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Oral misoprostol vs. intravenous oxytocin in reducing blood loss after emergency cesarean delivery
International Journal of Gynecology and Obstetrics (2006) 95, 2 — 7
www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after emergency cesarean delivery O. Lapaire a, M.C. Schneider b, M. Stotz b, D.V. Surbek a, W. Holzgreve a, I.M. Hoesli a,* a b
Women’s University Hospital, Basel, Switzerland University Hospital Basel, Department of Anesthesia, Basel, Switzerland
Received 20 January 2006; received in revised form 18 May 2006; accepted 24 May 2006
KEYWORDS Maternal; Morbidity; Mortality; Pregnancy; Postpartum hemorrhage; Cesarean delivery
Abstract Objective: To compare the effectiveness of oral misoprostol and intravenous oxytocin in reducing blood loss in women undergoing indicated or elective cesarean delivery (CD) under spinal anesthesia. Methods: In this prospective, double-blind pilot study, 56 parturients who received 5 IU of intravenous oxytocin after cord clamping were randomized to further receive either misoprostol orally and a placebo infusion intravenously or placebo orally and an oxytocin infusion intravenously. Results: After adjustment was made for the sonographically estimated amniotic fluid volume, there was no statistical difference in blood loss between the 2 groups (mean F S.D., 1083 F 920 mL in the oxytocin group vs. 970 F 560 mL in the misoprostol group; P = .59). Conclusion: Oxytocin followed by oral misoprostol is as effective as an oxytocin injection followed by an oxytocin infusion in reducing postoperative blood loss after CD, and the protocol may be a safe, valuable, and cost-effective alternative to oxytocin alone. Visual estimation of intraoperative blood loss undervalues the effective value of misoprostol use by 30%. D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding author. Universita ¨ts-Frauenklinik Basel Spitalstrasse 21 CH-4031 Basel, Switzerland. Tel.: +41 61 265 90 17; fax: +41 61 265 91 98. E-mail address: [email protected] (I.M. Hoesli).
Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide, and the number of maternal deaths due to PPH is estimated to exceed 100,000 each year [1]. Post-
0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2006.05.031
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after cesarean delivery partum hemorrhage is defined as a blood loss of more than 1000 mL in the first 24 h following delivery [2]. Active management of the third stage of labor, use of uterotonic agents, and early cord clamping with controlled cord traction [3] have contributed to reducing the incidence of PPH by 40% [4,5]. However, oxytocin, ergot preparations, and prostaglandins such as sulprostone, which have been traditionally used to control postpartum bleeding, are associated with adverse effects and complications when administered within a dose range likely to be effective in cases of PPH. The effectiveness of misoprostol, a prostaglandin E1 derivative, in preventing PPH after vaginal delivery has been well established [6]. A low-cost drug that can be taken orally and remains stable even when stored at elevated temperatures, misoprostol appears to be particularly suitable for use in developing countries. The present study was designed to compare the effectiveness of oral misoprostol as an uterotonic drug with that of intravenous oxytocin in patients undergoing indicated or elective or cesarean deliveries (CDs). Intraoperative and postoperative blood loss, a quantitative parameter of postpartum hemorrhage, was compared for the 2 drugs, as well as drugrelated adverse effects in women treated by the same surgical and anesthesiological team in one institution.
2. Materials and methods 2.1. Study design This prospective, double blind, placebo-controlled pilot study was approved by the Basel Women’s University Hospital institutional review board, and written informed consent was obtained from all participants. The trial was posted on the Clinical Trials Web site (available at: www.clinicaltrials. gov). A total of 56 pregnant women at low risk for PPH who underwent indicated or elective CD after the 37th week of pregnancy were included in the study whether or not labor had begun. Indications for CD were breech presentation, malposition, intrauterine growth retardation, placenta previa marginalis, twin pregnancy, previous CD, maternal disease, and failure of labor to progress. Exclusion criteria were emergency CD within 30 min of admission, fetal distress, fetal malformations, preeclampsia, or HELLP (hemolysis, elevated liver enzymes, and low platelet count), hypersensitivity to prostaglandins, coagulopathy, severe systemic
3
disorders, an American Society of Anesthesiologists physical status of 3 or greater, severe asthma, prior myomectomy, and fever (N 38.5 8C). The resident and attending physician were responsible for the enrollment of the participants. The hospital pharmacy performed the 1:1 computer-generated randomization that assigned the participants to their group. The pharmacy also provided the study drugs and placebos in unidentifiable form. Numbered containers held either 800-Ag tablets of misoprostol (Cytotec; Pfizer, Zurich, Switzerland) to be taken orally plus a syringe filled with a normal saline solution supplemented with placebo, or a placebo tablet to be taken orally plus a syringe filled with a normal saline solution supplemented with 20 IU of oxytocin (Syntocinon; Novartis Pharma, Berne, Switzerland). Preoperatively, an ultrasonographic evaluation was performed to estimate the amniotic fluid volume, which was calculated as an amniotic volume index (AFI) [7]. One AFI centimeter was estimated to be equivalent to an AF volume of 30 mL [8]. Postoperatively, following cord clamping and as soon as written informed consent was received, 5 IU of oxytocin were administered intravenously. When the membranes had ruptured before the CD procedure, the amount of intraoperative and postoperative blood loss was calculated by determining the difference in weight of cloths and pads used to absorb blood during surgery and postoperatively in the intermediate care unit. When the membranes had not ruptured preoperatively, the amount of blood loss was assessed by collecting the blood in suction bottles and subtracting the estimated amniotic fluid volume. A 100-g increase in cloth and pad weight was considered equivalent to 100 mL of blood or amniotic fluid. The women participating in this study remained at least 6 h in the postoperative care unit for control of vital parameters. A questionnaire was used by obstetricians and anesthesiologists to record the volume of administered perioperative fluid, blood loss, and urine, as well as any adverse effect and complication. Hemoglobin levels were assessed preoperatively and postoperatively after 24 h and 48 h. All CSs were performed using a transperitoneal approach and transverse lower uterine segment incision under spinal anesthesia. All participants received a 5-IU bolus of oxytocin intravenously. Afterwards, they were randomized to receive immediately after cord clamping either (A) 800 Ag of misoprostol orally plus an infusion of normal saline solution (1000 mL over 8 h) supplemented with placebo, or (B) an oral placebo plus an infusion of normal
4
O. Lapaire et al.
saline solution (1000 mL over 8 h) supplemented with 20 IU of oxytocin. Three patients in the oxytocin group were excluded from statistical analysis because of errors in drug administration. Additional administration of uterotonics was allowed in cases of severe bleeding, but was not needed in either group). After surgery, all participants received 5000 IE of low-molecular-weight heparin subcutaneously as thromboprophylaxis. The primary outcomes were intraoperative and postoperative blood loss as well as drug-related adverse effects. To date it is unclear whether oral misoprostol has the same potent effect in reducing blood loss after indicated or elective CD. A power calculation was performed before initiating the study based on a median estimated blood loss of 1000 mL during CD [9]. It was calculated that a sample size of 46 patients was needed to detect a 25% difference in blood loss (250 mL) between the 2 groups, with a power of 80% at a significance level of .05 [10].
2.2. Statistical analysis The t test, and Welch test if variances in groups were unequal, were used to compare approximately normally distributed data between the groups; the Mann—Whitney U test was used for groups with ordinal data; and the Spearman rank-order correlation was calculated as a measure of correlation. To describe associations in crosstabs, the Fisher exact test was performed. P b.05 was considered significant. Results were reported as mean F S.D. and percentages. All analyses were performed using the SPSS statistical software, version 11.5.1 (SPSS Inc., Chicago, IL, USA).
Table 1
3. Results From January 1999 to February 2002, 56 pregnant women at low risk for PPH who underwent a CD after the 37th week of pregnancy were included in the study. The study period consisted of the CD duration and surveillance in the intermediate care unit. All participants were equally allocated to either group. Both groups were similar in terms of demographic data, obstetric history (Table 1), indications for CD (Table 2), duration of hospital stay, and fetal outcome (Table 1). There was no difference in blood loss between the study groups. After correcting for the sonographically estimated AF volume, total blood loss was 1083 F 920 mL in the misoprostol group and 970 F 560 mL in the oxytocin group ( P = .59) (Table 3). Intraoperatively, estimated blood loss was 627 F 223 mL in the misoprostol group and 656 F 255 mL in the oxytocin group ( P = .66). Postoperatively, until discharge from the intermediate care unit, blood loss was 126 F 145 mL in the misoprostol group and 98 F 55 mL in the oxytocin group ( P = .38), covering a wider range in the misoprostol group. Differences in preoperative and postoperative hemoglobin and hematocrit values were similar in the 2 groups. There was a significant negative correlation between the volume of intraoperative fluid administration and the 48-h postoperative hemoglobin level (correlation coefficient, 0.332; P = .04). Another significant difference was the incidence of shivering observed by the anesthesiologist in 10 (36%) of 28 participants in the misoprostol group and 2 (8%) of 25 remaining participants in the oxytocin group ( P = .04). There was no significant difference in the frequencies of other adverse effects such as headache, nausea, and flush (1
Demographic and obstetric characteristics and fetal outcomea
Variable
Age, years Parity Gravidity Gestational age at delivery, weeks AFI Preoperative Hb level, g/dL) Intraoperative volume application (crystalloids), mL Intraoperative volume application (colloids), mL Birth weight, g Arterial pH of the umbilical cord blood Apgar score at 5 min
Drug used Misoprostol
Oxytocin
P value
32.18 F 6.5 1.38 (1—4) 2.12 (1—6) 38.6 F 1.3 12.1 F 3.6 12.2 F 0.7 883.3 F 411.2 526.2 F 245.8 3236.4 F 476.0 7.27 F 0.05 9.74 F 0.66
31.15 ( F 5.1) 1.58 (1—3) 2.04 (1—6) 38.7 F 1.3 13.0 F 4.8 12.5 F 1.4 934.1 F 358.0 690.9 F 468.9 3273.4 F 724.3 7.29 F 0.05 9.88 F 0.60
.52b .56c .43c .74b .44b .29b .66b .16b .83b .16b .43b
Abbreviation: Hb, hemoglobin. a Values are given as mean F S.D. or mean (range) unless otherwise indicated. b By the t test. c By the Mann—Whitney U test.
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after cesarean delivery Table 2 Indications for cesarean delivery in 2 drug groups of 28 participants eacha Indication
No. of women treated with misoprostol
No. of women treated with oxytocin
Elective CD or breech presentation Malposition Twin pregnancy Repeated CD Ineffective induction of labor Ineffective induction of labor and infection Failure of labor to progress Hip dysplasia Intrauterine growth retardation Ankylosing spondylitis Macrosomia Placenta previa Increased pressure not indicated(retinal disease, colposuspension) Dropped out of the study
15
16
1 1 5 0
0 0 0 2
0
1
1
0
1 0
0 2
1 1 2 0
0 1 0 3
0
3
Abbreviation: CD, cesarean delivery. a This is a cross-classified table.
case of each was reported in the oxytocin group) and intestinal cramps (1 case was reported in both groups). No participant required additional drugs to control postoperative bleeding or any postoperative blood transfusion. As a result of the uncomplicated postoperative courses, no significant differences in hospital stay were seen between the 2 groups (the median stay was 7.5 F 1.86 days in the misoprostol group and 7.28 F 2.56 days in the oxytocin group; P = .72).
5
both intravenous and intramuscular drug administration in the participating trial centers. Most previous published studies concerning the treatment of PPH have focused on vaginal births. Intraoperative and postoperative hemorrhage a common adverse effect of CD. One trial assessed the use of misoprostol vs. intravenous oxytocin for reducing intraoperative blood loss [13]. Another study found a reduced need for additional uterotonics during CD after oral administration of misoprostol [14], whereas one randomized trial of 500 Ag of oral misoprostol vs. 10 IU of intravenous oxytocin with women undergoing elective or emergency CS did not [15]. In comparison to the latter study, the present study included a higher number of patients (56 vs. 40). Furthermore, this study’s participants underwent elective and indicated, but not emergency CD. Additionally, the blood loss was quantified by weighting cloths and pads intraoperatively and postoperatively as well as using suction bottles, and the gross underestimation of intraoperative and postoperative blood loss could be assessed. However, in agreement with Likugamage and colleagues [15] and Acharya and colleagues [13], there was no difference in mean blood loss between the misoprostol and oxytocin group. Despite the lack of a significant difference in mean blood loss, there was a much wider range in blood volumes lost during the postoperative period in women receiving misoprostol, indicating less reliability in terms of effectiveness. In addition, women were found to be at higher risk of experiencing adverse effects with misoprostol in the present study as well as in other trials [16]. Moreover, because the time to plasma peak levels will be different from the times achieved by injectable uterotonics, differences in onset of therapeutic action may limit the efficacy Table 3 Calculated and estimated blood loss and duration of hospital staya
4. Discussion The literature referring to major PPH provides some evidence that the use of injectable uterotonic agents such as oxytocin tends to be more effective than misoprostol administered orally during active management of the third stage of labor [4,11,12]. In a multicenter World Health Organization trial that included more than 18,500 participants, the risk of PPH was 4% for those who received misoprostol vs. 3% for those who received oxytocin [11]. However, the discussion still goes on as uncertainties remain. The trial design did not control for population heterogeneity within the oxytocin group; furthermore, it introduced a potential performance bias by allowing a policy of
Drug used Estimated blood loss, mL Calculated blood loss, mL Hb level 24 h postoperatively, g/dL Hb level 48 h postoperatively, g/dL Hospital stay, days
Misoprostol
Oxytocin
P valueb
626.8 F 223.4
656.3 F 254.7
.66
1083 F 920
970 F 560
.59
11.0 F 1.2
11.3 F 1.7
.42
10.9 F 1.3
11.4 F 1.5
.29
7.5 F 1.9
7.3 F 2.6
.73
Abbreviation: Hb, hemoglobin. a Values are given as mean F S.D. unless otherwise indicated. b By the t test.
6 and usefulness of oral or rectal misoprostol [17]. Misoprostol acid reaches its peak 20 to 30 min after oral administration, not as fast as intravenous or intramuscular oxytocin [18]. Shivering is a common adverse effect of misoprostol use, occurring in 30% to 70% of cases [19]. In this study shivering was observed in 10 (36%) of the 28 women who receive the drug. Epidural analgesia as a potential confounder and risk factor for shivering was not established in any study participant who received oral misoprostol in this study. The authors speculated that 800 Ag might be more effective than the 600 Ag used in other studies [6], and with fewer side effects than the 1000-Ag dose of rectal misoprostol that has also been used [20]. Alternative routes of misoprostol administration (sublingual, rectal, or in an oral solution) may increase its efficacy while lowering the incidence of adverse effects [21]. Oral absorption of misoprostol must be very rapid; however, a study with 200-Ag misoprostol was unable to demonstrate a decrease in blood loss [22]. A potential weakness in the present study was the application of 5 IU of oxytocin intravenously after cord clamping in both groups, which could have had an influence on intraoperative blood loss. This regimen was imposed by the institutional ethics committee as a consequence of a Cochrane Library Review [23], which was based on results following vaginal delivery. Further, it could be confirmed that visual estimation of intraoperative blood loss undervalues misoprostol effectiveness by 30%. In conclusion, the findings of this study indicate that oral misoprostol is not likely to become a universal substitute for traditional uterotonic agents such as intravenous oxytocin in CDs with or without labor. The importance of a fast and effective treatment of life-threatening PPH cannot be overrated. With its similar efficacy, misoprostol, whether orally or rectally administered, remains an interesting and promising drug. And whereas classic uterotonics must be stored at low temperatures, the physico-chemical stability of misoprostol allows storage at high temperatures—which solves a problem in countries with a tropical climate and limited refrigeration capabilities. Therefore, despite of the results reported here, misoprostol offers a safe and effective alternative to classic uterotonics in the prevention of PPH, and this warrants further evaluation in larger studies [24].
Acknowledgment We thank the Scientific Pool of the Basel University Hospital for funding this study.
O. Lapaire et al.
References [1] Mousa HA, Alfirevic Z. Treatment for primary postpartum haemorrhage (Cochrane Review). Chichester, UK: John Wiley & Sons Ltd. The Cochrane Library, 2004, Issue 4. [2] Adamson P. A failure of imagination: progress of nations. UNICEF. p. 2 – 9. [3] Khan GQ, John IS, Wani S, Doherty T, Sibai BM. Controlled cord traction versus minimal intervention techniques in delivery of the placenta: a randomized controlled trial. Am J Obstet Gynecol 1997;177:770 – 4. [4] Villar J, Gqlmezoglu AM, Hofmeyr GJ, Forna F. Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage. Obstet Gynecol 2002;100: 1301 – 12. [5] Joy SD, Sanchez-Ramos L, Kaunitz AM. Misoprostol use during the third stage of labor. Int J Obstet Gynecol 2003; 82:143 – 52. [6] Surbek DV, Fehr PM, Hfsli I, Holzgreve W. Oral misoprostol for third stage of labor: a randomized placebo-controlled trial. Obstet Gynecol 1999;94:255 – 8. [7] Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. J Reprod Med 1987;32:601 – 4. [8] Grover J, Mentakis E, Gross M. Three dimensional method for determination of amniotic fluid volume in intrauterine pockets. Obstet Gynecol 1997;90:1006 – 10. [9] Altman DG. Statistics and ethics in medical research: how large a sample? Br Med J 1980;281:1336 – 8. [10] Pritchard JA, Baldwin RM, Dickey JC, Wiggings KM. Blood volume changes in pregnancy and the puerperium. Am J Obstet Gynecol 1962;84:1271 – 82. [11] Gqlmezoglu AM, Vilar J, Ngoc NN, Piaggio G, Carroli G, Adetoro L. The WHO multicentre double-blind randomized controlled trial to evaluate the use of misoprostol in the management of the third stage of labor. Lancet 2001; 358:689 – 95. [12] Gqlmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for prevention of postpartum haemorrhage (Cochrane Review). Chichester, UK: John Wiley & Sons Ltd. The Cochrane Library, 2004, Issue 1. [13] Acharya G, Al-Sammarai MT, Patel N, Al-Habib A, Kiserud T. A randomized, controlled trial comparing effect of oral misoprostol and intravenous syntocinon on intra-operative blood loss during cesarean section. Acta Obstet Gynecol Scand 2001;80:245 – 50. [14] Hamm J, Russell Z, Botha T, Carlan SJ, Richichi K. Buccal misoprostol to prevent hemorrhage at cesarean delivery: a randomized study. Am J Obstet Gynecol 2005;192:1404 – 6. [15] Likugamage AU, Paine M, Bassaw-Balroop K, Sullivan KR, Refaey HE, Rodeck CH. Active management of the third stage at cesarean section: a randomised controlled trial of misoprostol versus syntocinon. Aust N Z J Obstet Gynaecol 2001;41:411 – 4. [16] Lumbiganon P, Villar J, Piaggio G, Gqlmezoglu AM, Adetoro G, Carolli G. Side-effects of oral misoprostol during the first 24 hours after administration in the third stage of labor. Br J Obstet Gynaecol 2002;109:1222 – 6. [17] Abdel-Aleem H, Vilar J, Gulmezoglu AM, Mostafa SA, Youssef AA, Shokry M, et al. The pharmakokinetics of prostaglandin E1 analogue misoprostol in plasma and colostrums after postpartum oral administration. Eur J Obstet Gynecol Reprod Biol 2003;108:25 – 8. [18] 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.
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after cesarean delivery [19] Villar J, Gqlmezoglu AM, Hofmeyr GJ, Forna F. Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage. Obstet Gynecol 2002; 100:1301 – 12. [20] O’Brien P, El-Refaey H, Gordon A, Geary M, Rodeck CH. Rectally administered misoprostol for the treatment of postpartum hemorrhage unresponsive to oxytocin and ergometrine: a descriptive study. Obstet Gynecol 1998; 92:212 – 4. [21] 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
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different routes after vaginal delivery. Eur J Obstet Gynecol Reprod Biol 2004;113:191 – 8. [22] Bhullar A, Carlan SJ, Hamm J, Lamberty N, White L, Richichi K. Buccal misoprostol to decrease blood loss after vaginal delivery: a randomized trial. Obstet Gynecol 2004; 104:1282 – 8. [23] Elbourne DR, Prendiville WJ, Carroli G, Wood J, McDonald S. Prophylactic use of oxytocin in the third stage of labor. Cochrane Database Syst Rev 2001;4: [CD001808. Review]. [24] Darney PD. Misoprostol: a boon to safe motherhood . . . or not? Lancet 2001;358:682 – 3.
www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after emergency cesarean delivery O. Lapaire a, M.C. Schneider b, M. Stotz b, D.V. Surbek a, W. Holzgreve a, I.M. Hoesli a,* a b
Women’s University Hospital, Basel, Switzerland University Hospital Basel, Department of Anesthesia, Basel, Switzerland
Received 20 January 2006; received in revised form 18 May 2006; accepted 24 May 2006
KEYWORDS Maternal; Morbidity; Mortality; Pregnancy; Postpartum hemorrhage; Cesarean delivery
Abstract Objective: To compare the effectiveness of oral misoprostol and intravenous oxytocin in reducing blood loss in women undergoing indicated or elective cesarean delivery (CD) under spinal anesthesia. Methods: In this prospective, double-blind pilot study, 56 parturients who received 5 IU of intravenous oxytocin after cord clamping were randomized to further receive either misoprostol orally and a placebo infusion intravenously or placebo orally and an oxytocin infusion intravenously. Results: After adjustment was made for the sonographically estimated amniotic fluid volume, there was no statistical difference in blood loss between the 2 groups (mean F S.D., 1083 F 920 mL in the oxytocin group vs. 970 F 560 mL in the misoprostol group; P = .59). Conclusion: Oxytocin followed by oral misoprostol is as effective as an oxytocin injection followed by an oxytocin infusion in reducing postoperative blood loss after CD, and the protocol may be a safe, valuable, and cost-effective alternative to oxytocin alone. Visual estimation of intraoperative blood loss undervalues the effective value of misoprostol use by 30%. D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding author. Universita ¨ts-Frauenklinik Basel Spitalstrasse 21 CH-4031 Basel, Switzerland. Tel.: +41 61 265 90 17; fax: +41 61 265 91 98. E-mail address: [email protected] (I.M. Hoesli).
Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide, and the number of maternal deaths due to PPH is estimated to exceed 100,000 each year [1]. Post-
0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2006.05.031
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after cesarean delivery partum hemorrhage is defined as a blood loss of more than 1000 mL in the first 24 h following delivery [2]. Active management of the third stage of labor, use of uterotonic agents, and early cord clamping with controlled cord traction [3] have contributed to reducing the incidence of PPH by 40% [4,5]. However, oxytocin, ergot preparations, and prostaglandins such as sulprostone, which have been traditionally used to control postpartum bleeding, are associated with adverse effects and complications when administered within a dose range likely to be effective in cases of PPH. The effectiveness of misoprostol, a prostaglandin E1 derivative, in preventing PPH after vaginal delivery has been well established [6]. A low-cost drug that can be taken orally and remains stable even when stored at elevated temperatures, misoprostol appears to be particularly suitable for use in developing countries. The present study was designed to compare the effectiveness of oral misoprostol as an uterotonic drug with that of intravenous oxytocin in patients undergoing indicated or elective or cesarean deliveries (CDs). Intraoperative and postoperative blood loss, a quantitative parameter of postpartum hemorrhage, was compared for the 2 drugs, as well as drugrelated adverse effects in women treated by the same surgical and anesthesiological team in one institution.
2. Materials and methods 2.1. Study design This prospective, double blind, placebo-controlled pilot study was approved by the Basel Women’s University Hospital institutional review board, and written informed consent was obtained from all participants. The trial was posted on the Clinical Trials Web site (available at: www.clinicaltrials. gov). A total of 56 pregnant women at low risk for PPH who underwent indicated or elective CD after the 37th week of pregnancy were included in the study whether or not labor had begun. Indications for CD were breech presentation, malposition, intrauterine growth retardation, placenta previa marginalis, twin pregnancy, previous CD, maternal disease, and failure of labor to progress. Exclusion criteria were emergency CD within 30 min of admission, fetal distress, fetal malformations, preeclampsia, or HELLP (hemolysis, elevated liver enzymes, and low platelet count), hypersensitivity to prostaglandins, coagulopathy, severe systemic
3
disorders, an American Society of Anesthesiologists physical status of 3 or greater, severe asthma, prior myomectomy, and fever (N 38.5 8C). The resident and attending physician were responsible for the enrollment of the participants. The hospital pharmacy performed the 1:1 computer-generated randomization that assigned the participants to their group. The pharmacy also provided the study drugs and placebos in unidentifiable form. Numbered containers held either 800-Ag tablets of misoprostol (Cytotec; Pfizer, Zurich, Switzerland) to be taken orally plus a syringe filled with a normal saline solution supplemented with placebo, or a placebo tablet to be taken orally plus a syringe filled with a normal saline solution supplemented with 20 IU of oxytocin (Syntocinon; Novartis Pharma, Berne, Switzerland). Preoperatively, an ultrasonographic evaluation was performed to estimate the amniotic fluid volume, which was calculated as an amniotic volume index (AFI) [7]. One AFI centimeter was estimated to be equivalent to an AF volume of 30 mL [8]. Postoperatively, following cord clamping and as soon as written informed consent was received, 5 IU of oxytocin were administered intravenously. When the membranes had ruptured before the CD procedure, the amount of intraoperative and postoperative blood loss was calculated by determining the difference in weight of cloths and pads used to absorb blood during surgery and postoperatively in the intermediate care unit. When the membranes had not ruptured preoperatively, the amount of blood loss was assessed by collecting the blood in suction bottles and subtracting the estimated amniotic fluid volume. A 100-g increase in cloth and pad weight was considered equivalent to 100 mL of blood or amniotic fluid. The women participating in this study remained at least 6 h in the postoperative care unit for control of vital parameters. A questionnaire was used by obstetricians and anesthesiologists to record the volume of administered perioperative fluid, blood loss, and urine, as well as any adverse effect and complication. Hemoglobin levels were assessed preoperatively and postoperatively after 24 h and 48 h. All CSs were performed using a transperitoneal approach and transverse lower uterine segment incision under spinal anesthesia. All participants received a 5-IU bolus of oxytocin intravenously. Afterwards, they were randomized to receive immediately after cord clamping either (A) 800 Ag of misoprostol orally plus an infusion of normal saline solution (1000 mL over 8 h) supplemented with placebo, or (B) an oral placebo plus an infusion of normal
4
O. Lapaire et al.
saline solution (1000 mL over 8 h) supplemented with 20 IU of oxytocin. Three patients in the oxytocin group were excluded from statistical analysis because of errors in drug administration. Additional administration of uterotonics was allowed in cases of severe bleeding, but was not needed in either group). After surgery, all participants received 5000 IE of low-molecular-weight heparin subcutaneously as thromboprophylaxis. The primary outcomes were intraoperative and postoperative blood loss as well as drug-related adverse effects. To date it is unclear whether oral misoprostol has the same potent effect in reducing blood loss after indicated or elective CD. A power calculation was performed before initiating the study based on a median estimated blood loss of 1000 mL during CD [9]. It was calculated that a sample size of 46 patients was needed to detect a 25% difference in blood loss (250 mL) between the 2 groups, with a power of 80% at a significance level of .05 [10].
2.2. Statistical analysis The t test, and Welch test if variances in groups were unequal, were used to compare approximately normally distributed data between the groups; the Mann—Whitney U test was used for groups with ordinal data; and the Spearman rank-order correlation was calculated as a measure of correlation. To describe associations in crosstabs, the Fisher exact test was performed. P b.05 was considered significant. Results were reported as mean F S.D. and percentages. All analyses were performed using the SPSS statistical software, version 11.5.1 (SPSS Inc., Chicago, IL, USA).
Table 1
3. Results From January 1999 to February 2002, 56 pregnant women at low risk for PPH who underwent a CD after the 37th week of pregnancy were included in the study. The study period consisted of the CD duration and surveillance in the intermediate care unit. All participants were equally allocated to either group. Both groups were similar in terms of demographic data, obstetric history (Table 1), indications for CD (Table 2), duration of hospital stay, and fetal outcome (Table 1). There was no difference in blood loss between the study groups. After correcting for the sonographically estimated AF volume, total blood loss was 1083 F 920 mL in the misoprostol group and 970 F 560 mL in the oxytocin group ( P = .59) (Table 3). Intraoperatively, estimated blood loss was 627 F 223 mL in the misoprostol group and 656 F 255 mL in the oxytocin group ( P = .66). Postoperatively, until discharge from the intermediate care unit, blood loss was 126 F 145 mL in the misoprostol group and 98 F 55 mL in the oxytocin group ( P = .38), covering a wider range in the misoprostol group. Differences in preoperative and postoperative hemoglobin and hematocrit values were similar in the 2 groups. There was a significant negative correlation between the volume of intraoperative fluid administration and the 48-h postoperative hemoglobin level (correlation coefficient, 0.332; P = .04). Another significant difference was the incidence of shivering observed by the anesthesiologist in 10 (36%) of 28 participants in the misoprostol group and 2 (8%) of 25 remaining participants in the oxytocin group ( P = .04). There was no significant difference in the frequencies of other adverse effects such as headache, nausea, and flush (1
Demographic and obstetric characteristics and fetal outcomea
Variable
Age, years Parity Gravidity Gestational age at delivery, weeks AFI Preoperative Hb level, g/dL) Intraoperative volume application (crystalloids), mL Intraoperative volume application (colloids), mL Birth weight, g Arterial pH of the umbilical cord blood Apgar score at 5 min
Drug used Misoprostol
Oxytocin
P value
32.18 F 6.5 1.38 (1—4) 2.12 (1—6) 38.6 F 1.3 12.1 F 3.6 12.2 F 0.7 883.3 F 411.2 526.2 F 245.8 3236.4 F 476.0 7.27 F 0.05 9.74 F 0.66
31.15 ( F 5.1) 1.58 (1—3) 2.04 (1—6) 38.7 F 1.3 13.0 F 4.8 12.5 F 1.4 934.1 F 358.0 690.9 F 468.9 3273.4 F 724.3 7.29 F 0.05 9.88 F 0.60
.52b .56c .43c .74b .44b .29b .66b .16b .83b .16b .43b
Abbreviation: Hb, hemoglobin. a Values are given as mean F S.D. or mean (range) unless otherwise indicated. b By the t test. c By the Mann—Whitney U test.
Oral misoprostol vs. intravenous oxytocin in reducing blood loss after cesarean delivery Table 2 Indications for cesarean delivery in 2 drug groups of 28 participants eacha Indication
No. of women treated with misoprostol
No. of women treated with oxytocin
Elective CD or breech presentation Malposition Twin pregnancy Repeated CD Ineffective induction of labor Ineffective induction of labor and infection Failure of labor to progress Hip dysplasia Intrauterine growth retardation Ankylosing spondylitis Macrosomia Placenta previa Increased pressure not indicated(retinal disease, colposuspension) Dropped out of the study
15
16
1 1 5 0
0 0 0 2
0
1
1
0
1 0
0 2
1 1 2 0
0 1 0 3
0
3
Abbreviation: CD, cesarean delivery. a This is a cross-classified table.
case of each was reported in the oxytocin group) and intestinal cramps (1 case was reported in both groups). No participant required additional drugs to control postoperative bleeding or any postoperative blood transfusion. As a result of the uncomplicated postoperative courses, no significant differences in hospital stay were seen between the 2 groups (the median stay was 7.5 F 1.86 days in the misoprostol group and 7.28 F 2.56 days in the oxytocin group; P = .72).
5
both intravenous and intramuscular drug administration in the participating trial centers. Most previous published studies concerning the treatment of PPH have focused on vaginal births. Intraoperative and postoperative hemorrhage a common adverse effect of CD. One trial assessed the use of misoprostol vs. intravenous oxytocin for reducing intraoperative blood loss [13]. Another study found a reduced need for additional uterotonics during CD after oral administration of misoprostol [14], whereas one randomized trial of 500 Ag of oral misoprostol vs. 10 IU of intravenous oxytocin with women undergoing elective or emergency CS did not [15]. In comparison to the latter study, the present study included a higher number of patients (56 vs. 40). Furthermore, this study’s participants underwent elective and indicated, but not emergency CD. Additionally, the blood loss was quantified by weighting cloths and pads intraoperatively and postoperatively as well as using suction bottles, and the gross underestimation of intraoperative and postoperative blood loss could be assessed. However, in agreement with Likugamage and colleagues [15] and Acharya and colleagues [13], there was no difference in mean blood loss between the misoprostol and oxytocin group. Despite the lack of a significant difference in mean blood loss, there was a much wider range in blood volumes lost during the postoperative period in women receiving misoprostol, indicating less reliability in terms of effectiveness. In addition, women were found to be at higher risk of experiencing adverse effects with misoprostol in the present study as well as in other trials [16]. Moreover, because the time to plasma peak levels will be different from the times achieved by injectable uterotonics, differences in onset of therapeutic action may limit the efficacy Table 3 Calculated and estimated blood loss and duration of hospital staya
4. Discussion The literature referring to major PPH provides some evidence that the use of injectable uterotonic agents such as oxytocin tends to be more effective than misoprostol administered orally during active management of the third stage of labor [4,11,12]. In a multicenter World Health Organization trial that included more than 18,500 participants, the risk of PPH was 4% for those who received misoprostol vs. 3% for those who received oxytocin [11]. However, the discussion still goes on as uncertainties remain. The trial design did not control for population heterogeneity within the oxytocin group; furthermore, it introduced a potential performance bias by allowing a policy of
Drug used Estimated blood loss, mL Calculated blood loss, mL Hb level 24 h postoperatively, g/dL Hb level 48 h postoperatively, g/dL Hospital stay, days
Misoprostol
Oxytocin
P valueb
626.8 F 223.4
656.3 F 254.7
.66
1083 F 920
970 F 560
.59
11.0 F 1.2
11.3 F 1.7
.42
10.9 F 1.3
11.4 F 1.5
.29
7.5 F 1.9
7.3 F 2.6
.73
Abbreviation: Hb, hemoglobin. a Values are given as mean F S.D. unless otherwise indicated. b By the t test.
6 and usefulness of oral or rectal misoprostol [17]. Misoprostol acid reaches its peak 20 to 30 min after oral administration, not as fast as intravenous or intramuscular oxytocin [18]. Shivering is a common adverse effect of misoprostol use, occurring in 30% to 70% of cases [19]. In this study shivering was observed in 10 (36%) of the 28 women who receive the drug. Epidural analgesia as a potential confounder and risk factor for shivering was not established in any study participant who received oral misoprostol in this study. The authors speculated that 800 Ag might be more effective than the 600 Ag used in other studies [6], and with fewer side effects than the 1000-Ag dose of rectal misoprostol that has also been used [20]. Alternative routes of misoprostol administration (sublingual, rectal, or in an oral solution) may increase its efficacy while lowering the incidence of adverse effects [21]. Oral absorption of misoprostol must be very rapid; however, a study with 200-Ag misoprostol was unable to demonstrate a decrease in blood loss [22]. A potential weakness in the present study was the application of 5 IU of oxytocin intravenously after cord clamping in both groups, which could have had an influence on intraoperative blood loss. This regimen was imposed by the institutional ethics committee as a consequence of a Cochrane Library Review [23], which was based on results following vaginal delivery. Further, it could be confirmed that visual estimation of intraoperative blood loss undervalues misoprostol effectiveness by 30%. In conclusion, the findings of this study indicate that oral misoprostol is not likely to become a universal substitute for traditional uterotonic agents such as intravenous oxytocin in CDs with or without labor. The importance of a fast and effective treatment of life-threatening PPH cannot be overrated. With its similar efficacy, misoprostol, whether orally or rectally administered, remains an interesting and promising drug. And whereas classic uterotonics must be stored at low temperatures, the physico-chemical stability of misoprostol allows storage at high temperatures—which solves a problem in countries with a tropical climate and limited refrigeration capabilities. Therefore, despite of the results reported here, misoprostol offers a safe and effective alternative to classic uterotonics in the prevention of PPH, and this warrants further evaluation in larger studies [24].
Acknowledgment We thank the Scientific Pool of the Basel University Hospital for funding this study.
O. Lapaire et al.
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