed necessary. Participants who developed tachysystole and/or hyperstimulation were treated according to standard protocol of the hospital—immediate discontinuation of oxytocin infusion if in use, infusion of normal saline with a fresh infusion set, maternal positional change (left lateral positioning), and supplementary oxygen through an intranasal catheter. An injection of salbutamol, 10 mg, was added in 1 l of normal saline and titrated against uterine contraction if contractions did not reduce to the desired level. Persistence of tachysystole and/or hyperstimulation, if in the vaginal misoprostol group, was managed with irrigation of the vagina using normal saline via a 50-ml syringe without the needle, and repeating several times until the pill fragments were no longer recovered. In addition, where necessary, 4 g of magnesium sulfate was given by intravenous load over 20 min followed by a 2-g/h infusion as well as close feto-maternal monitoring and other interventions as may be indicated. Participants’ baseline data that were recorded included maternal age, parity, gestational age, and the initial Bishop score. The primary outcome measures included induction– vaginal delivery interval, route of delivery, Apgar score at birth, need for oxytocin augmentation, and maternal satisfaction with the route of administration, while the secondary outcome measures included number of doses of misoprostol required, frequency of tachysystole, hypertonus, hyperstimulation, uterine rupture, and other maternal side effects such as fever, vomiting, diarrhea, abdominal pain, and the cesarean section rate. A structured interviewer-administered questionnaire was given to each of the participants as soon as possible after delivery to assess the acceptance and satisfaction with the received method of induction of labor. To ensure consistency, the questionnaire was administered by the same interviewer throughout the study. Induction–delivery interval was defined as the interval between the time of insertion of an agent and delivery of the baby, tachysystole as development of more than 5 (C6) contractions in 10 min for two consecutive 10-min intervals, hypertonus as development of uterine contraction lasting more than or equal to 2 min (C120 s), and hyperstimulation as tachysytole in the presence of abnormal fetal heart rate [17].
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The definitions of maternal perception and satisfaction with a method of induction of labor were adapted from a previous related study [12]. Thus; maternal perception of a particular method was described as acceptable, not acceptable, or indifferent. A method is said to be acceptable to a participant if the participant is pleased or happy with the method, and vice versa. Maternal satisfaction with a particular method of induction of labor was defined as patient’s expression of preference and willingness to consent to the same method if induction of labor is indicated in any subsequent pregnancies [12]. On the other hand, maternal satisfaction with the obstetrician’s care was defined as her expression of happiness with the way the obstetrician conducted the labor process [12]. Labor pain experience was assessed ‘categorically’ by asking if the woman experienced more pain than expected, less than expected, or as expected [12]. All data collected from the study were recorded on ‘case record forms’ prepared for the study. Statistical Package for Social Sciences (SPSS) computer software version 16 was used for data analyses. Intention to treat was adopted for analysis. Continuous and categorical data were compared using Student’s t test and Fisher’s exact test, respectively. Relationships were expressed using relative risks and confidence intervals. All tests were two sided and statistical significance was considered to be at a probability value of \0.05.
Results Within the 14-month study period, 1,197 deliveries took place out of which 161 were induced. This gave an induction rate of 13.5 %. One hundred and fifty-three women were eligible for the study, but 140 were randomized—70 per group (Fig. 1). All the women enrolled in the study participated to the end. There were no significant differences between the two groups with respect to their baseline characteristics, including the pre-induction Bishop score and the indications for induction of labor (Table 1). Post-datism was the most frequent indication in the two groups, accounting for 45 (64.3 %) in the ‘oral group’ and 50 (71.4 %) in the ‘vaginal group’ (Table 1). The induction–vaginal delivery interval (in h) was significantly higher in the oral group than in the vaginal group (20.7 ± 12.1 vs. 16.2 ± 10.4; mean difference: 4.50, 95 % CI 0.63–0.82; p = 0.02). Similarly, the mean number of doses of misoprostol required to achieve induction of labor was significantly higher in the oral group than in the vaginal group (2.5 ± 1.3 vs. 2.0 ± 1.1; mean difference: 0.50, 95 % CI 0.10–0.90; p = 0.02). The need for oxytocin augmentation in labor was significantly higher in the oral group compared to the vaginal group [39/70 (55.7 %) vs.
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Fig. 1 Study flowchart
25/70 (35.7 %); RR: 1.56; 95 % CI: 1.07–2.28; p = 0.02]. Furthermore, the mean duration (in h) of oxytocin use (when indicated) was significantly longer in the oral group compared to the vaginal group (4.6 ± 3.2 vs. 3.4 ± 3.1; mean difference: 1.20, 95 % CI 0.15–0.23; p = 0.03), respectively (4.6 ± 3.2 vs. 3.4 ± 3.1; p = 0.03). A total of eight (11.4 %) women in the oral group and five (7.1 %) in the vaginal group could not achieve an active phase of labor after 24 h of commencement of the induction process (RR: 1.60; 95 % CI: 0.55–4.65; p = 0.39). All the 13 women (in both groups) who had ‘method failure’ requested for cesarean delivery with favorable outcome. The route of delivery and labor complications were similar between the two groups (Table 2). Likewise, the neonatal outcomes including the 1st and 5th min APGAR scores, birth weight, and the need for admission into newborn special care unit (NBSCU) were similar between the two groups (Table 3). With respect to maternal complications that developed during labor, tachysystole was significantly less in the oral group than in the vaginal group [2/70 (2.85 %) vs. 15/70
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(21.42 %): RR: 0.13; 95 % CI: 0.03–0.56; p = 0.01). Other maternal complications were similar in the two groups (Table 4). There was no recorded case of hypertonus, uterine hyperstimulation, or uterine rupture in either of the two groups. There were no stillbirths or neonatal deaths recorded in both the study groups. However, two babies were noted to have tight cord around the neck during cesarean section and both belonged to the vaginal misoprostol group. With respect to the post-induction survey of the participants, equal number of women: 69 (98.6 %) in each group felt some discomfort with the method of induction used. There was also no significant difference in the women’s perception of the methods used with regard to acceptability of the route of administration of misoprostol [53/70 (75.7 %), oral group vs. 61/70 (87.1 %), vaginal group; p = 0.20). Similarly, there was no significant difference in the likelihood to give consent in future for the same method if labor induction is indicated in subsequent pregnancies (maternal satisfaction) [49/70 (70 %), oral group vs. 50/70 (80 %), vaginal group; p = 0.17]. Furthermore, there was
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Discussion
Table 1 Baseline characteristics of the participants Oral group (n = 70)
Vaginal group (n = 70)
p value
27.24 ± 4.53
28.24 ± 3.66
0.15
Primary education Secondary education
1
2
1.00
22
27
0.72
Tertiary education
37
43
0.39
Age (years) Educational status
Parity
0.77 ± 1.21
0.79 ± 1.17
0.92
Nulliparous
44 (62.9 %)
42 (60.0 %)
0.86
Primiparous
11 (15.7 %)
11 (15.7 %)
1.00
Multiparous
15 (21.4 %)
17 (24.3 %)
0.84
Gestational age (weeks)
40.59 ± 1.48
40.66 ± 1.63
0.79
Pre-induction Bishop score 0–5
43 (61.4)
39 (55.7)
0.57
6–13
27 (38.6)
31 (44.3)
0.56 0.47
Indications for induction of labor Post-datism
45 (64.3 %)
50 (71.4 %)
Pre-eclampsia
7 (10.0 %)
3 (4.3 %)
0.33
Diabetes mellitus
2 (2.9 %)
1 (1.4 %)
1.00
IUGR
12 (17.1 %)
13 (18.6 %)
1.00
Maternal request
4 (5.7 %)
3 (4.3 %)
1.00
t test for continuous variables and Fisher’s exact test for categorical variables IUGR intrauterine growth restriction
Table 2 Route of delivery Route of delivery
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
p value
Vaginal
46 (65.7)
49 (70.0)
0.86
46 (65.7)
48 (68.6)
0.85
Spontaneous Assisted (vacuum) Cesarean section
0 (0)
1 (1.4)
–
24 (34.3)
21 (30.0)
0.72
8 (11.4)
5 (7.1)
0.39
Poor progress in labor
12 (17.1)
11 (15.7)
1.00
Fetal distress
4 (5.7)
5 (7.1)
1.00
Indications for C/S Maternal request
Fisher’s exact test
no significant difference in the labor pain experiences and in the participants’ satisfaction with the obstetrician’s care during labor between the two groups (p [ 0.05). Details are shown in Table 5.
Misoprostol is being increasingly used for induction of labor in low-resource settings because of its low cost and effectiveness. The result of the present study revealed that 50 lg of oral and vaginal misoprostol is effective for induction of labor at term with comparable maternal satisfaction. However, the vaginal route has the added advantage of shorter induction–delivery interval, less number of doses of misoprostol required to achieve induction of labor, and less duration of oxytocin augmentation whenever indicated. The clinical significance of the shorter induction– delivery interval obtained in this study with the vaginal route is that the route may be more suitable in clinical situations where there is need to expedite delivery. Additionally, the shorter induction–delivery interval recorded in the vaginal route could result in shorter hospital stay, lesser family dislocation, and reduced period of anxiety. This resultant social/family harmony together with a reduced economic burden would ultimately lead to a less psychologically traumatized mother with a more fulfilled childbirth experience—a significant goal of modern obstetrics. However, despite these demonstrable advantages of vaginal route over the oral route as evident in this study, there is increasing report in literature that the oral or sublingual route of administration is more preferred by women as the former is thought to be embarrassing or inconveniencing to the women [11–16]. In view of this concern, recent researchers are advocating for consideration of the oral or sublingual route whenever misoprostol induction of labor is indicated [11, 12]. The present study has, however, proven otherwise, as pregnant Nigerian women at least in southeastern Nigeria do not abhor the vaginal route of administration because there was no demonstrable difference in maternal satisfaction or labor pain experiences between the two groups. It therefore means that the vaginal route should be highly considered in our environment whenever misoprostol induction of labor is indicated, since it is more effective than the oral route and has comparable acceptability and maternal satisfaction. Nevertheless, women should also be given the option for the oral route since it is also effective. The significant reduction in the need for oxytocin augmentation when the vaginal route is used for induction of labor as demonstrated in this study may suggest that the risks associated with oxytocin augmentation of labor can be largely obviated when the vaginal route is used. Furthermore, the additional cost of oxytocin augmentation of labor can to some extent be avoided. This is very important in low-resource settings like our environment where payment for maternal and neonatal services is almost entirely out of pocket.
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Table 3 Neonatal outcome
Neonatal variable
Oral group (n = 70)
Vaginal group (n = 70)
p value
Birth weight (kg)
3.44 ± 0.42
3.32 ± 0.51
0.14
\7
11 (15.7 %)
8 (11.4 %)
0.62
C7
59 (84.3 %)
62 (88.6 %)
0.62
\7
2 (2.9 %)
0 (0.0 %)
–
C7
68 (97.1 %)
70 (100 %)
0.50
Supplemental O2 required
13 (18.57 %)
8 (11.43 %)
0.35
Admission to NBSCU
8 (11.43 %)
7 (10.00 %)
1.00
1st min APGAR score
5th min APGAR score
t test for continuous variables and Fisher’s exact test for categorical variables
Table 4 Maternal complications that developed following induction of labor Maternal Complications
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
Tachysystole
2 (2.85)
15 (21.42)
Fever
1 (1.4)
2 (2.9)
p value
Table 5 Comparison of women’s experiences with induction of labor in the two groups
RR (95 % CI)
Oral group (n = 70) (%)
Vaginal group (n = 70) (%)
p value
69 (98.6)
69 (98.6)
1.00
0.01
0.13 (0.03–0.56)
Ever felt discomfort in labor
–
–
Level of discomfort felt
Vomiting
2 (2.9)
0 (0.0)
–
–
Mild-moderate
41 (58.0)
38 (53.6)
0.73
Postpartum hemorrhage
1 (1.4)
1 (1.4)
–
–
Severe
29 (42.0)
32 (46.4)
0.73
Maternal perception of the method
Fisher’s exact test
Acceptable
53 (75.71)
61 (87.14)
0.12
RR relative risk, CI confidence interval
Not acceptable
16 (22.9)
8 (11.4)
0.11
1 (1.4)
1 (1.4)
1.00
Indifferent
Although some previous studies have compared the efficacy of oral versus vaginal misoprostol for induction of labor at term, comparing the results of these studies is difficult due to considerable heterogeneity of the studies. Different doses of misoprostol have been used and, even when similar, the interval for vaginal or oral drug administration varied. Again, the gestations at recruitment of the women for the studies varied widely. Nevertheless, the significantly shorter interval to achieve induction of labor in the vaginal route in this study was similar to the findings of other researchers [2–9]. The reason for the greater effectiveness of the vaginal route could be because of the greater bioavailability of the drug following vaginal administration compared to the oral route. Though the oral route of administration has quicker onset of action, first pass effect reduces its bioavailability [22, 23]. In fact, the bioavailability of vaginally administered misoprostol is three times higher than that of orally administered misoprostol [23]. However, the result of the presented study is different from the report by Bano and co-workers [24] who demonstrated that 50 lg of misoprostol through the oral route was as effective as 50 lg through the vaginal route in terms of induction–delivery interval and number of doses of misoprostol required. The dosing interval of 6 hourly used in this report compared to
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Maternal satisfaction with the method Satisfied
49 (70.0)
56 (80.0)
0.17
Not satisfied
21 (30)
14 (20)
0.17
Maternal satisfaction with obstetrician’s care Satisfied 69 (98.6) 65 (92.9) Not satisfied
0.09
1 (1.4)
5 (7.1)
0.09
More than expected
35 (50.0)
44 (62.86)
0.17
Just as expected
29 (41.43)
25 (35.71)
0.60
6 (8.57)
1 (1.43)
0.11
Labor pain experience
Less than expected Fisher’s exact test
the 4-hourly interval used by Bano and co-workers may have contributed to the differences in the results obtained. Another reason for the differences obtained might be the possibilities of racial and environmental differences in individual responses to misoprostol as postulated by previous authors [17, 19]. The increased risk of tachysystole with the vaginal route observed in this report could be explained by the relatively longer half-life of misoprostol and its metabolites in maternal serum after vaginal administration compared to the oral administration [22, 23]. This finding is in
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agreement with previous related studies [2, 3, 6, 7, 10]. The absence of other contractile abnormalities in this study including hypertonus, hyperstimulation, or uterine rupture was similar to previous reports from our environment [17, 19]. The incidence of minimal contractile abnormalities together with the low cesarean section rate obtained in this study might be explained by the low dose of misoprostol (50 lg) used in this study and the strict adherence to the protocol of 6-hourly dosing interval, with non-commencement of oxytocin infusion until 6 h had elapsed after the last dose of intravaginal or oral misoprostol, since the terminal half-lives of misoprostol metabolites averaged 4.5 h for the variety of animals, including the human subjects [22]. These probably minimized the risks of possible cumulative drug effects which could result from a more frequent dosing regimen and the action summation that could result from interaction between misoprostol and oxytocin. This favorable finding further confirms that misoprostol is safe for induction of labor in our environment and that it is rarely associated with contractile abnormalities when used at doses not more than 50 lg and at intervals not less than 6 hourly. This study demonstrated that there was no difference in the rate of cesarean section as well as the route of delivery between the two groups. Similarly, the neonatal outcomes in terms of the APGAR scores and need for admission into the NBSCU were similar in both groups. All these findings are in agreement with previous trials on effectiveness of vaginal and oral misoprostol for induction of labor [2, 25]. The study further revealed that there was no significant difference in maternal satisfaction or labor pain experiences between the two groups with 80 % of the women who received vaginal misoprostol expressing satisfaction with the method. This finding is in contrary with the report by Nassar and co-worker [12] who observed a much lower maternal satisfaction rate of 25 % with the vaginal route. It is however in agreement with a previous related report which did not find any significant difference in the maternal satisfaction rate between the two routes of administration [26]. Despite the randomized design of this trial, there were some limitations. The misoprostol tablets were manually divided into four parts with the assistance of the hospital pharmacist and so we are not sure of the equality of the fourths. Nevertheless, the effect of this possible inequality on the study’s outcome is likely to be minimal and nondirectional. Furthermore, there was inability to mask the attending obstetrician or the women on the method of misoprostol administration assigned, and therefore we could not exclude the possibility that some biases were unavoidable. Cardiotocograph (CTG) was not applied in this study, and thus subtle fetal/contractile CTG abnormalities might have been missed. Measurement of neonatal
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outcome in terms of incidence of birth asphyxia was limited to the use of APGAR scores without any corresponding arterial umbilical cord PH analysis. Also, feeding of the women prior to commencement of labor was not under the control of the attending obstetricians and so the possible effect of food on the metabolism of misoprostol following oral administration could not be controlled. Another important limitation of the study is that the sample size used for the study was not large enough to study for the rarer complications and adverse effects of misoprostol induction of labor such as fever, vomiting, and postpartum hemorrhage. In conclusion, this study has demonstrated that orally and vaginally administered misoprostol is effective for induction of labor at term with comparable maternal satisfaction. However, the vaginal route has the added advantages of shorter induction–delivery interval, fewer doses of misoprostol needed to achieve induction of labor, and reduced need of oxytocin augmentation. It should therefore be highly considered when induction of labor is indicated at term. Conflict of interest
We declare that we have no conflict of interest.
References 1. Orhue AA (1997) Review of induction of labor. Trop J Obstet Gynaecol 14:1–14 2. Rasheed R, Alam AA, Younus S, Raza F (2007) Oral versus vaginal misoprostol for labor induction. J Pak Med Assoc 57(8):404–407 3. Akhtar Z, Tahir Saleem S, Lateef F (2010) Comparison of oral versus vaginal misoprostol for induction of labor at term. JRMC 14(1):104–106 4. Shetty A, Danielian P, Templeton A (2001) A comparison of oral and vaginal misoprostol tablets in induction of labor at term. BJOG 108(3):238–243 5. Ayaz A, Saeed S, Farooq MU, Ahmad I, Ali Bahoo ML, Saeed M (2009) Labor induction with randomized comparison of oral and intravaginal misoprostol in post-date multigravida women. Malays J Med Sci 16(1):34–38 6. Fisher SA, Mackenzie VP, Davies GA (2001) Oral versus vaginal misoprostol for induction of labor at term: a double blind randomised controlled trial. Am J Obstet Gynecol 185(4):906–910 7. Nopdonrattakoon L (2003) A comparison between intravaginal and oral misoprostol for labor induction: a randomised controlled trial. J Obstet Gynaecol Res 29(2):87–91 8. Deshmukh VL, Yelikar KA, Waso V (2013) Comparative study of efficacy and safety of oral versus vaginal misoprostol for induction or labour. J Obstet Gynaecol India 63(5):321–324 9. Mehrotra S, Singh U, Gupta HP (2010) A prospective double blind study using oral versus vaginal misoprostol for labour induction. J Obstet Gynaecol 30(5):461–464 10. Komala K, Reddy M, Quadri IJ, B S, V R (2013) Comparative study of oral and vaginal misoprostol for induction of labor, maternal and fetal outcome. J Clin Diagn Res 7(12):2866–2869 11. Alfirevic Z, Weeks A (2006) Oral misoprostol for induction of labour. Cochrane Database Sys Rev 2:CD001338 (Review)
123
544 12. Nassar AH, Awwad J, Khalil AM, Abu-Musa A, Mehio G, Usta IM (2007) A randomised comparison of patient satisfaction with vaginal and sublingual misoprostol for induction of labour at term. BJOG 114(10):1215–1221 13. Cheng S, Ming H, Lee J (2008) Titrated oral compared with vaginal misoprostol for labor induction: a randomised controlled trial. Obstet Gynecol 111(1):119–125 14. Wing DA, Park MR, Paul RH (2000) A randomized comparison of oral and intravaginal misoprostol for labor induction. Obstet Gynecol 95(6):905–908 15. Arvidsson C, Hellborg M, Gemzell-Danielsson K (2005) Preference and acceptability of oral versus vaginal administration of misoprostol in medical abortion with mifepristone. Eur J Obstet Gynecol Reprod Biol 123(1):87–91 16. Oppegaard KS, Qvigstad E, Nesheim BI (2006) Oral versus selfadministered vaginal misoprostol at home before surgical termination of pregnancy: a randomised controlled trial. BJOG 113(1):58–64 17. Ugwu EO, Onah HE, Obi SN, Dim CC, Okezie OA, Chigbu CO, Okoro OS (2013) Effect of the Foley catheter and synchronous low dose misoprostol administration on cervical ripening: a randomised controlled trial. J Obstet Gynaecol 33(6):572–577 18. Ekele BA, Nnadi DC, Gana MA, Shehu CE, Ahmed Y, Nwaobodo EI (2007) Misoprostol use for cervical ripening and induction of labor in a Nigerian Teaching Hospital. Niger J Clin Pract 10(3):234–237 19. Adeniji OA, Oladokun A, Olayemi O, Adeniji OI, Odukogbe AA, Ogunbode A, Aimakhu CO, Omigbodun AO, Ilesanmi AO
123
Arch Gynecol Obstet (2015) 291:537–544
20.
21.
22.
23.
24.
25.
26.
(2005) Pre-induction cervical ripening: trans-cervical Foley catheter versus intravaginal misoprostol. J Obstet Gynaecol 25(2):134–139 Fawole AO, Adegbola O, Adeyemi AS, Oladapo OT, Alao MO (2008) Misoprostol for induction of labour: a survey of attitude and practice in southwestern Nigeria. Arch Gynecol Obstet 278(4):353–358 Ugwu EO, Obi SN, Iferikigwe ES, Dim CC, Ezugwu FO (2014) Membrane stripping to prevent post-term pregnancy in Enugu, Nigeria: a randomized controlled trial. Arch Gynecol Obstet 289(1):29–34 Schoenhard G, Oppermann J, Kohn FE (1985) Metabolism and pharmacokinetic studies of misoprostol. Dig Dis Sci 30:126S– 128S Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD (1997) Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 90(1):88–92 Bano K, Mahjabeen Bhutta SZ (2009) Oral versus vaginal misoprostol for induction of labour at term. J Surg Pak (International) 14(1):38–41 Akter S, Chowdhury SB, Fatema N (2010) A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labour induction. ORION Med J 33(1):710–713 Colo´n I, Clawson K, Hunter K, Druzin ML, Taslimi MM (2005) Prospective randomized clinical trial of inpatient cervical ripening with stepwise oral misoprostol vs vaginal misoprostol. Am J Obstet Gynecol 192(3):747–752
