MOJ ISSN: 2475-5494 MOJWH

Women's Health
Research Article
Volume 3 Issue 1 - 2016
Titrated Oral Misoprostol as a Safe Route for Induction of Labour at Term (A Clinical Trial)
Hend S Saleh* and Hala E Mowafy
Department of Obstetrics and Gynecology, Zagazig University, Egypt
Received: October 13, 2016 | Published: November 22, 2016
*Corresponding author: Hend S Saleh, Department of Obstetrics and Gynecology, Faculty of Medicine , Zagazig University, Egypt, Tel: 00201143288238; Email:
Citation: Saleh HS, Mowafy HE (2016) Titrated Oral Misoprostol as a Safe Route for Induction of Labour at Term (A Clinical Trial). MOJ Womens Health 3(1): 00058. DOI: 10.15406/mojwh.2016.03.00058

Abstract

Objective: To assess safety and efficacy of induction of labour at term by low doses of oral misoprostol in the form of titration versus the standard regimen of vaginal misoprostol in the term of induction delivery interval, operative interventions and fetal outcome.

Methods: Clinical comparative study was carried out for a period of one year from November 2008 to October 2009 at Zagazig university hospital. The study protocol was approved by the ethics committee of our hospital. One hundred women at term with indication of labour and Bishop score less than or equal 5, no either Obstetric or maternal contraindications for induction of labour were randomly assigned to receive oral (titrated) or vaginal misoprostol for induction of labour. The oral group received a basal of 20ml misoprostol solution (1mcg/ml) every hour for four doses and then were titrated according uterine response individually, the vaginal group received 25 mcg every 4 hours(maximum number of doses limited to six) until cervix became more favorable. The induction delivery interval, oxytocin need, mode of delivery, frequency of side effects and neonatal and maternal outcome were assessed. Chi-square or Fisher exact test, Student's T-test and Wilcoxon rank sum test were used for analysis the data statistically.

Results: The oral misoprostol group had 50 women (50%) and was given it in the form of titrated oral solution and vaginal misoprostol group had 50 women (50%). Vaginal delivery occurred within 12 hours in 38 women (76%) in oral group and in 12 women (24%) in vaginal group. The median interval from starting induction by misoprostol to vaginal delivery was significantly shorter in oral titrated misoprostol group (7.5 h) compared with vaginal misoprostol group (16.1h) with P value <0.01.The incidence of hyper-stimulation in oral group was 0.0% compared with 12% in vaginal group with P value <0.01 which is significantly different. More women had nausea 8% in oral group but fewer infants had Apgar score less than 7 at 1 minute in oral group than in vaginal group.

Conclusion: Oral misoprostol in the form of titration is associated with lower incidence of uterine hyper-stimulation and lower cesarean delivery rate, better fetal outcome than vaginal misoprostol for labour induction at term in patients with unripe cervix.

Keywords: Misoprostol; Induction of labour; Hyper-stimulation

Introduction

Induction of labour is to start uterine contraction prior to their spontaneous onset accompanied with cervical dilatation, effacement and descent of fetal presenting part [1]. Induction of labour is frequently indicated for a variety of obstetric and medical problems to achieve benefit to the health of mother and/or baby which must exceed that to be gained by continuing the pregnancy [2]. It is carried out in over 20% of pregnancy in developed countries [3]. As prenatal mortality and fetal compromise increase progressively with gestation beyond 37 weeks. Induction of labour between 37 weeks and 41weeks has the potential to improve neonatal outcome [4].

Induction of labour at term in the presence of an unfavorable cervix is associated with an increased risk of failed induction and caesarean section. Therefore, cervical ripening for induction should be assessed before a regimen is selected. Assessment is accomplished by calculating Bishop score [5]. Although the indications of induction of labour have clearly changed during the past 200 years from a need to expel a dead fetus to reduce the threat to fetal or maternal health, effective and safe methods of achieving delivery must always be the primary objectives. Among the more old common approaches for induction of labour are frequent walking, vaginal intercourse, consumption of laxative, spicy food or herbal tea, nipple stimulation and administration of an enema [6]. During the past 40 years, labour induction had mostly involved combining the recognized advantages of physical manipulation with a pharmacological myometrial stimulant. Prostaglandin preparations with or without oxytocin infusion is widely recognized and accepted as standard method of labour induction [7]. Prostaglandins remain the single most effective means of achieving cervical ripening and inducing labour when combined with a timed amniotomy, providing good clinical effectiveness. Prostaglandin E2 is registered for labour induction in many countries. However it is expensive in developing countries and because it is sensitive to temperature changes, it needs to be kept under refrigeration so they are inconvenient to use [8]. Thus, there is a need for less costly and less temperature-sensitive alternative. Misoprostol, a prostaglandin E1 analogue, is an alternative agent for induction of labour. It is less expensive than dinoproston and requires no special storage arrangement [9]. Misoprostol is an oral prostaglandin compound, structurally related to prostaglandin E1 and manufactured as treatment for peptic ulcer disease [10]. Though unlicensed for this indication, it is being used increasingly in induction of labour with vaginal or oral administration [1].

A number of randomized controlled trials support the effectiveness of misoprostol administration at term for cervical ripening and induction of labour [11]. Some studies suggest that vaginal administration of misoprostol is more effective than oral but there is significant increase in tachysystol and hyper stimulation with the use of vaginal misoprostol compared to oral use [12]. Oral misoprostol has some advantages in comparison with vaginal misoprostol like ease of administration and avoidance of repeated vaginal examination to insert it [13]. Based on pharmacokinetic findings, it was found that peak serum concentration after oral administration is 34 minutes and half-life of 20-40 minutes. Peak serum concentration is 60-80 minutes for vaginal misoprostol and this level is sustained for up to 4 hours [14]. So, the shorter half-life of the oral misoprostol, delivery may be safe in the event of uterine hyper stimulation although vaginal one has advantageous direct local effect in cervical ripening [15]. There are different recommendations about ideal dose of either vaginal or oral administration of misoprostol. In this study; the objective was evaluation of safety and efficacy of using repeated small doses of oral misoprostol by titration in comparison to vaginal administered vaginal misoprostol in induction of labour at term.

Materials and Methods

This randomized clinical study was carried out between November 2008 to October 2009 in obstetric Department at Zagazig University Hospital. The study protocol was approved by the ethics committee of Zagazig University hospitals. The randomization was performed using a computer-generated random number table. An informed consent was obtained from the selected women. Sample size was 100 pregnant women at or beyond term were scheduled for induction of labour due to an obstetric or medical indication. Inclusion criteria were: singleton pregnancy, cephalic presentation, gestational age of 37-42 weeks confirmed by menstrual dates and first ultrasound, Bishop score ≤ 5. Exclusion criteria were: Previous uterine scar, parity more than four, non reassuring fetal heart pattern, mal presentation, multiple pregnancy, placental abruption and known allergy to prostaglandins. Fifty cases were allotted to either group of two groups. Group (1) was oral (titration) misoprostol and Group (2) was vaginal misoprostol. After complete history and clinical examination, a reassuring fetal heart tracing was confirmed with cardiotocography. Vaginal examination was performed to assess Bishop score. Women of the vaginal group received 25 mcg every 4 hours into the posterior fornix of vagina until cervix became more favorable (Bishop score ≥ 7 or adequate uterine activity; more than or equal to 3 contractions in 10 minutes or entering active labour, the maximum number of doses limited to six. Women of the oral (titrated) misoprostol group were started induction with a basal unit of 20 ml misoprostol solution (1mcgml) every one hour prepared by dissolving one tablet of misoprostol 200mcg in 200 ml distilled water in medicine bottle [16] until adequate uterine contractions were achieved. If contractions did not occur after four doses of those before, the dosage was increased to 40 mcg and repeated every hour until uterine contractions were achieved, with a maximum of four more doses. If the uterine activity still remained weak, the dosage was increased to 60 mcg per hour until adequate response. Once that occurred no more misoprostol was given. If uterine activity subsequently became insufficient, again hourly doses of misoprostol solution were started with 10 mcg and could be increased to 20mcg and could be 40mcg according to uterine response. The misoprostol solution was used completely within 24 hours after preparation or discarded. Fetal well being was confirmed by cardiotocography and Bishop Score was assessed prior to every dose of misoprostol either given vaginally or orally. Fetal heart rate and uterine activity were continuous monitored throughout labour induction. If diagnosis of labour was made or the Bishop`s score was 8 or more the woman was transferred to labour room and artificial rupture of membrane could be formed if it had not occurred. The use of oxytocin as supplementation if uterine activity were insufficient when entering the active phase due to weak response to misoprostol, was according to protocol of the hospital and was not started less than 4 hours after the last dose of misoprostol either orally or vaginally. It administrated through an infusion with an initial dose of 1mumin to a maximum of 32mumin. A partogram recording the progress of labour was maintained. Induction failure was clear as not entering into active phase after 24 hours of misoprostol conduct. Cesarean delivery was presented to those patients had failed induction or prolonged active phase. If uterine hyper stimulation occurred, intravenous magnesium sulfate in the dose of 4 g through 30 minutes was given. Adequate uterine contraction in the study was defined as occurance of it every 2-3 minutes and lasting 60-90 seconds. Hypertonus was defined as a single contraction lasting more than 2 minutes. Tachysystol as the presence of at least six contractions in 10 minutes over at least two 10 minutes windows. Hyper stimulation was defined as tachysystol or hypertonus with non reassuring FHR changes like; late deceleration, severe variable deceleration, prolonged deceleration, tachycardia or reduced FHR variability need intervention by tocolytics or delivery. Induction failure was defined as not entering into the active phase after 24 hours of misoprostol treatment. The primary measures used to evaluate efficacy were: The interval from the first misoprostol dose to vaginal delivery and percentages of women delivered vaginally within 12 hours and 24 hours of induction. The primary measures used to evaluate safety were the frequency of tachysystol, hypertonus, nonreassuring FHR andor uterine hyper-stimulation. The secondary measures accustomed to evaluate efficacy or safety included total dosage of misoprostol, rate of women given oxytocin, cesarean delivery and induction failure, neonatal outcomes counting lower Apgar score <7 at 5 minutes, need positive pressure ventilation, intubation or admission to neonatal intensive care unit. Statistical analysis was performed with the use of Chi-square or Fisher exact test for discontinuous variables such as parity, mode of delivery, Apgar score and the number of complications. Student's t-test was used to analyze group differences in maternal age. The interval between use of misoprostol to delivery, and total dosage of used misoprostol with Wilcoxon rank test. P value of < 0.05 was considered statistically significant.

Results

One hundred women were incorporated in this study. 50 women (50%) received oral misoprostol in the form of titrated solution and 50 women (50%) received vaginal misoprostol. The demographic characteristics of them were shown in (Table 1), There were no statistically significant differences in maternal age, parity or initial Bishop score. The indications of induction of labour were shown in (Table 2). The two groups were similar in most of those indications. The primary outcomes of induction were shown in (Table 3). The median interval from the first dose of misoprostol to delivery was 7.5 hours in the oral titrated group and 16.1 hours in vaginal group (P<.01).There were significantly more women who delivered vaginally in the oral group within 12 hours (76%) and in 24 hours (96%) compared to vaginal group who within 12 hours (24%) and within 24 hours (64%). There were no significant differences between both groups in occurrence of hypertonus. Tachysystol developed in 3 (6%) women in oral titrated group and 8 (16%) in vaginal group. When tachysystol happened in oral titrated group misoprostol was stopped immediately in this group. So hyper stimulation did not occur in oral titrated group but happened in 6 women (12%) in vaginal group (Table 3). Non reassuring FHR patterns that need urgent delivery was renowned in one (2%) woman in oral titrated group and in 6 (12%) women in the vaginal group. The median total dosage of misoprostol was 190 mcg in oral titrated group and 50 mcg in the vaginal group (P<.01). About oxytocin augmentation 4 (8%) women only need it in oral titrated group but in 23 (46%) women in vaginal group So there was significant differences between the two group (Table 4). The mode of delivery differed significantly between the both group; Six (12 %) women in the vaginal group underwent cesarean section compared with two (4 %) women only in oral titrated group. About maternal adverse effects; there was significant difference between two groups in nausea, it happened in 4 (8 %) and vomiting in two (4 % ) in the oral titrated group and no patients had nausea or vomiting in vaginal group. No significant difference between both group in occurrence of shivering, pyrexia or diarrhea (Table 5). There were significant difference in neonatal outcomes according to Apgar score in 1 minute (Table 6) as more newborn with Apgar score less than 7 at 1 minute in vaginal group. Two newborn need resuscitation and were admitted to neonatal intensive care unit in the same group.

Character

Oral Titrated Misoprostol n=50

Vaginal Misoprostol n= 50

P

Age

23.2 ± 3.2

24.7 ± 3.6

0.4

Gestational age

39.3 ± 1.2

39.8 ± 1.4

0.3

Bishop score ≤5

50100%

50100%

0.5

Nullipara

2448%

2652%

0.1

Multipara

2652%

2448%

0.1

Table 1: Characteristics of women of study.

Data are presented as means ± standard deviation. n=number.

Indications

Oral Titrated Misoprostol n=50

Vaginal Misoprostol n= 50

P

Postterm

26(52%)

24(48 %)

0.65

Premature rupture of membranes

15(30%)

16(32%)

0.1

Hypertension

3(6%)

3(6%)

0.1

Diabetes

2(4%)

2(4%)

0.35

Social causes

4(8%)

5(10%)

0.67

Table 2: Indications for induction.

Data of indications are (%) with no significant differences

Outcome

Oral Titrated  Misoprostol n=50

Vaginal Misoprostol n= 50

P

Starting dose to vaginal delivery (h)

7.5 (QR 5.1)

16.1 (QR 17.5)

<0.01

Vaginal delivery in12h

38 (76%)

12 (24%)

<0.01

Vaginal delivery in24h

48 (96%)

32 (64%)

<0.1

Non reassuring FHR

1 (2%)

6 (8%)

0.6

Tachysystole

3 (6%)

8 (16%)

0.7

Hypertonus

0 (0%)

0 (0%)

1

Hyper stimulation

0 (0%)

6 (12%)

<0.01

Repture uterus

0 (0%)

0 (0%)

1

Use of tocolysis for hyper tstimulation

0 (0%)

6 (8%)

0.05

Table 3: Primary induction outcomes.

QR: Quartile Range; Data are median, or (%); FHR: Fetal Heart Rate.

Outcome

Oral Titrated Misoprostol n=50

Vaginal Misoprostol n= 50

P

Total dosage (mcg)

190(QR 200)

50(QR 25)

<0.01

Oxytocin augmentation

4(8%)

23(46%)

<0.01

Vaginal delivaries

48(96%)

44(89%)

<0.01

Cesarean section delivaries

2(4%)

6(12%)

<0.01

Induction failure

0(0%)

5(10%)

<0.01

Table 4: Secondary outcomes of labour induction.

QR: Quartile Range; Data are median or (%).

Adverse Effects

Oral Titrated  Misoprostol n=50

Vaginal Misoprostol  n= 50

P

Nausea

4(8%)

1(2%)

<0.01

Vomiting

2(4%)

0(0%)

<0 .01

Diarrhea

1(2%)

0(0%)

< 0.5

Shivering

1(2%)

1(2%)

1

Pyrexia

0(0%)

1(2%)

0.5

Table 5: Maternal adverse effects.

Data are (%).

Oral titrated Misoprostol n=50

Vaginal Misoprostol n= 50

P

1 min Apgar score <7

0%

5(10%)

0.03

5 min Apgar score <7

0%

3(6%)

0.18

Need for PPV

0%

2(4%)

0.16

Need for intubation

0%

2(4%)

0.16

NICU admission

0%

2(4%)

0.16

Table 6: Neonatal outcomes.

NICU: Neonatal Intensive Care Unit; PPV: Positive Pressure Ventilation.

Discussion

In recent years, there has been significant interest in the use of misoprostol for cervical ripening and induction of labour. Misoprostol administrated either vaginally or orally [1]. Different doses of misoprostol were studied but the most widely used was 25 mcg every 4 hours as accompanied with least number of complications and accepted as the most effective(17). The aim of this study to assess clinical outcome and compare the efficacy and safety of new dosing regimen of oral titrated misoprostol in comparing it with the widely used regimen of vaginal misoprostol every 4 hours. Vaginal rout of misoprostol is associated with Uterinetachysystol and hyperstimulation as probable disadvantages. Furthermore, the risk of introducing ascending infection [2]. Thus, oral rout may be a better alternative. In this study, It was tried to use oral misoprostol in small, frequent doses in titration to avoid uterine hyper stimulation and shorten time of labour induction to vaginal delivery. Measures used to assess efficacy were the interval from the first dose of misoprostol to vaginal delivery, the percentages of women who delivered vaginally within 12 and 24 hours of labour induction and induction failure. It was found that the median interval from first dose to vaginal delivery was significantly shorter in oral titrated group (7.5 hours) in comparing to vaginal group (16.1 hours). Also there were more women delivered vaginally within 12 hours (76%) and within 24 hours (98%) in oral titrated group in comparing to vaginal group. Therefore these results hold that the efficacy of oral titration misoprostol is better than vaginal rout of misoprostol. The measures used to assess safety in this study were incidence of tachysystol, hypertonus, uterine hyper stimulation, and neonatal outcomes. In spite of occurrence of tachysystol in (6 %) of women in oral titrated group, the oral titrated solution was stopped immediately until uterine contractions decreased so, no woman had developed hyper stimulation. These results proposed that small dosage with continuous adjustment according to response is superior way to reduce incidence of uterine hyper-stimulation. The median total dosage in oral titrated group was 190 mcg which was more than three times that of vaginal group, but the need of oxytocin augmentation was less in oral titrated group as misoprostol has both uterotropic and uterotonic effects. These findings agreed with Shi-Yann et al. [17] who found that titrated oral misoprostol was associated with a lower incidence of uterine hyper stimulation than vaginal misoprostol for labour induction in patients with unfavorable cervix. In this study, the percentage of cesarean section in the women received oral titrated misoprostol was significantly lower than in vaginal group and this suggests that the repeated small oral doses of misoprostol ripened cervix and enhanced the vaginal delivery in term pregnancy with unfavorable cervix. The maternal adverse side effects of misoprostol were more frequent in oral titrated group but less than those recorded in other studies like study of Shetty et al. [13] as they used high oral doses. Neonatal outcome in oral titrated group were better than vaginal group as regard Apgar score assessment at 1 minute also no one need admission to neonatal intensive care unit in comparing to vaginal group.

Conclusion

This study suggests that oral misoprostol in small, repeated doses in the form of titration has more efficacy and safety and associated with a low incidence of uterine hyper-stimulation and low cesarean delivery rate than vaginal misoprostol for induction of labour at term with unripe cervix.

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