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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Obstetrics and Gynecology, Department of Nursing, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Address reprint requests to: Boonsri Chanrachakul, MD Department of Obstetrics and Gynecology Ramathibodi Hospital Mahidol University Rama VI Road Bangkok, 10400 Thailand E-mail: rabcr{at}mahidol.ac.th
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Abstract |
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Methods: One hundred ten women with term pregnancies referred for induction of labor with Bishop scores of 6 or less were randomly assigned to receive a 500-µg glyceryl trinitrate tablet vaginally (n = 54) or a 3-mg PGE2 tablet vaginally (n = 56), every 6 hours for maximum of two doses. Subjects were sent to the labor ward for amniotomy or oxytocin if their Bishop scores were more than 6 or their cervices were not ripe 24 hours after treatment. Adverse effects, changes in the Bishop scores, progress, and outcomes of labor were assessed.
Results: Glyceryl trinitrate was associated with fewer episodes of uterine tachysystole (0% versus 9%; P = .02). The median Bishop score after 12 hours was lower in women given glyceryl trinitrate compared with those given PGE2. Adverse effects, including headache and palpitations, were more frequent with glyceryl trinitrate than with PGE2. The cesarean rate was not significantly different between groups.
Conclusion: Cervical ripening with glyceryl trinitrate resulted in fewer episodes of tachysystole, but there were significantly more minor side effects. It can be used for cervical ripening at term, but it was not as effective as PGE2.
Although there is no ideal predictor of successful induction of labor, cervical status is now accepted as the most useful characteristic.1,2 Different methods have been used for cervical ripening, and prostaglandins (PG) are the most favored.3 Prostaglandin E2 is approved as an effective agent, whereas misoprostol is the most interesting drug to be used recently because it is effective and inexpensive.3,4 However, they are associated with several adverse effects, such as gastrointestinal symptoms, fever, pain and high incidence of tachysystole, uterine hyperstimulation, and even uterine rupture.5,6
Animal studies have shown that nitric oxide, a free radical, is a fundamental mediator for cervical ripening.7,8 A study in pregnant guinea pigs showed that local application of nitric oxide effectively produced cervical ripening without inducing labor.9 Nitric oxide in humans caused uterine relaxation.10 Several reports described the effectiveness of nitroglycerine, a nitric oxide derivative, for easing external cephalic version, difficult vaginal or cesarean delivery, manual exploration of uterus, and for inhibiting premature contractions.11–13 Recently nitric oxide was effective for cervical ripening for first-trimester termination of pregnancy with fewer side effects than PG analogues.14 Because those agents produce uterine relaxation and ripening in first-trimester cervices, they can also be used to prepare cervices for induction of labor without causing uterine contractions, which is the common side effect of PGs.
We postulated that nitric oxide can induce cervical ripening with fewer adverse effects than PGE2. This study compared adverse effects of glyceryl trinitrate with PGE2 for cervical ripening at term.
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Materials and Methods |
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Each subject had a vaginal examination by one of us (BC or YH) in the antenatal ward to assess Bishop score and to reduce individual variation. The first group was given nitric oxide donor glyceryl trinitrate (500 µg) one tablet (Angised, The Wellcome Foundation Ltd, Greenford, United Kingdom) in the posterior vaginal fornix, the second group was given PGE2 (3 mg) one tablet (Dinoprostone, Pharmacia & Upjohn, West Sussex, United Kingdom) in the posterior vaginal fornix. Subjects were examined regularly at 3, 6, 12, and 24 hours after taking the medication by obstetricians who did not know which medication was given. Vital signs, symptoms, and fetal heart rate (FHR) were monitored for 1 hour, then routinely checked every 4 hours. Women were asked to report to the nurses when they had uterine contraction pain or abnormal symptoms such as palpitation, dizziness, fainting, and gastrointestinal symptoms. Continuous FHR monitoring was done if abnormalities were detected. The second dose of medication was given by one of us (BC or YH) if Bishop score was less than or equal to 6 at 6 hours, otherwise they were sent to the labor ward for induction. Twenty-four hours after the first medication, the remaining women were sent to the labor ward. Amniotomy was done and oxytocin given if adequate uterine contractions were not achieved after 2 hours. If amniotomy was not feasible, oxytocin was given and followed by amniotomy. Women were treated in the labor ward by the staff according to protocol.
Maternal demographics, labor and delivery characteristics, and neonatal outcomes were examined. Active phase of labor was defined as progressive cervical dilation beyond 3 cm with 100% effacement. Failed induction was defined as inability to achieve active phase of labor despite an adequate oxytocin stimulation that lasted at least 6 hours after amniotomy. Regular uterine contractions were defined as at least three in 10 minutes. Uterine tachysystole was defined as six or more uterine contractions in 10 minutes without FHR abnormalities. Uterine hyperstimulation was defined as six or more uterine contractions in 10 minutes with FHR abnormalities. Favorable cervix was defined as Bishop score of more than 6. Cesarean delivery was done for obstetric indications, including arrest of dilation, arrest of descent, and persistent nonreassuring FHR pattern after resuscitation. Maternal outcome measures included need for cesarean, uterine tachysystole, and postpartum complications. Neonatal outcome measures were birth weight, Apgar scores at 1 and 5 minutes, and neonatal morbidity and mortality. We recorded Bishop scores before and after cervical priming, time from first medication to vaginal delivery, time from start of medication to first contraction pain, and time from amniotomy or oxytocin infusion to active phase of labor.
According to our pilot study that compared PGE2 with glyceryl trinitrate, the difference in incidence of tachysystole was 10% (10%:0%). Thus, 54 women were needed in each group for a power of 80% at a type I error rate of 0.1. Statistical analysis was calculated with the SPSS program for Windows version 7.5 (SPSS Inc., Chicago, IL) for 
2 test, unpaired t test, and repeated measures analysis of variance. Two-tailed P < .05 was considered statistically significant.
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Results |
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. Thirty-three women (61%) in the glyceryl trinitrate group and 42 women (75%) in the PGE2 group were nulliparous (P = .1). Figure 1 shows changes in Bishop scores after treatment. Repeated measures analysis of variance did not show a significant difference in Bishop scores between groups (P = .47), but the median of Bishop scores 12 hours after medication in the PGE2 group was higher (Figure 1). Thirty-three women (59%) in the PGE2 group and 21 (39%) in the glyceryl trinitrate group went into active phase of labor or had Bishop scores of more than 6 within 24 hours of starting medication (P = .06).
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shows the course of delivery and dose of oxytocin in each group. Thirty-five women (65%) in the glyceryl trinitrate group delivered vaginally compared with 36 women (64%) in the PGE2 group.
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). Headache, dizziness, and palpitation were seen in the glyceryl trinitrate group, but only two women needed medication to relieve symptoms, and both had normal vital signs.
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. The most common indication for cesarean in both groups was poor progress in labor (12 [63%] in glyceryl trinitrate compared with 14 [70%] in PGE2).
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Discussion |
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A randomized trial by Thomson et al14 found that nitric oxide can induce cervical ripening for first-trimester termination of pregnancy with fewer side effects than PG analogues. The adverse effects of nitric oxide donor glyceryl trinitrate in our study were less than those reported by Thomson et al (68%).14 Eighty-five percent of pregnant women who were given nitric oxide did not have any complications compared with 78% in the PGE2 group which might have been caused by a different kind of nitric oxide donor (isosorbide mononitrate was used in the study by Thomson et al14) and the physiologic hemodilution of pregnancy causing lower serum concentrations of drugs given vaginally.19
Uterine tachysystole, which can cause FHR abnormalities in compromised fetuses usually associated with the use of PGs,20 occurred in 9% of women treated with PGE2 in this study, whereas none of those treated with nitric oxide donor glyceryl trinitrate had it. Uterine hyperstimulation with evidence of fetal compromise was not different between groups. The myometrial relaxant effect of nitric oxide did not cause any significant excess in postpartum hemorrhage in the nitric oxide group.
There were other adverse effects noted more frequently with glyceryl trinitrate, including headache and palpitation, but there was no significant change in maternal blood pressure, pulse rate, or FHR. Only two women needed medication, and their symptoms were relieved with paracetamol and phenergan. This study also found no differences in fetal outcomes between groups, but we did not have adequate power to evaluate that outcome.
Glyceryl trinitrate was effective for ripening cervices, but changes in Bishop scores were less than those for PGE2 after 12 hours (Figure 1
). That was because the main effect of nitric oxide is rearrangement of collagen and the ground substance, thus softening the cervix without causing uterine contractions.21,22 Consequently, glyceryl trinitrate is less effective than PGE2 for induction of labor because there is a longer latent phase and longer induction-to-vaginal-delivery time (Table 2). The need for oxytocin was also greater than in the PGE2 group (Table 2). However, rates of failed induction and the cesarean rates were not different.
A high cesarean rate was noted in this study but it was not significantly different between groups. This study was not designed to nor did it have the power to compare cesarean rates. Although the obstetricians responsible for intrapartum care were not masked to study group allocation, they treated all women according to the research and labor management protocol, including decisions regarding timing of amniotomy, oxytocin augmentation, and criteria for cesarean.
One obvious advantage of glyceryl trinitrate over PGE2 is that it is inexpensive. The retail cost per tablet of glyceryl trinitrate is 5.7 cents compared with US$21.40 for PGE2.
Twenty-two percent of women in the glyceryl trinitrate group went into labor without oxytocin. Perhaps that was because nitric oxide induces production of cyclooxygenase, the precursor of PGs, but it might not be enough to cause effective uterine contractions in most women.23
Our results showed that glyceryl trinitrate caused less tachysystole, but was less effective than PGE2 for cervical ripening at term, which might have been because the dose was too low. Increasing the dose to effective levels might cause more adverse effects. Further randomized trials are needed to determine the optimal dose, interval, and effectiveness of glyceryl trinitrate for ripening of cervices at term.
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Footnotes |
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Received February 16, 2000. Received in revised form May 19, 2000. Accepted June 15, 2000.
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References |
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2. Watson WJ, Stevens D, Welter S, Day D. Factors predicting successful labor induction. Obstet Gynecol 1996;88:990–2.[Abstract]
3. Kierse MJNC. Prostaglandins in preinduction cervical ripening: Meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89–100.[Medline]
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5. Maymon R, Shulman A, Pomeranz M, Holtzinger M, Haimovich L, Bahary C. Uterine rupture at term pregnancy with the use of intracervical prostaglandin E2 gel for induction of labor. Am J Obstet Gynecol 1991;165:368–70.[Medline]
6. Herabutya Y, O-Prasertsawat P, Pokpirom J. A comparison of intravaginal misoprostol and intracervical prostaglandin E2 gel for ripening of unfavourable cervix and labor induction. J Obstet Gynaecol Res 1997;23:369–74.[Medline]
7. Buhimachi I, Ali M, Jain V, Chwalisz K, Garfield R. Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labor. Hum Reprod 1996;11:1755–66.
8. Ali M, Yallampalli C, Chwalisz K, Garfield R. Changes in mRNA level of nitric oxide syntheses in rat uterus and cervix during pregnancy. J Soc Gynaecol Invest 1995;2:256.
9. Chwalisz K, Shao-Qing S, Garfield RE, Bier HM. Cervical ripening in guineapigs after a local application of nitric oxide. Hum Reprod 1997;12:2093–101.
10. Lees C, Campbell S, Jauniaux E, Brown R, Ramsay B, Gibb D, et al. Arrest of preterm labor and prolongation of gestation with glyceryl trinitrate, a nitric oxide. Lancet 1994;343:1325–6.[Medline]
11. Redick LF, Livingston E, Bell E. Sublingual aerosol nitroglycerine for uterine relaxation in attempted external version. Am J Obstet Gynecol 1997;176:496–7.[Medline]
12. David M, Halle H, Lichtenegger W, Sinha P, Zimmermann T. Nitroglycerine to facilitate fetal extraction during caesarean delivery. Obstet Gynecol 1998;91:119–24.[Abstract]
13. Lowenwirt IP, Zauk RM, Handwerker SM. Safety of intravenous glyceryl trinitrate in management of retained placenta. Aust N Z J Obstet Gynaecol 1997;37:20–4.[Medline]
14. Thomson AJ, Lunan CB, Ledingham M, Howat RCL, Cameron IT, Greer IA, et al. Randomized trial of nitric oxide versus prostaglandin for cervical ripening before first-trimester termination of pregnancy. Lancet 1998;352:1093–6.[Medline]
15. Bishop EM. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266–8.
16. Sanchez-Ramos L, Peterson DE, Delke I, Gaudier FL, Kaunitz AM. Labor induction with prostaglandin E1 misoprostol compared with dinoprostone vaginal insert: A randomized trial. Obstet Gynecol 1998;91:401–5.[Abstract]
17. 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]
18. Granstrom L, Ekman G, Ulmsten U. Myometrial activity after local application of prostaglandin E2 for cervical ripening and term labor induction. Am J Obstet Gynecol 1990;162:691–4.[Medline]
19. Bulletti C, De Ziegler D, Flamigni C, Giacomucci E, Polli V, Bolelli G, et al. Targeted drug delivery in gynecology: The first uterine pass effect. Hum Reprod 1997;12:1073–9.
20. Egarter CH, Husslein PW, Rayburn WF. Uterine hyperstimulation after low-dose prostaglandin E2 therapy: Tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990;163:794–6.[Medline]
21. Ledingham MA, Denison FC, Riley SC, Norman JE. Matrix metalloproteinases 2 and 9 and their inhibitors are produced by the human uterine cervix but their secretion is not regulated by nitric oxide donors. Hum Reprod 1999;14:2089–96.
22. Ledingham MA, Denison FC, Kelly RW, Young A, Norman JE. Nitric oxide donors stimulate prostaglandin F (2 alpha) and inhibit thromboxane B(2) production in the human cervix during the first trimester of pregnancy. Mol Hum Reprod 1999;5:973–82.
23. Chwalisz K, Garfield RE. New molecular challenge in the induction of cervical ripening: Nitric oxide as the final metabolic mediator of cervical ripening. Hum Reprod 1998;13:245–8.
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