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Excessive Uterine Activity Accompanying Induced Labor

From the Department of Obstetrics and Gynecology, Health Care Corporation of St. John’s, St. John’s, Newfoundland, Canada.

Address reprint requests to: Joan Crane, MD Department of Obstetrics and Gynecology Health Care Corporation of St. John’s 300 Prince Phillip Drive St. John’s, Newfoundland A1B 3V6 Canada

	Abstract

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Objective: To estimate the incidence and timing of excessive uterine activity accompanying induction of labor with misoprostol using different routes (oral or vaginal) and forms (intact tablet or crushed) and to compare these with dinoprostone gel, oxytocin, and spontaneous labor.

Methods: This retrospective cohort study included 519 women at term who had labor induced and 86 women at term in spontaneous labor. Induction agents included misoprostol, dinoprostone, or oxytocin. Fetal heart rate and uterine activity tracings were analyzed independently by three maternal-fetal medicine physicians. The diagnosis of tachysystole or hyperstimulation required the agreement of two or more reviewers.

Results: The incidence of tachysystole was highest with misoprostol administered by vaginal tablet (misoprostol vaginal tablet 50 µg every 4 hours, 48.6%; vaginal tablet crushed 50 µg and suspended in hydroxyethyl gel every 4 hours, 30.7%, P = .009; oral tablet 50 µg every 4 hours, 22.2%, P = .001; oral tablet crushed 50 µg every 4 hours, 15.5%, P < .001; dinoprostone gel, 33.0%, P = .022; intravenous oxytocin, 30.2%, P = .027; and spontaneous onset of labor, 23.3%, P < .001). Hyperstimulation occurred more often with dinoprostone gel (16.5%) than with other forms of induction or spontaneous labor. Hyperstimulation occurred significantly more often with vaginal misoprostol crushed tablet (7.9%) and vaginal misoprostol intact tablet (7.6%) than with crushed oral misoprostol (1.0%) (P = .016 and .018, respectively). There was a shorter time to tachysystole with increasing doses of vaginal misoprostol tablet (P = .01).

Conclusion: The incidence of tachysystole and hyper-stimulation, and time to tachysystole, varied depending on the route and form of misoprostol given.

Studies of misoprostol for induction of labor reported a wide range in the incidence of hyperstimulation and tachysystole.^1–4 Standard terminology has not been used consistently by all authors reporting excessive uterine activity.⁵ The use of standard terminology would help to minimize confusion. Other confounding factors include interobserver and intraobserver variation in the interpretation of uterine activity and fetal heart rate tracings. Also, the route, form, and dose of misoprostol might influence uterine activity because of pharmacokinetic differences.^6,7

Excessive uterine activity is a concern^1,2 particularly when nonreassuring fetal heart rate (FHR) changes occur because they might reflect compromises of fetal well being. Therefore, women receiving prostaglandins for labor induction need to be monitored. Few studies have described the timing of excessive uterine activity with misoprostol.^8–12 The primary objective of this study was to describe the incidence and timing of excessive uterine activity, including tachysystole and hyperstimulation, with labor induction using misoprostol in different forms and routes. These results also were compared with spontaneous labor and with other forms of labor induction, including oxytocin or dinoprostone.

	Methods

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This retrospective cohort study was performed at the Grace General Hospital, St. John’s, Newfoundland, Canada from March 30, 1994 to December 19, 1997. This provincial tertiary care center serves an almost entirely white population and is the site of 2400 of the province’s 5500 annual births. The study included women enrolled in each of three randomized controlled trials evaluating misoprostol for labor induction,^13–15 as well as a cohort of women who presented in spontaneous labor during this period. Randomization in the three trials was done using opaque sequentially numbered sealed envelopes containing cards indicating study allocation that were prepared by administrative staff not directly involved in patient care. The study was approved by the hospital and the Human Investigation Committee of the Faculty of Medicine of Memorial University of Newfoundland. Inclusion criteria were a single live fetus in cephalic presentation, gestation longer than 37 weeks, and FHR and uterine activity graphs available for review. Exclusion criteria were nonreassurring FHR tracing before induction (or on admission in the spontaneous labor cohort), prior uterine surgery, contraindication to vaginal birth, and age less than 19 years. For women who had labor induced, known hypersensitivity to misoprostol or other prostaglandins was an exclusion criterion.

One misoprostol randomized controlled trial enrolled only women with term premature rupture of membranes,¹⁵ whereas the other two included only women with intact membranes.^13,14 The details of the three randomized controlled trials have been published.^13–15 For women who had labor induced, the cohorts were as follows: 50-µg misoprostol tablet (half a 100-µg tablet) vaginally every 4 hours, 50 µg misoprostol crushed and mixed with juice given orally every 4 hours, 50 µg misoprostol (half a 100-µg tablet) given orally every 4 hours (for premature rupture of membranes [PROM]), 50 µg misoprostol crushed and suspended in hydroxyethyl gel given vaginally every 4 hours, 0.5 mg intracervical dinoprostone gel every 6 hours or intravaginal dinoprostone gel 1 mg or 2 mg every 6 hours, and intravenous oxytocin infusion beginning at 2 mIU/minute and increasing by 2 mIU/minute every 15–30 minutes. The women in spontaneous labor would have otherwise met the criteria for induction of labor (but were in spontaneous labor) and had at least 6 hours of FHR and uterine activity graphing. Eighty-six percent of neonates had cord blood sampling for arterial pH and base excess.

The FHR and uterine activity graphs were analyzed independently and individually by three maternal-fetal medicine physicians. These analyses were not done at the time of the original studies; the fetal heart rate strips were recovered and analyzed for the current study. Tachysystole was defined as a contraction frequency of more than five within 10 minutes for two consecutive 10-minute periods.^5,9 Hyperstimulation was defined as exaggerated uterine response with late FHR decelerations or fetal tachycardia greater than 160 beats per minute or other worrisome FHR changes.^5,9 Tachysystole or hyperstimulation was judged to occur if at least two of three graph reviewers agreed with the diagnosis. For women who received the crushed forms of misoprostol, placebo use and allocation concealment was done to mask the reviewers to group assignment until data analysis was completed. For the other cohorts, although the reviewers were not formally blinded, they did not actively seek to reveal the cohort (by reading the woman’s chart) until analysis of graphs was completed. No attempt was made to delete comments of caregivers written on tracings.

The timing of the excessive uterine activity was determined relative to misoprostol dosing. If tachysystole or hyperstimulation recurred after subsequent doses of misoprostol, the timing of each episode was determined. To minimize confounding, women who had tachysystole or hyperstimulation only after oxytocin augmentation was initiated or during the second stage of labor with pushing were not included in the data on timing of excessive uterine activity.

This study was carried out on the convenience sample of previously completed randomized controlled trials. The sample size required was based on the estimated incidence of tachysystole in the misoprostol and oxytocin cohorts. For a two-tailed = .05 and ß= .20, 51 women in each group were required to detect a significant difference between 35% incidence in one cohort and 10% incidence in another cohort. A power analysis for tachysystole of vaginal misoprostol versus spontaneous labor was determined, using a two-tailed = .05, for a power of 95%. A power analysis for hyperstimulation, using a two-tailed = .05, found a power of 92% comparing dinoprostone with spontaneous labor. Data were analyzed using Statistix 4.1 (Analytical Software, Tallahassee, FL). Categoric variables were analyzed by ² and Fisher exact test where appropriate. Continuous variables not normally distributed were analyzed using Kruskal-Wallis test. Statistical significance was set at P < .05. Because of multiple testing all comparisons other than the primary outcome of tachysystole were considered only as hypothesis generation. Kappa statistic was used to determine interobserver variation for tachysystole and hyperstimulation.

	Results

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Five hundred nineteen women who had labor induced and 86 women admitted in spontaneous labor were included in the study. The demographic characteristics of these women have been described previously (except for the spontaneous labor cohort).^13–15 Table 1 summarizes the incidence of excessive uterine activity, including tachysystole and hyperstimulation, in each group. Tachysystole occurred more frequently with the misoprostol vaginal tablet than other forms or routes of induction or spontaneous labor. In addition, tachysystole occurred more frequently when misoprostol was given vaginally (tablet or gel) compared with orally (tablet or crushed) (P < .001).

The time from induction to tachysystole was no different for the different forms and routes of misoprostol (Table 2). In addition, if tachysystole occurred after the first dose, before further dosing, its timing was similar among the groups (Table 2). The time from the last dose of misoprostol to tachysystole was shorter with the vaginal misoprostol tablet compared with crushed misoprostol. This result might be due to the shorter time to tachysystole with subsequent doses of the vaginal tablet (Table 3). That result was not found with crushed misoprostol tablet (Table 4). A trend to shorter time to tachysystole with oral misoprostol in the crushed and intact forms was noted but did not reach statistical significance unless both groups were combined (ie, all oral misoprostol) (Table 4).

	Discussion

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The incidence of tachysystole with misoprostol, although high, is in keeping with results of earlier studies.^1,2 By using a strict definition and several physicians reviewing the tracings we were able to better estimate its true incidence. We found a higher rate of tachysystole when misoprostol was given as an intact tablet vaginally compared with gel form or oral administration. Hyperstimulation occurred more frequently with vaginal administration compared with the crushed form given orally. This finding might be explained by the pharmacokinetics of misoprostol. Zeiman et al⁶ found that the systemic bioavailability of vaginally administered misoprostol (tablet form) was three times higher than that of the orally administered tablet. With vaginal administration, peak plasma levels were reached more slowly but were sustained more than 4 hours. These findings were confirmed by Danielsson et al,⁷ who found that after vaginal administration, but not after oral administration, uterine activity increased continuously for 4 hours. This increase might lead to a cumulative effect with subsequent dosing. Persistent increased uterine activity and possible cumulative effect might explain the increased incidence of excessive uterine activity with vaginally administered misoprostol tablets. Approximately two-thirds of the episodes of tachysystole with vaginal tablets occurred on subsequent dosing, whereas in the other misoprostol and dinoprostone cohorts, tachysystole occurred primarily after the first dose. It might also explain the shorter time to onset of tachysystole with subsequent doses of vaginal misoprostol tablet, as bioavailable misoprostol is still present 4 hours after dosing, when the next dose would usually be given. Some authors described excessive uterine activity shortly after subsequent misoprostol doses, when mild, irregular but frequent tightenings were occurring before the last dose was given.^10,17 In such women it is important to recognize that with such irregular but frequent uterine activity, additional misoprostol could lead to abnormal excessive uterine activity. Unlike our study, Alfirevic et al² found no significant difference in uterine hyperstimulation between oral and vaginal misoprostol. However, that meta-analysis was last updated in November 1998 and only included two trials in which oral misoprostol was given in doses of 100 µg and 200 µg. Our studies used a lower dose of 50 µg, which might explain the lower rate of excessive uterine activity in the present study.

The pharmacokinetics of misoprostol suspended in gel and given vaginally has not been evaluated directly. Carlan et al¹⁸ noted that intravaginal misoprostol gel resulted in fewer uterine contraction abnormalities than the tablet form of the drug, but also resulted in longer times to labor and delivery. We found less tachysystole with the vaginal gel form compared with the vaginal tablet, confirming their study. In addition, the time to tachysystole with the vaginal gel was not significantly different after subsequent doses compared with the first dose. Therefore, we postulate that the bioavailability of misoprostol given vaginally might be different depending on the form used. The gel might result in less total or prolonged bioavailability and less of a cumulative effect, leading to a lower frequency of excessive uterine activity. As a result, the timing of excessive activity is different between the two forms, with the tablet leading to a quicker onset of excessive uterine activity with subsequent doses.

In our study the cohort given crushed misoprostol orally had the lowest incidence of tachysystole and hyperstimulation. Perhaps this group had the least prolonged bioavailability or cumulative effect. A meta-analysis of oral misoprostol for induction of labor² found a higher hyperstimulation rate than ours, but it was based on studies that used higher doses of misoprostol (100 µg and 200 µg).^19,20

We found a higher rate of hyperstimulation with dinoprostone intracervical or intravaginal gel than with other forms of induction. This is an interesting finding because these substances are approved methods of cervical ripening and labor induction and because of concern about misoprostol causing excessive uterine activity. The use of a standard definition for tachysystole offers an obvious improvement in reporting such events but is nonetheless arbitrary, with no research to support it based on fetal or neonatal outcomes. Furthermore, tachysystole as defined can occur with spontaneous labor.

The shortcomings of our study should be addressed. First, all cohorts were not part of a single randomized controlled trial but comprised three randomized controlled trials plus a spontaneous labor cohort. These three studies had similar inclusion and exclusion criteria with the exception of membrane status. One study included only women with spontaneous rupture of membranes,¹⁵ whereas the other two studies included women with intact membranes only.^13,14 Second, in only one trial were the reviewers formally blinded to group assignment. However, the reviewers did not actively seek to reveal the cohort until analysis of graphs was completed. Finally, it should be recognized that with the small sample sizes in these groups we did not have adequate power to examine rarer outcomes, including hyperstimulation. Despite this, significant differences in this outcome were seen between dinoprostone and other forms of induction, and between vaginal and oral misoprostol.

By understanding the timing of excessive uterine activity, obstetricians can monitor and potentially anticipate the onset of excessive uterine activity, thereby allowing appropriate and timely intervention. Researchers also can use such information to design further trials to develop the safest effective dose, form, and route of misoprostol. Potential areas of interest for misoprostol use for labor induction include oral administration and a crushed or gel form, in addition to lowering the dose and increasing the interval between administrations. Hyperstimulation occurs much less frequently than tachysystole. When hyperstimulation occurs one should be concerned about fetal well being. Hyperstimulation occured more frequently with dinoprostone intracervical or intravaginal gel than various forms and routes of misoprostol. Although this study and previous meta-analyses^1–4 have not found an increase in serious perinatal morbidity or mortality with vaginal or oral misoprostol use, the sample size was not sufficiently large enough to exclude the possibility of uncommon serious adverse effects. Therefore, any form, route, or dosing of misoprostol that can minimize excessive uterine activity is important to consider.

	Footnotes

 
PII S0029-7844(01)01332-1

Received October 30, 2000. Received in revised form December 18, 2000. Accepted January 31, 2001.

	References

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1. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol administered vaginally for cervical ripening and labour induction in late pregnancy (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software, 2000.

2. Alfirevic Z, Howarth G, Gausmann A. Oral misoprostol for induction of labour with a viable fetus (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software, 2000.

3. Young D, Bennett K, Butt K, Mundle W, Windrim R. Induction of labor with misoprostol: A review. J Soc Obstet Gynaecol (Canada)1996;18:1153–7.

4. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: A meta-analysis. Obstet Gynecol 1997;89:633–42.[Abstract]

5. Curtis P, Evans S, Resnick J. Uterine hyperstimulation: The need for standard terminology. J Reprod Med 1987;32:91–5.[Medline]

6. Zeiman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92.[Abstract]

7. Danielsson KG, 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.[Abstract/Free Full Text]

8. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostaglandin E₂ gel for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1804–10.[Medline]

9. Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: An effective agent for cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1811–6.[Medline]

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15. Butt KD, Bennett KA, Crane JMG, Hutchens D, Young DC. Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture. Obstet Gynecol 1999;94:994–9.[Abstract/Free Full Text]

16. American College of Obstetricians and Gynecologists. Fetal distress and birth asphyxia. ACOG committee opinion no. 137. Washington, DC: American College of Obstetricians and Gynecologists, 1994.

17. Varaklis K, Gumina R, Stubblefield PG. Randomized controlled trial of vaginal misoprostol and intracervical prostaglandin E₂ gel for induction of labor at term. Obstet Gynecol 1995;86:541–4.[Abstract]

18. Carlan SJ, Bouldin S, O’Brian WF. Extemporaneous preparation of misoprostol gel for cervical ripening: A randomized trial. Obstet Gynecol 1997;90:911–5.[Abstract]

19. Toppazada MK, Anwar MYM, Hassan HA, El-Gazaerly WS. Oral or vaginal misoprostol for induction of labour. Int J Gynaecol Obstet 1997;56:135–9.[Medline]

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