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ORIGINAL RESEARCH |
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Faculty of Medicine, and Division of Obstetrics and Gynaecology, Department of Nursing, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Address reprint requests to: Apichart Chittacharoen, MD, Ramathibodi Hospital, Mahidol University, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Bangkok 10400, Thailand; E-mail: raaco{at}mahidol.ac.th.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Eighty pregnant women at 16–41 weeks’ gestation with intrauterine fetal death were randomized in two groups to receive either 400 µg of misoprostol orally every 4 hours (n = 40) or 200 µg of misoprostol vaginally every 12 hours (n = 40) until the termination of pregnancy was completed. The adverse effects, progress, and outcomes of delivery were assessed.
RESULTS: The groups were similar in age, weight, height, gestational age, parity, and modified Bishop scores before intervention. The mean induction-to-delivery time in the oral group (13.95 [standard deviation (SD) = 5.63] hours) was significantly shorter than the time in the vaginal group (18.87 [SD = 10.38] hours, P = .001). The number of deliveries within 24 hours after the initial drug administration in the oral group (92.5%) was significantly higher than the number in the vaginal group (67.5%, P < .001), and all delivered within 48 hours after the initial drug administration. However, the gastrointestinal side effects in the oral group was significantly higher than in the vaginal group (P = .005).
CONCLUSION: Misoprostol (400 µg given orally every 4 hours) was more effective than misoprostol (200 µg given vaginally every 12 hours) for the termination of second and third trimester pregnancy with intrauterine fetal death, but with more gastrointestinal side effects.
Intrauterine fetal death is a common problem in obstetric practice. This condition may be complicated by psychogenic problems, infection, and consumptive coagulopathy.1,2 For the physician confronted with intrauterine fetal death, the management of this condition poses a dilemma. Although a significant number of these patients will spontaneously go into labor within several weeks, many do not. Moreover, after the diagnosis, the social pressures and emotional aspects of delivery are usually considerable, and the medical consequences of postponing delivery can be significant. Unfortunately, the drug most commonly used for the induction of labor, oxytocin, is frequently ineffective in stimulating the uterus, especially the preterm one. Within the past 2 decades, the prostaglandins (PGs) have provided an alternative method for the induction of labor in women with fetal death. Prostaglandin E2 vaginal suppositories have been reliably used for the management of intrauterine fetal death up to 28 weeks’ gestation.3,4
Misoprostol, a synthetic analogue PGE1, is principally used to prevent peptic ulcer induced by the ingestion of nonsteroidal antiinflammatory agents. Srisomboon and Pongpisuttinun5 reported on the use of 200 µg of intra-cervicovaginal misoprostol every 12 hours in the termination of fetal death. Although the result was excellent, the administration of the drug into the cervical canal requires technical skill and instrumentation. Neto et al6 used 400 µg of oral misoprostol every 4 hours for second and third trimester pregnancy termination with high therapeutic effectiveness and low side effects. Herabutya and O-Prasertsawat7 reported using 200 µg of intravaginal misoprostol every 12 hours in the management of missed abortion. Vaginal administration of misoprostol produced spontaneous expulsion of the pregnancy and reduced the need for surgical treatment.
The purpose of this study is to evaluate the effectiveness and side effects of oral versus vaginal misoprostol for the termination of second and third trimester pregnancies with intrauterine fetal death.
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MATERIALS AND METHODS |
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Intrauterine fetal death was confirmed by ultrasonography. Gestational age was calculated from the last menstrual period or from earlier ultrasonography of the viable pregnancy. Cervical assessment using modified Bishop scores8 such as cervical dilatation, effacement, and consistency (maximum score = 8) was performed by one of the authors (AC). Inclusion criteria were intrauterine fetal death, gestational age of 16 weeks or more, modified Bishop cervical scores of 4 or less, and the absence of uterine contraction. Exclusion criteria consisted of a previous classic uterine scar and maternal history of hypersensitivity to PGs. After the cervical assessment, randomization into the two treatment groups was undertaken by means of computer-generated random numbers in sealed opaque envelopes.
The first group received two tablets of 200 µg of misoprostol orally. Vital signs, uterine contractions, and side effects were monitored. The progression of labor was evaluated by cervical examination before subsequent dosage at 4-hour intervals until delivery.
The second group received one tablet of 200 µg of misoprostol inserted high in the posterior fornix and a subsequent dose of 200 µg at 12-hour intervals until delivery. Vital signs, uterine contractions, progression of labor, and side effects were also monitored.
Induction-to-delivery time was defined as the time from the initial administration of misoprostol to the complete delivery of the fetus. If the conceptive products were not completely delivered, either instrumental or manual evacuation was then carried out. Fever was defined as body temperature of 38C or more after the start of the induction. Postpartum hemorrhage was defined as blood loss in excess of 500 mL after the delivery of the conceptive products. Diarrhea was defined as more than three times a day. Acetaminophen (500–1000 mg) was given orally in case of body temperature of 38C or higher. Meperidine (50–100 mg) was given intramuscularly in case of severe labor pain. The following parameters were also recorded: maternal demographics, induction-to-delivery time, side effects of medication, and complications.
Statistical analysis was undertaken employing the 
2 test, unpaired t test, and Fisher exact test. Statistical significance was considered at P < .05.
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RESULTS |
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Forty women received 400 µg of misoprostol orally every 4 hours, and another 40 received 200 µg of misoprostol vaginally every 12 hours. There were no significant differences between the treatment groups in relation to age, weight, height, gestational age, parity, and modified Bishop scores before the intervention (Table 1
). Ranges of gestational age were 16–41 weeks in the oral group and 16–37 weeks in the vaginal group, respectively. The mean induction-to-delivery time in the oral group was significantly less than in the vaginal group (13.95 [standard deviation (SD) = 5.63] versus 18.87 [SD = 10.38] hours, P = .001). The number of deliveries within 12 hours after the initial drug administration did not significantly differ between the two groups (40% in the oral group versus 35% in the vaginal group), but the number of deliveries within 24 hours after the initial drug administration was significantly higher in the oral group (92.5% vs 67.5%, P < .001). However, all deliveries were made within 48 hours after the initial drug administration (Table 2). The results of induction-to-delivery time according to gestational age group are shown in Table 3. There were no siginificant differences in the induction-to-delivery time between the 16–22 weeks and over 28 weeks of gestational age groups using either oral or vaginal misoprostol, the mean induction-to-delivery time in the 23–28 weeks group differed significantly.
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DISCUSSION |
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), oral misoprostol was more effective in the 23–28 weeks gestational age group. In the 29 weeks or more gestational age group, the number in each group was not sufficient to be tested, but the results suggest that oral misoprostol could be significantly more effective in the oral group. This is because usually the uterus becomes more sensitive to uterotonic agents with increasing gestational age. Also based on our findings, 400 µg of oral misoprostol every 4 hours was more effective than 200 µg of vaginal misoprostol every 12 hours for the termination of second and third trimester pregnancies with intrauterine fetal death. Although the pharmacokinetics of the oral route have been well defined, the pharmacokinetics of the vaginal route have recently been studied by Zieman et al.14 In this report, the plasma concentration in the subjects receiving oral misoprostol rose quickly and peaked between 12.5 and 60 minutes, then fell steeply by 120 minutes, and remained low for the duration of the study (4 hours). In contrast, the plasma concentration of misoprostol in the subjects receiving vaginal doses rose gradually, reaching maximum levels between 60 and 120 minutes, and declined slowly to an average of 61% of the peak level at 240 minutes after administration. Assuming the clinical effect of misoprostol is related to its concentration in plasma, the more frequent oral dosing at frequent intervals achieves efficacy comparable with vaginal administration. Southern et al15 reported the use of 20 mg of vaginal PGE2 applied at 3–5-hour intervals in the management of 709 cases of fetal intrauterine death with gestational ages ranging from 12 to 44 weeks. They achieved an induction-to-delivery time of 10.7 hours. Lauersen et al3 and Kent et al4 used similarly high doses to achieve induction-to-delivery times of 8.9 and 8.7 hours, respectively. The success rate of PGE2 for all three studies was almost 100%,3,4,15 but with a high incidence of gastrointestinal side effects. Herabutya and O-Prasertsawat16 used 3 mg of intracervical PGE2 every 6 hours in the management of 74 cases of intrauterine fetal death and showed a mean induction-to-delivery time of 17.6 hours, with fewer side effects than other studies.3,4,15 All of these results compare favorably to our study’s induction-to-delivery time of 13.95 hours in the orally treated group and 18.86 hours in the vaginally treated group. Bugalho et al17 compared vaginal misoprostol with oxytocin, starting with an infusion rate of 15 mIU per minute and reaching a maximum rate of 60 mIU per minute for induction of labor in women with late fetal death. The study showed that the induction-to-delivery time in the vaginal misoprostol group was significantly less than that in the oxytocin group (14.8 versus 31.0 hours). In our study, the induction-to-delivery time in both treatment groups was less than that in the oxytocin group of Bugalho et al.17 Taking into account the cost of infusion control and PGE2, it appears that misoprostol is advantageous in the management of pregnancy with intrauterine fetal death.
Side effects occurred infrequently in both of our treatment groups, but women in the oral treatment group had significantly more diarrhea (17.5%) than those in the vaginal group. We speculate that orally administered misoprostol had systemic effects that stimulated generalized smooth muscle contraction, especially in the gastrointestinal tract. Although the efficacy of vaginally administered misoprostol may be due to a local effect, it had less side effects than the oral form.
Misoprostol offers an alternative treatment in the management of intrauterine fetal death besides waiting for spontaneous labor to occur. It is easy to use and can be stored at room temperature, unlike other PGs. In our study, 400 µg of misoprostol administered orally every 4 hours was more effective than 200 µg of misoprostol administered vaginally every 12 hours, although diarrhea was found more in the oral treatment group.
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Footnotes |
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Received February 22, 2002. Received in revised form August 12, 2002. Accepted August 22, 2002.
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REFERENCES |
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2. Jimenez JM, Prichard JA. Pathogenesis and treatment of coagulation defects resulting from fetal death. Obstet Gynecol 1968;32:449–53.
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This article has been cited by other articles:
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  K. Kleinhaus, S. Teal, A. Chittacharoen, Y. Herabutya, and P. Punyavachira A Randomized Trial of Oral and Vaginal Misoprostol to Manage Delivery in Cases of Fetal Death Obstet. Gynecol., June 1, 2003; 101(6): 1353 - 1354. [Full Text] [PDF]
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