- Email: [email protected]
Pilot Study of Labor Induction with Titrated oral Misoprostol
■ ORIGINAL ARTICLE ■
PILOT STUDY OF LABOR INDUCTION WITH TITRATED ORAL MISOPROSTOL Shi-Yann Cheng*, Tai-Chang Chen Department of Obstetrics and Gynecology, China Medical University Peikang Hospital, Yun Lin, Taiwan.
SUMMARY Objective: To evaluate the safety and efficacy of titrated oral misoprostol for labor induction at term. Materials and Methods: Seventy-seven pregnant women (37 nullipara and 40 multipara), with medical or obstetric indications for labor induction after 37 weeks of gestation and unfavorable cervices (Bishop’s score < 7), were induced according to the principles of titrated oral doses of misoprostol against uterine response. Our primary outcome measurements were the percentage of patients who had a vaginal delivery within 24 hours of induction and the interval from induction to vaginal delivery. Secondary measurements included oxytocin requirement, total misoprostol dosage, number of cesarean deliveries, induction failure, uterine hyperstimulation rates and neonatal outcomes. Results: Seventy-five women (97.4%) experienced active labor within 24 hours, with 72 (93.5%) completing vaginal delivery within 24 hours. The mean interval from induction to vaginal delivery for all the women was 9.7 hours, with a 2.3-hour active phase. The mean misoprostol dosage was 206 μg, with eight women (10.4%) requiring oxytocin augmentation. There was no uterine hyperstimulation or induction failure, except for seven cases of uterine tachysystole (9.1%). Conclusion: Titrated oral misoprostol is a safe and effective method of labor induction because the dosage can be adjusted according to individual response. [Taiwanese J Obstet Gynecol 2006;45(3):225–229] Key Words: cervical ripening, labor induction, misoprostol
Introduction There are many indications for term labor induction, including postdate pregnancy, preeclampsia, diabetes mellitus, oligohydramnios, intrauterine fetal growth retardation and abnormal antepartum fetal surveillance results [1]. With more than 15% of all gravid women requiring aid in cervical ripening and labor induction, there is widespread interest in, and demand for, an effective and safe method of assistance. The immature cervix is the greatest barrier to labor induction. As oxytocin affects only uterine contractions and not cervical ripening, prostaglandin agents are the first
*Correspondence to: Dr Shi-Yann Cheng, Department of Obstetrics and Gynecology, China Medical University Peikang Hospital, 123, Shin Der Road, Peikang, Yun Lin 651, Taiwan. E-mail: [email protected] Accepted: May 24, 2006
Taiwanese J Obstet Gynecol • September 2006 • Vol 45 • No 3
choice for labor inductions as they exert a local effect on the cervix, causing effacement and dilatation, and stimulate myometrial contraction, increasing the likelihood of success. Dinoprostone has been the agent of choice for preinduction cervical ripening for several decades and it is currently one of the pharmacologic agents approved by the United States’ Food and Drug Administration (FDA) for this purpose. Although widely used, it has two disadvantages: it is expensive and it requires continuous refrigeration. Thus, there is a need for less costly and less temperature-sensitive alternatives. A proposed alternative is misoprostol, a synthetic prostaglandin E1 analog. Misoprostol, initially used to treat peptic ulcers caused by prostaglandin synthetase inhibitors, was approved by the FDA for obstetric use in April 2002. Since the 1992 letter of Margulies et al, published in the Lancet [2], and the initial American clinical report by Sanchez-Ramos et al, detailing the use of misoprostol for cervical ripening and labor induction [3], there
225
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has been growing interest in this agent [4–6]. The preferred dosage is 100 μg orally or 25 μg vaginally every 4 hours. However, excessive uterine contractility resulting in fetal distress is a cause for concern [7–15]. Comparing the oral and vaginal administrations of misoprostol, oral administration is easier and has greater acceptability among women. Further, absorption is more rapid and possibly more predictable, with a peak serum concentration following oral administration of 34 minutes and a half-life of 20–40 minutes. Peak serum concentration for vaginal administration is 60–80 minutes, this level being sustained for up to 4 hours [16]. Although the direct local effect of vaginal administration on cervical ripening may be advantageous [17], the shorter half-life of oral delivery may be beneficial in the event of uterine hyperstimulation. In order to avoid uterine hyperstimulation, it appears reasonable to suggest that oral misoprostol should be administered in small, frequent doses, titrated against the uterine response [18,19]. The aim of this study was to evaluate the safety and efficacy of titrated oral misoprostol for labor induction.
Materials and Methods This study was conducted between July 2002 and June 2005. The sample population comprised 77 pregnant women (37 nullipara and 40 multipara) with live singleton, cephalic presentations requiring labor induction after 37 weeks of gestation due to medical, obstetric or psychosocial indications. Exclusion criteria were: parity over five; previous cesarean section; more favorable cervix (Bishop’s score ≥ 7). Since the length of active labor differs between nulliparous and multiparous women [20,21], the sample population was subgrouped in order to analyze the outcomes of labor induction. Although misoprostol is manufactured as oral tablets, it is water soluble. The uterine activity produced by an oral solution is faster and stronger than that of an oral tablet, or via the rectal or vaginal route [22]. To overcome the inaccuracy inherent in manual division of the misoprostol tablet, one tablet (200 μg) was dissolved in 200 mL of water in a medicine bottle by the on-duty nurse. The bottle was shaken well before each administration [18]. The 1 μg/mL misoprostol solution facilitated accurate control of titrated oral dosage. Labor was induced with the 1 μg/mL solution according to the principles of titrated oral dosing [19], the basic general principles of which are as follows: 1. One tablet (200 μg) of misoprostol is dissolved in 200 mL of water (1 μg/mL of water).
226
2. The maximum cumulative dosage of misoprostol is 1,600 μg. 3. Initial administration of 20 μg/hour is undertaken until adequate uterine contractions are achieved. If contractions do not occur after four of the above doses, the dosage is increased to 40 μg and repeated every hour until uterine contractions are achieved, with a maximum of four more doses. If response still remains poor after 8 hours, the dosage should be increased to 60 μg/hour until adequate contractions occur. 4. Once uterine activity is deemed adequate, no further misoprostol is given. 5. If contractions subsequently become inadequate, hourly doses of misoprostol solution are started at 10 μg and may be increased to 20 μg and perhaps 40 μg, based on uterine responsiveness. This is repeated until adequate uterine contractions occur. 6. Fetal heart rate and uterine activity are continuously monitored throughout labor induction. 7. Induction failure is defined as not entering into the active phase after 36 hours using misoprostol solution with a maximum cumulative dosage of 1,600 μg. 8. Intravenous magnesium sulfate (4 g over 30 minutes) may be given if uterine hyperstimulation occurs. If rupture of the membranes has not occurred despite a Bishop’s score of 9 or above, artificial rupture of the membranes may be performed. Supplemental oxytocin may be used when uterine contractions are inadequate when entering the active phase because of poor response to misoprostol. Cesarean section is performed after induction failure or a prolonged active phase. Adequate uterine contractions are defined as contractions that occur every 2–3 minutes and last 60–90 seconds with an intrauterine pressure of 50–60 mmHg. Tachysystole is defined as the presence of at least six contractions in 10 minutes over at least two 10-minute windows. Hyperstimulation is defined as prolonged uterine contractions (each contraction lasting at least 2 minutes) or tachysystole that result in fetal heart deceleration requiring intervention, either by tocolytics or by delivery. Our main outcome measurements were the number of women who delivered infants vaginally within 12, 24 and 36 hours of induction. Other efficacy measurements included the interval from induction to vaginal delivery and active phase, total dosage of misoprostol, number of women given oxytocin and the number of induction failures. The number of cesarean deliveries, uterine tachysystole, hyperstimulation rates and occurrence of side effects were also recorded, as were neonatal outcomes including low Apgar score (< 7 at 5 minutes)
Taiwanese J Obstet Gynecol • September 2006 • Vol 45 • No 3
Titrated Oral Misoprostol Labor Induction
and neonatal unit admission. The entry characteristics of the patients, including age, height, weight, parity, gestational age at induction, indication for induction and cervical score before the start of induction, were also recorded.
Results Seventy-seven pregnant women (37 nullipara and 40 multipara) were enrolled in this study. Demographic characteristics and indications for induction are presented in Tables 1 and 2, respectively. Seventy-five women experienced active labor within 24 hours (97.4%; 35 nullipara and 40 multipara), and 72 completed vaginal delivery within 24 hours (93.5%; 32 nullipara and 40 multipara). Seventy-four women completed vaginal delivery within 36 hours (96.1%; 34 nullipara and 40 multipara), with three (three nullipara) delivering by cesarean section due to a prolonged active phase. Eight women (10.4%) required oxytocin augmentation due to poor response to misoprostol when entering the active phase. Except for the seven patients (9.1%) who Table 1. Demographic characteristics of 77 patients (37 nulliparas, 40 multiparas) Characteristic
Median
Age (yr) Height (cm) Weight (kg) Gestation (wk)
26.8 158.0 65.0 39.1
Range 17.9–45.4 144–172 49.0–102.0 36.3–42.1
experienced uterine tachysystole, there was no uterine hyperstimulation or induction failure (Table 3). The mean Bishop’s score for both nullipara and multipara subgroups was 4. The mean interval from induction to vaginal delivery for all the women was 9.7 hours, with a 2.3-hour active phase. The mean induction intervals for the nullipara and multipara subgroups were 12.2 hours with a 3.0-hour active phase and 7.6 hours with a 1.7-hour active phase, respectively. The mean dosage for the entire sample was 206 μg, while for the nullipara and multipara subgroups was 228 μg and 185 μg, respectively (Table 4). Common side effects included nausea (11.7%) and vomiting (10.4%); rare side effects were diarrhea (2.6%) and shivering (1.3%). No pyrexia was seen. The median birth weight of the newborns was 3,050 g (range, 2,100– 4,200 g) and neonatal outcomes were all good as no infant had a low Apgar score (< 7 at 5 minutes) requiring admittance to the neonatal unit.
Table 2. Indications for labor induction Indication
n (%)
Post-term Hypertension IUGR PROM Psychosocial GDM Other
5 (6.5) 6 (7.8) 3 (3.9) 15 (19.5) 8 (10.4) 2 (2.6) 38 (49.4)
IUGR = intrauterine growth retardation; PROM = premature rupture of membrane; GDM = gestational diabetes mellitus.
Table 3. Outcomes of labor induction Nullipara (n = 37)
Multipara (n = 40)
Total (n = 77)
%
Active labor within 12 hr 24 hr 36 hr
27 35 37
37 40 40
64 75 77
83.1 97.4 100.0
Vaginal delivery within 12 hr 24 hr 36 hr
21 32 34
36 40 40
57 72 74
74.0 93.5 96.1
Augmentation with oxytocin
4
4
8
10.4
Cesarean section
3
0
3
3.9
Uterine tachysystole
4
3
7
9.1
Uterine hyperstimulation
0
0
0
0.0
Induction failure
0
0
0
0.0
Fetal distress
0
0
0
0.0
Outcome
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Table 4. Induction dosage and interval Nullipara (n = 37) Mean Bishop’s score Dosage (μg) Latent phase interval (hr) Active phase interval (hr) Induction to vaginal delivery interval (hr)
4 228 9.2 3.0 12.2
Range
Mean
1–6 40–1,120 0.5–31.3 0.7–9.5 1.9–35.0
Discussion Given the pharmacokinetics of misoprostol [16] and the extreme inter- and intraindividual variation in terms of uterine sensitivity, regular administration of oral misoprostol every 4 hours is not safe at high doses (≥ 100 μg) [11]. In order to avoid uterine hyperstimulation and to shorten the interval from induction to vaginal delivery, we adopted the principle that misoprostol should be administered orally in small, frequent doses (one dose per hour generally), titrated against uterine response and analogous to the conventional titrated use of oxytocin. The 1-hour interval of oral administration was developed according to the mathematical model of the time to peak serum concentration (Tmax) and halflife (T1/2) of oral misoprostol after absorption, which virtually maintains a steady serum level of misoprostol acid without large fluctuations, and increases by one and one-third the peak serum concentration (Cmax) of 20 μg absorptive misoprostol every 4 hours [19]. This method is easier to administer than vaginal suppositories and is less expensive than intravenous oxytocin given via an adjusting pump machine. Parameters evaluated for safety were uterine tachysystole rate, uterine hyperstimulation rate, neonatal outcome with low Apgar score and neonatal unit admission. All these were satisfactory except tachysystole, which occurred in seven patients (9.1%). When tachysystole was found, the oral intake of misoprostol solution was halted until uterine contractions became inadequate and there was no uterine hyperstimulation. The common side effects of nausea and vomiting were not higher than other studies of high oral doses [15]. Clearly, small dosage incrementation, with continuous adjustment according to response, is the best way to decrease the incidence of uterine hyperstimulation. Next, the parameters we evaluated for efficacy were the percentage of women delivering vaginally within 24 hours of induction, total misoprostol dosage and induction failure rate. It is encouraging to note that the percentage of women with intervals from
228
Multipara (n = 40)
4 185 5.9 1.7 7.6
Range 1–6 40–560 1.0–13.5 0.3–5.5 2.3–16.0
Total (n = 77) Mean 4 206 7.5 2.3 9.7
induction to vaginal delivery within 24 hours was above 90%, when compared with other studies [11,18]. Of particular interest were the lack of induction failure and the range of doses from 40 to 1,120 μg below the maximum cumulative dosage. It was also noted that, with titrated oral misoprostol dosing, duration of the active phase was shorter than the usual natural course for both nullipara and multipara groups [20,21]. In conclusion, titrated oral misoprostol is a safe and effective method of labor induction as dosage can be adjusted according to individual response. After the encouraging results of this pilot study, in future, it would be worth comparing titrated oral misoprostol with regular 4-hourly high doses of 100 μg to determine the optimal method of labor induction.
References 1.
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5. 6.
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Committee on Obstetrics. Induction of Labor. Washington: American College of Obstetricians and Gynecologists, 1995, ACOG Technical Bulletin No. 217. Margulies M, Campos Perez G, Voto LS. Misoprostol to induce labour. Lancet 1992;339:64. [Letter] Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with prostaglandin E1 methyl analogue misoprostol versus oxytocin: a randomized trial. Obstet Gynecol 1993;81:332–6. Hofmeyr GJ, Gulmezoglu AM, Alfirevic Z. Misoprostol for the induction of labour: a systemic review. Br J Obstet Gynecol 1999;106:798–803. Wing DA. Labor induction with misoprostol. Am J Obstet Gynecol 1999;180:339–44. Keirse MJNC. Prostaglandins in preinduction cervical ripening: meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89–98. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and labour induction in late pregnancy (Cochrane review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software. Alfirevic Z, Howarth G, Gausmann A. Oral misoprostol for induction of labour with a viable fetus (Cochrane review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
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9.
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Bennett KA, Butt K, Grane JMG, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92:481–6. Wing DA, Ham D, Paul RH. A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labor induction. Am J Obstet Gynecol 1999;180:1155–60. Wing DA, Park MR, Paul RH. A randomized comparison of oral and intravaginal misoprostol for labor induction. Obstet Gynecol 2000;95:905–8. Shetty A, Martin R, Danielian P, Templeton A. A comparison of two dosage regimens of oral misoprostol for labor induction at term. Acta Obstet Gynecol Scand 2002;81: 337–42. Kolderup L, Mclean L, Grullon K, Safford RN, Kilpatrick SJ. Misoprostol is more efficacious for labor induction than prostaglandin E2, but is it associated with more risk? Am J Obstet Gynecol 1999;180:1543–7. Shetty A, Danielian P, Templeton A. A comparison of oral and vaginal misoprostol tablets in the induction of labor at term. Br J Obstet Gynaecol 2001;108:1–6. Shetty A, Mackie L, Danielian P, Rice P, Templeton A. Sublingual compared with oral misoprostol in term labour
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16.
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20. 21. 22.
induction: a randomized controlled trial. Br J Obstet Gynecol 2002;109:645–50. Zeiman M, Fong SK, Benowitz NL, Bankster D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92. Daneilsson GK, Marions L, Rodriguez A, Spur BW, Wong PYK, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275–80. Hofmeyr GJ, Matonhodze BB, Alfirevic Z, et al. Titrated oral misoprostol solution—a new method of labour induction. S Afr Med J 2001;91:775–6. Cheng SY. Labor induction using titrated oral doses of misoprostol in pregnancy with myoma. Taiwanese J Obstet Gynecol 2003;42:147–51. Kilpatrich SJ, Laros RK. Characteristics of normal labor. Obstet Gynecol 1989;74:81–7. Albers LL, Schiff M, Gorwoda JG. The length of active labor in normal pregnancy. Obstet Gynecol 1996;87:355–9. Chong YS, Chua S, Shen L, Arulkumaran S. Does the route of administration of misoprostol make a difference? The uterotonic effect and side effects of misoprostol given by different routes after vaginal delivery. Eur J Obstet Gynecol Reprod Biol 2004;113:191–8.
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PILOT STUDY OF LABOR INDUCTION WITH TITRATED ORAL MISOPROSTOL Shi-Yann Cheng*, Tai-Chang Chen Department of Obstetrics and Gynecology, China Medical University Peikang Hospital, Yun Lin, Taiwan.
SUMMARY Objective: To evaluate the safety and efficacy of titrated oral misoprostol for labor induction at term. Materials and Methods: Seventy-seven pregnant women (37 nullipara and 40 multipara), with medical or obstetric indications for labor induction after 37 weeks of gestation and unfavorable cervices (Bishop’s score < 7), were induced according to the principles of titrated oral doses of misoprostol against uterine response. Our primary outcome measurements were the percentage of patients who had a vaginal delivery within 24 hours of induction and the interval from induction to vaginal delivery. Secondary measurements included oxytocin requirement, total misoprostol dosage, number of cesarean deliveries, induction failure, uterine hyperstimulation rates and neonatal outcomes. Results: Seventy-five women (97.4%) experienced active labor within 24 hours, with 72 (93.5%) completing vaginal delivery within 24 hours. The mean interval from induction to vaginal delivery for all the women was 9.7 hours, with a 2.3-hour active phase. The mean misoprostol dosage was 206 μg, with eight women (10.4%) requiring oxytocin augmentation. There was no uterine hyperstimulation or induction failure, except for seven cases of uterine tachysystole (9.1%). Conclusion: Titrated oral misoprostol is a safe and effective method of labor induction because the dosage can be adjusted according to individual response. [Taiwanese J Obstet Gynecol 2006;45(3):225–229] Key Words: cervical ripening, labor induction, misoprostol
Introduction There are many indications for term labor induction, including postdate pregnancy, preeclampsia, diabetes mellitus, oligohydramnios, intrauterine fetal growth retardation and abnormal antepartum fetal surveillance results [1]. With more than 15% of all gravid women requiring aid in cervical ripening and labor induction, there is widespread interest in, and demand for, an effective and safe method of assistance. The immature cervix is the greatest barrier to labor induction. As oxytocin affects only uterine contractions and not cervical ripening, prostaglandin agents are the first
*Correspondence to: Dr Shi-Yann Cheng, Department of Obstetrics and Gynecology, China Medical University Peikang Hospital, 123, Shin Der Road, Peikang, Yun Lin 651, Taiwan. E-mail: [email protected] Accepted: May 24, 2006
Taiwanese J Obstet Gynecol • September 2006 • Vol 45 • No 3
choice for labor inductions as they exert a local effect on the cervix, causing effacement and dilatation, and stimulate myometrial contraction, increasing the likelihood of success. Dinoprostone has been the agent of choice for preinduction cervical ripening for several decades and it is currently one of the pharmacologic agents approved by the United States’ Food and Drug Administration (FDA) for this purpose. Although widely used, it has two disadvantages: it is expensive and it requires continuous refrigeration. Thus, there is a need for less costly and less temperature-sensitive alternatives. A proposed alternative is misoprostol, a synthetic prostaglandin E1 analog. Misoprostol, initially used to treat peptic ulcers caused by prostaglandin synthetase inhibitors, was approved by the FDA for obstetric use in April 2002. Since the 1992 letter of Margulies et al, published in the Lancet [2], and the initial American clinical report by Sanchez-Ramos et al, detailing the use of misoprostol for cervical ripening and labor induction [3], there
225
S.Y. Cheng, T.C. Chen
has been growing interest in this agent [4–6]. The preferred dosage is 100 μg orally or 25 μg vaginally every 4 hours. However, excessive uterine contractility resulting in fetal distress is a cause for concern [7–15]. Comparing the oral and vaginal administrations of misoprostol, oral administration is easier and has greater acceptability among women. Further, absorption is more rapid and possibly more predictable, with a peak serum concentration following oral administration of 34 minutes and a half-life of 20–40 minutes. Peak serum concentration for vaginal administration is 60–80 minutes, this level being sustained for up to 4 hours [16]. Although the direct local effect of vaginal administration on cervical ripening may be advantageous [17], the shorter half-life of oral delivery may be beneficial in the event of uterine hyperstimulation. In order to avoid uterine hyperstimulation, it appears reasonable to suggest that oral misoprostol should be administered in small, frequent doses, titrated against the uterine response [18,19]. The aim of this study was to evaluate the safety and efficacy of titrated oral misoprostol for labor induction.
Materials and Methods This study was conducted between July 2002 and June 2005. The sample population comprised 77 pregnant women (37 nullipara and 40 multipara) with live singleton, cephalic presentations requiring labor induction after 37 weeks of gestation due to medical, obstetric or psychosocial indications. Exclusion criteria were: parity over five; previous cesarean section; more favorable cervix (Bishop’s score ≥ 7). Since the length of active labor differs between nulliparous and multiparous women [20,21], the sample population was subgrouped in order to analyze the outcomes of labor induction. Although misoprostol is manufactured as oral tablets, it is water soluble. The uterine activity produced by an oral solution is faster and stronger than that of an oral tablet, or via the rectal or vaginal route [22]. To overcome the inaccuracy inherent in manual division of the misoprostol tablet, one tablet (200 μg) was dissolved in 200 mL of water in a medicine bottle by the on-duty nurse. The bottle was shaken well before each administration [18]. The 1 μg/mL misoprostol solution facilitated accurate control of titrated oral dosage. Labor was induced with the 1 μg/mL solution according to the principles of titrated oral dosing [19], the basic general principles of which are as follows: 1. One tablet (200 μg) of misoprostol is dissolved in 200 mL of water (1 μg/mL of water).
226
2. The maximum cumulative dosage of misoprostol is 1,600 μg. 3. Initial administration of 20 μg/hour is undertaken until adequate uterine contractions are achieved. If contractions do not occur after four of the above doses, the dosage is increased to 40 μg and repeated every hour until uterine contractions are achieved, with a maximum of four more doses. If response still remains poor after 8 hours, the dosage should be increased to 60 μg/hour until adequate contractions occur. 4. Once uterine activity is deemed adequate, no further misoprostol is given. 5. If contractions subsequently become inadequate, hourly doses of misoprostol solution are started at 10 μg and may be increased to 20 μg and perhaps 40 μg, based on uterine responsiveness. This is repeated until adequate uterine contractions occur. 6. Fetal heart rate and uterine activity are continuously monitored throughout labor induction. 7. Induction failure is defined as not entering into the active phase after 36 hours using misoprostol solution with a maximum cumulative dosage of 1,600 μg. 8. Intravenous magnesium sulfate (4 g over 30 minutes) may be given if uterine hyperstimulation occurs. If rupture of the membranes has not occurred despite a Bishop’s score of 9 or above, artificial rupture of the membranes may be performed. Supplemental oxytocin may be used when uterine contractions are inadequate when entering the active phase because of poor response to misoprostol. Cesarean section is performed after induction failure or a prolonged active phase. Adequate uterine contractions are defined as contractions that occur every 2–3 minutes and last 60–90 seconds with an intrauterine pressure of 50–60 mmHg. Tachysystole is defined as the presence of at least six contractions in 10 minutes over at least two 10-minute windows. Hyperstimulation is defined as prolonged uterine contractions (each contraction lasting at least 2 minutes) or tachysystole that result in fetal heart deceleration requiring intervention, either by tocolytics or by delivery. Our main outcome measurements were the number of women who delivered infants vaginally within 12, 24 and 36 hours of induction. Other efficacy measurements included the interval from induction to vaginal delivery and active phase, total dosage of misoprostol, number of women given oxytocin and the number of induction failures. The number of cesarean deliveries, uterine tachysystole, hyperstimulation rates and occurrence of side effects were also recorded, as were neonatal outcomes including low Apgar score (< 7 at 5 minutes)
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Titrated Oral Misoprostol Labor Induction
and neonatal unit admission. The entry characteristics of the patients, including age, height, weight, parity, gestational age at induction, indication for induction and cervical score before the start of induction, were also recorded.
Results Seventy-seven pregnant women (37 nullipara and 40 multipara) were enrolled in this study. Demographic characteristics and indications for induction are presented in Tables 1 and 2, respectively. Seventy-five women experienced active labor within 24 hours (97.4%; 35 nullipara and 40 multipara), and 72 completed vaginal delivery within 24 hours (93.5%; 32 nullipara and 40 multipara). Seventy-four women completed vaginal delivery within 36 hours (96.1%; 34 nullipara and 40 multipara), with three (three nullipara) delivering by cesarean section due to a prolonged active phase. Eight women (10.4%) required oxytocin augmentation due to poor response to misoprostol when entering the active phase. Except for the seven patients (9.1%) who Table 1. Demographic characteristics of 77 patients (37 nulliparas, 40 multiparas) Characteristic
Median
Age (yr) Height (cm) Weight (kg) Gestation (wk)
26.8 158.0 65.0 39.1
Range 17.9–45.4 144–172 49.0–102.0 36.3–42.1
experienced uterine tachysystole, there was no uterine hyperstimulation or induction failure (Table 3). The mean Bishop’s score for both nullipara and multipara subgroups was 4. The mean interval from induction to vaginal delivery for all the women was 9.7 hours, with a 2.3-hour active phase. The mean induction intervals for the nullipara and multipara subgroups were 12.2 hours with a 3.0-hour active phase and 7.6 hours with a 1.7-hour active phase, respectively. The mean dosage for the entire sample was 206 μg, while for the nullipara and multipara subgroups was 228 μg and 185 μg, respectively (Table 4). Common side effects included nausea (11.7%) and vomiting (10.4%); rare side effects were diarrhea (2.6%) and shivering (1.3%). No pyrexia was seen. The median birth weight of the newborns was 3,050 g (range, 2,100– 4,200 g) and neonatal outcomes were all good as no infant had a low Apgar score (< 7 at 5 minutes) requiring admittance to the neonatal unit.
Table 2. Indications for labor induction Indication
n (%)
Post-term Hypertension IUGR PROM Psychosocial GDM Other
5 (6.5) 6 (7.8) 3 (3.9) 15 (19.5) 8 (10.4) 2 (2.6) 38 (49.4)
IUGR = intrauterine growth retardation; PROM = premature rupture of membrane; GDM = gestational diabetes mellitus.
Table 3. Outcomes of labor induction Nullipara (n = 37)
Multipara (n = 40)
Total (n = 77)
%
Active labor within 12 hr 24 hr 36 hr
27 35 37
37 40 40
64 75 77
83.1 97.4 100.0
Vaginal delivery within 12 hr 24 hr 36 hr
21 32 34
36 40 40
57 72 74
74.0 93.5 96.1
Augmentation with oxytocin
4
4
8
10.4
Cesarean section
3
0
3
3.9
Uterine tachysystole
4
3
7
9.1
Uterine hyperstimulation
0
0
0
0.0
Induction failure
0
0
0
0.0
Fetal distress
0
0
0
0.0
Outcome
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Table 4. Induction dosage and interval Nullipara (n = 37) Mean Bishop’s score Dosage (μg) Latent phase interval (hr) Active phase interval (hr) Induction to vaginal delivery interval (hr)
4 228 9.2 3.0 12.2
Range
Mean
1–6 40–1,120 0.5–31.3 0.7–9.5 1.9–35.0
Discussion Given the pharmacokinetics of misoprostol [16] and the extreme inter- and intraindividual variation in terms of uterine sensitivity, regular administration of oral misoprostol every 4 hours is not safe at high doses (≥ 100 μg) [11]. In order to avoid uterine hyperstimulation and to shorten the interval from induction to vaginal delivery, we adopted the principle that misoprostol should be administered orally in small, frequent doses (one dose per hour generally), titrated against uterine response and analogous to the conventional titrated use of oxytocin. The 1-hour interval of oral administration was developed according to the mathematical model of the time to peak serum concentration (Tmax) and halflife (T1/2) of oral misoprostol after absorption, which virtually maintains a steady serum level of misoprostol acid without large fluctuations, and increases by one and one-third the peak serum concentration (Cmax) of 20 μg absorptive misoprostol every 4 hours [19]. This method is easier to administer than vaginal suppositories and is less expensive than intravenous oxytocin given via an adjusting pump machine. Parameters evaluated for safety were uterine tachysystole rate, uterine hyperstimulation rate, neonatal outcome with low Apgar score and neonatal unit admission. All these were satisfactory except tachysystole, which occurred in seven patients (9.1%). When tachysystole was found, the oral intake of misoprostol solution was halted until uterine contractions became inadequate and there was no uterine hyperstimulation. The common side effects of nausea and vomiting were not higher than other studies of high oral doses [15]. Clearly, small dosage incrementation, with continuous adjustment according to response, is the best way to decrease the incidence of uterine hyperstimulation. Next, the parameters we evaluated for efficacy were the percentage of women delivering vaginally within 24 hours of induction, total misoprostol dosage and induction failure rate. It is encouraging to note that the percentage of women with intervals from
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Multipara (n = 40)
4 185 5.9 1.7 7.6
Range 1–6 40–560 1.0–13.5 0.3–5.5 2.3–16.0
Total (n = 77) Mean 4 206 7.5 2.3 9.7
induction to vaginal delivery within 24 hours was above 90%, when compared with other studies [11,18]. Of particular interest were the lack of induction failure and the range of doses from 40 to 1,120 μg below the maximum cumulative dosage. It was also noted that, with titrated oral misoprostol dosing, duration of the active phase was shorter than the usual natural course for both nullipara and multipara groups [20,21]. In conclusion, titrated oral misoprostol is a safe and effective method of labor induction as dosage can be adjusted according to individual response. After the encouraging results of this pilot study, in future, it would be worth comparing titrated oral misoprostol with regular 4-hourly high doses of 100 μg to determine the optimal method of labor induction.
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