| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
kan, MDFrom the SSK Maternity and Women’s Health Teaching Hospital, Ankara, Turkey.
Address reprint requests to: Eray Çalikan, Ballibaba sok. No: 86/3, 06660 Küükesat, Ankara, Turkey; E-mail: eray68{at}hotmail.com.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: In a controlled trial, 1574 women were randomized into four groups, as follows: Group 1 received intravenous infusion of oxytocin 10 IU plus oral misoprostol 400 µg, followed by two doses of oral misoprostol 100 µg 4 hours apart; group 2 received oral misoprostol 400 µg, followed by two doses of oral misoprostol 100 µg 4 hours apart; group 3 received intravenous infusion of oxytocin 10 IU; and group 4 received intravenous infusion of oxytocin 10 IU plus intramuscular administration of methylergonovine maleate (Methergine) 0.2 mg. The incidence of postpartum hemorrhage and decrease in hemoglobin concentration from before delivery to 24 hours postpartum were the main outcome measures.
RESULTS: The primary outcome measures were similar in groups 2 and 3. The incidence of postpartum hemorrhage was 9% in group 2, compared with 3.2% in group 1 and 3.5% in group 4 (P < .01, and P = .01, respectively). There were no significant differences among the four groups regarding hemoglobin concentrations. Significantly more women needed additional oxytocin in group 2, when compared with group 4 (5.9% versus 2.2%; P = .01). The proportion of women requiring additional methylergonovine maleate was 4.8% in group 2, compared with 0.7% in group 1 and 1% in group 4 (P < .01 and P = .01, respectively).
CONCLUSION: Oral misoprostol alone is as effective as oxytocin alone for the prevention of postpartum hemorrhage; it is less effective than oxytocin plus methylergonovine maleate and oral misoprostol plus oxytocin.
Although the incidence of hemorrhage-related maternal deaths has dramatically declined in industrialized countries during the 20th century, postpartum hemorrhage still remains as the leading cause of maternal deaths in the developing world.1
Evidence from several controlled trials suggests that the prophylactic use of oxytocics in the third stage of labor has been beneficial in reducing blood loss and the incidence of severe postpartum hemorrhage.2 There are potential problems with the parenteral use of oxytocin and methylergonovine maleate (Methergine), such as the need of protection from light, requirement of refrigeration, and the need of clean needles and syringes (an important consideration in the era of hepatitis and human immunodeficiency virus infection).3 On the other hand, methylergonovine maleate is ineffective in reducing postpartum hemorrhage when administered orally.4
Oral misoprostol, a prostaglandin E1 analogue, is a stable and inexpensive drug with a simple method of administration. Based on their clinical observations, El-Refaey et al5 have been the first to suggest oral misoprostol as an alternative to conventional standard oxytocic drugs for the prevention of atonic postpartum hemorrhage in low-risk women.
The purpose of this randomized trial was to evaluate whether oral misoprostol is more effective alone or in combination with oxytocin at reducing the length of the third stage of labor, postpartum hemorrhage, and need for postpartum blood transfusion when compared with conventional oxytocics.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Women in labor were eligible to take part in the study. Written, informed consent was obtained from the patients on admission to the labor ward. Exclusion criteria included cesarean delivery, gestational age less than 32 weeks, and known hypersensitivity to prostaglandins.
The secretary of the labor ward carried out the randomization just after obtaining consent. A computerbased, random allocation was generated without any blocking or stratification. The list of medication to be applied in the third stage was printed out and put in sealed, consecutively numbered opaque envelopes. Immediately after cord clamping, the women received one of the following four treatments: 1) intramuscular administration of 1 mL saline (placebo), intravenous infusion of oxytocin 10 IU in 500 mL saline over 30 minutes, and two tablets of oral misoprostol (400 µg) (Cytotec, Ali Raif Co., Turkey), followed by two doses of misoprostol 100 µg (half tablets) orally at 4 and 8 hours postpartum (misoprostol–oxytocin group); 2) intramuscular administration of 1 mL saline (placebo), intravenous infusion of 500 mL saline over 30 minutes (placebo), and two tablets of oral misoprostol (400 µg), followed by two doses of misoprostol 100 µg (half tablets) orally at 4 and 8 hours postpartum (misoprostol group); 3) intramuscular administration of 1 mL saline (placebo), intravenous infusion of oxytocin 10 IU in 500 mL saline over 30 minutes, and two orally administered tablets of placebo (Placebo, Plantafarma Co., Turkey), followed by two doses of placebo (half tablets) orally at 4 and 8 hours postpartum (oxytocin group); and 4) intramuscular administration of 1 mL (0.2 mg) methylergonovine maleate (Methergine, Uterjin; Biofarma Co., Turkey), intravenous infusion of oxytocin 10 IU in 500 mL saline over 30 minutes, and two tablets of oral placebo, followed by two doses of placebo (half tablets) orally at 4 and 8 hours postpartum (oxytocin–methylergonovine maleate group).
The placebo tablets were similar in size and color but were not identical in shape to the misoprostol tablets. To minimize this limitation, the preparation and administration of the medication were carried out by a midwife who had not been involved in the management of the patient except for drug administration. The identity of medication was concealed from the resident physicians who managed the delivery and the third stage of labor. The caregivers and residents who followed up on the patient for the next 24 hours were also blind as to which patients received placebo and which received active medication. The randomization code was not broken until the completion of the study.
If an oxytocin infusion was used during labor, it was stopped at the end of the second stage. The management of the third stage of labor included active management. In all cases, early cord clamping was performed, the uterus was gently massaged, and the placenta was extracted by controlled cord traction. If the placenta was not delivered within 30 minutes of delivery, it was removed manually. Irrespective of the allocation of the medication, intravenous infusion of 20 IU oxytocin in 1000 mL saline over 1 hour was given if the uterus was not well contracted or if there was excessive vaginal bleeding as assessed by the resident physician attending the delivery. If bleeding continued despite oxytocin infusion or if an atonic uterus was palpated, an additional dose of intramuscular methylergonovine maleate 0.2 mg was given. Blood transfusions were performed to women whenever the hemoglobin concentrations were found to be less than 7.5 g/dL in the postpartum period.
The data collection was completed by the resident physician in charge of labor. This form contained information on maternal characteristics, such as age, parity, body mass index, gestational age at delivery, and obstetric history. Variables were recorded concerning labor, which consisted of induction and augmentation. No epidural analgesia was performed throughout the study period. Variables concerning delivery included mode of delivery, episiotomy, perineal tear, and birth weight. All episiotomies were performed mediolaterally throughout the study period. Frequency of postpartum blood transfusion, need for additional oxytocic drugs, length of the third stage of labor, manual removal of placenta, and subsequent evacuation of the uterus were also recorded. All patients were evaluated by a resident physician until 24 hours after delivery, and specific side effects associated with oral misoprostol were sought. The assessed side effects included nausea, vomiting, diarrhea, hot flushes, headache, fatigue, dizziness, shivering, and fever (temperature greater than 38C within 12 hours of delivery).
Starting immediately after delivery, resident physicians measured the volume of blood loss. The blood was collected into a sterile steel bedpan after birth with the help of plastic bed linen. All gauze and pads were collected 1 hour after the delivery of the placenta and weighed. The difference in after- and before-weight was calculated. A 100-g increase in weight was considered to be equivalent to 100 mL blood (ie, specific gravity is 1 g/mL).3
A blood sample was obtained before delivery for determination of hemoglobin concentration. A second blood sample for hemoglobin concentration was obtained 24 hours postpartum. Postpartum hemorrhage was defined as measured blood loss of 500 mL or more, whereas severe postpartum hemorrhage was defined as measured blood loss of 1000 mL or more.
The incidence of postpartum hemorrhage and the decrease in hemoglobin concentrations were the main outcomes of the trial. Secondary outcomes included the incidence of severe postpartum hemorrhage, mean blood loss, need for additional oxytocic drugs, incidence of postpartum blood transfusion, length of the third stage of labor, and specific side effects.
A power calculation was performed before the study. In a pilot survey at our institution, the incidence of postpartum hemorrhage was found to be 10% when intravenous infusion of oxytocin 10 IU was used routinely. We considered that a 3% change in the incidence of postpartum hemorrhage would be clinically important. Therefore, the sample size in this study was based on 384 subjects in each study group, to detect a 3% difference in the incidence of postpartum hemorrhage with 90% power at 
= 0.05.
The cesarean delivery rate at our institution was 21% in the preceding year; and women with previous cesarean deliveries accounted for 30% of all cesarean deliveries performed. Within the framework of this background, the probability of a patient undergoing cesarean delivery after randomization was calculated to be 14%. Therefore, 1800 patients were randomized into the four groups to obtain a sample size of approximately 400 women per group.
The statistical analysis of the data was performed using the Statistical Package for Social Sciences for Windows (SPSS Inc., Chicago, IL). Results were reported as mean ± standard deviation and percentages. Differences between the groups were assessed using 
2 test or Fisher exact test for categoric data whenever appropriate. Analysis of variance and Tukey tests were used to detect the differences of continuous variables between the groups, and P < .05 was considered statistically significant. A Bonferroni correction was performed for multiple pairwise comparisons of proportions, and P < .01 was considered statistically significant for this purpose. Because neither substantial discontinuations nor crossovers between treatments were identified, an intent-to-treat analysis was not performed in our study.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Those 206 study envelopes were replaced without breaking the randomization seal, and 1574 women concluded the study (misoprostol–oxytocin group, n = 404; misoprostol group, n = 388; oxytocin group, n = 384; and oxytocin–methylergonovine maleate group, n = 398).
|
). Table 2 compares the four groups in the first and second stages of labor. The four groups were comparable as to intrapartum data.
|
|
describes the effect of the trial treatments on the third stage of labor. The misoprostol group and the oxytocin group were similar as to the incidence of postpartum hemorrhage. The misoprostol–oxytocin group and the oxytocin–methylergonovine maleate group were similar as to the incidence of postpartum hemorrhage. The incidence of postpartum hemorrhage was significantly higher in the misoprostol group compared with the misoprostol–oxytocin group and the oxytocin–methylergonovine maleate group. The incidence of postpartum hemorrhage was found to be significantly higher in the oxytocin group when compared with the misoprostol–oxytocin group. The incidence of severe postpartum hemorrhage was not significantly higher in the misoprostol group when compared with the misoprostol–oxytocin group and the oxytocin–methylergonovine maleate group.
|
Significantly more women needed additional oxytocin in the misoprostol group when compared with the oxytocin–methylergonovine maleate group. The need for additional oxytocin was higher in the misoprostol group when compared with the misoprostol–oxytocin group, but it did not reach statistical significance. The proportion of women requiring additional oxytocin was significantly higher in the oxytocin group when compared with the misoprostol–oxytocin group.
The proportion of women requiring additional methylergonovine maleate was significantly higher in the misoprostol group compared with the misoprostol–oxytocin group and the oxytocin–methylergonovine maleate group. Significantly more women needed additional methylergonovine maleate in the oxytocin group when compared with the misoprostol–oxytocin group.
Although the proportion of women requiring postpartum blood transfusion was greater in the misoprostol group when compared with the misoprostol–oxytocin group and the oxytocin–methylergonovine maleate group, this difference was not statistically significant. The misoprostol–oxytocin group and the oxytocin group were not significantly different in terms of blood transfusion either.
No significant differences were detected among the four groups regarding decrease in hemoglobin concentrations (Table 3
). The length of the third stage of labor was significantly greater in the misoprostol group when compared with the oxytocin group and the oxytocin–methylergonovine maleate group.
The relative risk estimates of main and secondary outcome variables of treatment groups as compared with the oxytocin group are presented in Table 4. The misoprostol–oxytocin group had a 60% reduction in postpartum hemorrhage, a 70% reduction in severe postpartum hemorrhage, a 70% reduction in additional oxytocin need, and an 80% reduction in additional methylergonovine maleate need, whereas a 70% reduction in the risk of blood transfusion was still within the limits of chance. On the other hand, the misoprostol group was found to have similar risks of postpartum hemorrhage, severe postpartum hemorrhage, additional oxytocin and methylergonovine maleate need, and blood transfusion when compared with the oxytocin group.
|
). There were significantly more women experiencing shivering in the misoprostol group when compared with the oxytocin group and the oxytocin–methylergonovine maleate group. The proportion of women with fever was similar in the four groups.
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Oral misoprostol was reported to be effective in the management of the third stage of labor in several randomized, clinical trials.3,6–8 All of these previous reports except one3 used extensive exclusion criteria that resulted in a low-risk population. To observe the effectiveness of oral misoprostol in a larger, unselected population, limited exclusion criteria were stated in the current study.
Absorption of misoprostol is extremely rapid, detected in the circulation within 2 minutes of its oral ingestion.9 When orally administered, the plasma concentration of misoprostol rises quickly, peaks between 12.5 and 60 minutes after administration, falls steeply by 120 minutes, and remains low thereafter.10 The rationale for continuing misoprostol at 4 and 8 hours after delivery was to secure a stable plasma concentration of misoprostol, resulting in a sustained contraction of the uterus and subsequent reduction of blood loss in the hours after delivery, for preventing delayed hemorrhage. Although the effect of oral misoprostol on the postpartum uterus has been shown to be rapid,11 oral misoprostol 400 µg was reported to be significantly less effective than the traditional uterotonic agents in a recent study.12 Because postpartum hemorrhage related to uterine atony typically occurs in the immediate postpartum convalescence, delayed absorption would make misoprostol ineffective for this indication.
Amant et al8 have suggested a combination of rapid-onset parenteral and slow-onset oral uterotonic drugs to be a new, future direction in the prevention of postpartum hemorrhage. Our results provide a scientific basis for this suggestion. Combining oxytocin and misoprostol not only decreases the incidence of postpartum hemorrhage, but also decreases the length of the third stage and additional need of oxytocics, compared with the use of either drug alone. This finding is not surprising, because absorption of misoprostol probably occurs only in the stomach.9 The addition of oxytocin compensates during the critical period for orally administered misoprostol to reach therapeutic plasma concentration in the third stage of labor.
Visual estimation of blood loss during the postpartum period has been shown to underestimate true blood loss by about half,13 with the error increasing as the volume lost increases.14 However, as a method of managing the third stage of labor, clinical estimation of blood loss has been found to be an acceptable method in several previous randomized trials.3,6–8 Change in laboratory criteria, such as hematocrit or hemoglobin concentration, is a more objective measure than estimated blood loss. The objective laboratory measurement can be considered as a proxy for the clinical outcome of excessive blood loss.6 The American College of Obstetricians and Gynecologists suggests that the definition of postpartum hemorrhage may be based on change in laboratory findings in the postpartum period.15
However, no differences were found among the four groups in terms of the decrease in hemoglobin concentrations at 24 hours after delivery. The early active management of excessive bleeding with additional oxytocics and blood transfusions might have reduced the potential of the study to detect differences between the groups in regard to drop in hemoglobin concentrations. Although this suggestion seems to be very tenuous, it should be emphasized that no significant differences were detected among the four groups in regard to the mean predelivery hemoglobin concentration and frequency of antepartum blood transfusion. On the other hand, there was a trend toward an increased incidence of postpartum blood transfusion in the misoprostol group when compared with the oxytocin–misoprostol and the oxytocin–methylergonovine maleate combinations. Further trials, with larger numbers of patients, are needed to search the difference in the frequency of blood transfusion.
Shivering is a well-known side effect of oral misoprostol when it is used in the management of third stage of labor.3,6–8 Although shivering is also known to be a side effect of epidural analgesia,16 it should be emphasized that no epidural analgesia was performed throughout the study period. No women receiving misoprostol reported shivering as a serious side effect that could reduce the acceptability of the drug.
Fever is another side effect of oral misoprostol in the third stage of labor.6,8 The reported incidences of fever ranged between 22% and 34% in previous studies.6,8 However, the incidence of fever remained low in our study (3.9% in the misoprostol–oxytocin group and 4.3% in the misoprostol group). Misoprostol-induced fever is of interest in terms of possible prostaglandin-related mechanisms and their relevance to thermoregulatory physiology. Shivering and fever were well-tolerated side effects in the current study and seemed to be dose-related, consistent with the original findings of El-Refaey et al.17
The effects of oral misoprostol on the third stage of labor were studied in a large, unselected population in the current study. Within the framework of this background, we believe that our findings can be generalized to other populations. However, effectiveness of oral misoprostol for the third stage of labor in pregnant women with epidural anesthesia still remains an open question.
|
Footnotes |
|---|
Received November 19, 2001. Received in revised form June 14, 2002. Accepted July 11, 2002.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Prendiville W, Elbourne D, Chalmers I. The effects of routine oxytocic administration in the management of the third stage of labour: An overview of the evidence from controlled trials. Br J Obstet Gynaecol 1988;95:3–16.[Medline]
3. El-Refaey H, Nooh R, O’Brien P, Abdalla M, Geary M, Walder J, et al. The misoprostol third stage of labour study: A randomised controlled comparison between orally administered misoprostol and standard management. Br J Obstet Gynaecol 2000;107:1104–10.
4. de Groot A, van Roosmalen J, van Bongen PW, Bormen GF. A placebo-controlled trial of oral ergometrine to reduce postpartum hemorrhage. Acta Obstet Gynecol Scand 1996;75:464–8.[Medline]
5. El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for third stage of labour. Lancet 1996;347: 1257.
6. Walley RL, Wilson JB, Crane JMG, Mathews K, Sawyer E, Hutchens D. A double-blind placebo controlled randomised trial of misoprostol and oxytocin in the management of the third stage of labour. Br J Obstet Gynaecol 2000;107:1111–5.
7. Surbek DV, Fehr PM, Hosli I, Holzgreve W. Oral misoprostol for the third stage of labor: A randomized placebo-controlled trial. Obstet Gynecol 1999;94:255–8.
8. Amant F, Spitz B, Timmerman D, Corremans A, van Assche FA. Misoprostol compared with methylergometrine for the prevention of postpartum hemorrhage: A double-blind randomised trial. Br J Obstet Gynaecol 1999;106:1066–70.[Medline]
9. Karim A. Antiulcer prostaglandin misoprostol: Single and multiple dose pharmacokinetic profile. Prostaglandins 1987;33 Suppl:40–50.
10. Zieman 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]
11. Choo WL, Chua S, Chong YS, Vanaja K, Oei PL, Ho LM, et al. Correlation of change in uterine activity to blood loss in the third stage of labour. Gynecol Obstet Invest 1998; 46:178–80.[Medline]
12. Cook CM, Spurrett B, Murrey H. A randomised clinical trial comparing oral misoprostol with synthetic oxytocinor syntometrine in the third stage of labour. Aust N Z J Obstet Gynaecol 1999;39:414–9.[Medline]
13. Pritchard JA, Baldwin RM, Dickey JC, Wiggings KM. Blood volume changes in pregnancy and the puerperium. Am J Obstet Gynecol 1962;84:1271–82.
14. Bloomfield TH, Gordon H. Reaction to blood loss at delivery. J Obstet Gynaecol 1990;10:S13–6.
15. American College of Obstetricians and Gynecologists. Postpartum hemorrhage. ACOG educational bulletin no. 243. Washington: American College of Obstetricians and Gynecologists, 1998.
16. Jaameri KE, Jaukola A, Pertu J. On shivering in association with normal delivery. Acta Obstet Gynecol Scand 1996; 45:383–8.
17. El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Use of oral misoprostol in the prevention of postpartum hemorrhage. Br J Obstet Gynaecol 1997;104:336–9.[Medline]
This article has been cited by other articles:
|
|
 |
|
  A. Bhullar, S. J. Carlan, J. Hamm, N. Lamberty, L. White, and K. Richichi Buccal Misoprostol to Decrease Blood Loss After Vaginal Delivery: A Randomized Trial Obstet. Gynecol., December 1, 2004; 104(6): 1282 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Oral Misoprostol Effective in Preventing Postpartum Hemorrhage Journal Watch Women's Health, June 17, 2003; 2003(617): 4 - 4. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
