Contraception 89 (2014) 187 – 192
Original research article
Buccal misoprostol for treatment of fetal death at 14–28 weeks of pregnancy: a double-blind randomized controlled trial☆,☆☆ Hillary Bracken a,⁎, Nguyen Thi Nhu Ngoc b , Erika Banks c , Paul D. Blumenthal d , Richard J. Derman e , Ashlesha Patel f , Marji Gold c , Beverly Winikoff a Buccal misoprostol for IUFD Research Group a Gynuity Health Projects, New York, NY 10010, USA Center for Research and Consultancy in Reproductive Health, 16D Luy Ban Bich. Tan thoi Hoa Tan Phu, Hochiminh City, Vietnam c Albert Einstein College of Medicine, Bronx, NY 10461, USA d Family Planning Services and Research, Stanford University, Stanford, CA 94305-5317, USA e Christiana Care Health System, Department of OB/GYN Research, Newark, DE 19718, USA f Department of Obstetrics and Gynecology, JH Stroger Jr. Hospital of Cook County, Chicago, IL 60622, USA Received 26 July 2013; revised 6 November 2013; accepted 15 November 2013
b
Abstract Objective: To assess whether buccal misoprostol is effective for the treatment of intrauterine fetal death. Study Design: This double-blind randomized trial was conducted at five tertiary-level hospitals in the United States and Vietnam. One hundred fifty-three women with an intrauterine fetal death at 14–28 weeks of pregnancy received either 100 mcg buccal misoprostol or 200 mcg buccal misoprostol every 6 h for a maximum of 8 doses. The main outcome measure was the fetal-placental delivery rate within 48 hours of prostaglandin commencement without any additional intervention. Results: Most of the women (140/153) were recruited at the study site in Vietnam. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg. The 200 mcg dose was significantly more effective than the 100 mcg dose at expelling the fetus and placenta within 48 h [RR 0.68 (95% CI: 0.50–0.92; p=.03)]. The mean time to expulsion was significantly shorter using the 200 mcg dose (18.5±11.9 h) than the 100 mcg dose (23.9±12.5 h) (p=.02). Most women in both groups found the procedure satisfactory or very satisfactory (100 mcg: 76.7% (56/73); 200 mcg: 89.5% (68/76) [RR 0.86 (95% CI: 0.74–1.00)]. Conclusion: Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. A 200 mcg dose is significantly more effective than 100 mcg for evacuating the uterus within 48h. The treatment is highly acceptable to women. Implications: Administration of 200 mcg buccal misoprostol every six hours is an effective and acceptable method to effect the delivery of a demised fetus at 14–28 weeks that can be feasibly implemented in a wide variety of settings. © 2014 Elsevier Inc. All rights reserved. Keywords: Buccal misoprostol; Intrauterine fetal demise
1. Introduction
☆
Conflicts of interest: The authors declare no conflicts of interest. Clinical Trial Registration: The study is registered with Clinical Trials.gov, NCT 00671060. ⁎ Corresponding author. Gynuity Health Projects, New York, NY 10010. Tel.: + 1 212 448 1230; fax: + 1 212 448 1260. E-mail address: [email protected] (H. Bracken). ☆☆
0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2013.11.014
Globally, access to healthcare and differing methodologies for the classification of fetal demise contribute to wide variation in rates of fetal death in utero [1]. Timely evacuation can both avoid emotional distress and reduce the possibility of developing disseminated intravascular coagulapathy (DIC) [2,3]. Intrauterine fetal demise (IUFD) may be managed surgically with dilatation and evacuation (D&E) or
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labor induction with a variety of products including vaginal placement of prostaglandin E2 vaginal suppositories, misoprostol and/or oxytocin. Surgery is often expensive, potentially dangerous in settings with limited resources or a lack of trained providers, and is more difficult as the pregnancy becomes more advanced. Induction with misoprostol is a safe and effective option particularly in low-resource settings. Unlike other prostaglandins, misoprostol is stable at room temperature and very inexpensive. A systematic review found vaginal misoprostol as effective as, or more effective than, other prostaglandin preparations (including gemeprost [Cervagem], prostaglandin E2, and prostaglandin F2 alpha) and oral misoprostol for induction of labor in the second or third trimester for women following fetal death [4]. Pretreatment with mifepristone appears to significantly reduce the time to expulsion and side effects when compared to misoprostol alone [5–7]. However, mifepristone is expensive and not available in many settings so a safe, effective misoprostol alone regimen is still a desirable treatment option. Studies of misoprostol alone for IUFD have examined different modes of administration (oral, vaginal and sublingual). The use of buccal misoprostol for this indication is less studied. Researchers have evaluated buccal routes for labor induction [8,9] and induction of first and second trimester abortion either alone or after pre-treatment with mifepristone [10–12]. Pharmacokinetic studies show that the buccal route results in a serum concentration curve similar in shape to the curve associated with vaginal administration, the most commonly used route for IUFD [13,14]. Buccal administration may also be more acceptable to women as it does not necessitate frequent vaginal exams [13]. Our study documented the efficacy and side effect profile of two regimens (100 mcg and 200 mcg) of buccal misoprostol. A 100 mcg tablet is the smallest dose commercially available in many settings and eliminates the need to cut or dissolve tablets in solution, which may result in inaccurate or variable dosing.
2. Methods This double-blind randomized trial was approved by the institutional review boards of Montefiore Medical Center, Stanford University, Stroger Hospital, Christiana Health System, the Huong Vuong Hospital in Ho Chi Minh City, Viet Nam and the Allendale Investigational Review Board, an independent review board. Women who sought medical care for possible fetal demise in pregnancies of between 14 and 28 weeks at the five hospitals from December 2008 to December 2011 were screened. Confirmation of fetal demise and final gestational age were determined by ultrasound. Women were excluded if they had known allergies or other contraindications to the use of misoprostol; placental abruption with active hemorrhage, complete placenta previa, extreme uterine structural anomalies, or other contradictions
to vaginal delivery of the fetus; presentation in active labor (moderate to severe contractions every 10 minutes or less); history of prior uterine incision; or four or more previous deliveries. All subjects provided written informed consent. At enrollment, a medical history and physical examination were performed. Women were randomized to one of two study groups. Both women and providers were blinded to the treatment allocation. The groups were created by Gynuity Health Projects using a simple randomization sequence generated by computer with blocks of 10. Randomization was stratified by study site. A research assistant prepared numbered and sealed randomization packets before beginning enrollment. Each packet contained eight individually labeled dose envelopes. Each woman was administered a randomization envelope containing two tablets (either Group 1: a 100 mcg misoprostol tablet with a placebo pill made to resemble a 100 mcg tablet, or Group 2: two 100 mcg misoprostol tablets). The woman was instructed to hold the tablets in her cheeks for 20 minutes, after which she swallowed any remaining medication. Study drug was administered at 6-hourly intervals, for a maximum of 8 doses (either 800 or 1600 mcg depending on treatment arm). A woman was not administered the next dose if she was experiencing active labor. If at 48 hours the fetus and placenta remained undelivered, the case was considered a failure for purposes of the study, and the woman was treated according to established practice at the facility including surgical termination, expectant management or repeating the induction. No prophylactic medications were used for management of the gastrointestinal side effects of misoprostol. Women remained in the hospital for the duration of treatment. Patients were monitored for basic vital signs as well as every two hours for pain, cervical dilation, uterine contractility, and signs of possible complications. Pain management was according to the standard practice at each facility. No cervical osmotic dilators or laminaria were administered prior to trial entry for cervical preparation. Women who expelled the fetus within the study period were provided with a single dose of 200 mcg buccal misoprostol after expulsion of the fetus for placental management. Patient acceptability was assessed in an exit interview conducted prior to hospital discharge when the woman was fully stable. Satisfaction with the procedure was measured using a validated five-point Likert scale. The primary outcome was the fetal-placental delivery rate within 48 hours of misoprostol commencement without any additional intervention. Rates of success were compared across study arms. We anticipated that given the pharmacokinetic profile of buccal administration, results would be similar to those found with vaginally administered misoprostol. A systematic review conducted by one of the study authors gave us no reason to think that either of the two treatment doses would be superior to the other [15]. Thus, we designed the study as a separate, non-comparative efficacy study. In order to have 80% power (alpha=.05) to demonstrate that each misoprostol regimen was 95%, ± 5%, effective, we calculated that we would need to enroll 73
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women with second-trimester fetal death in each arm of the study, or 146 women total. The sample size also provided 80% power (alpha=.05) to detect a significant difference between treatments should the treatment arms differ in effectiveness by a sizeable margin (i.e. ± 10%). Results for the two treatment arms are presented separately. Differences between the two groups were compared using the chi-square (or Fischer’s exact) and Student’s t-test for categorical and continuous variables, respectively. All analyses were performed using SPSS Version 19.0. Time to expulsion was analyzed by survival methods, i.e. Kaplan Meier and log rank test. The analysis was intent-to-treat. According to the protocol, the data and safety monitoring committee conducted one interim analysis when approximately two-thirds of the study sample (98 of 146 women) had completed participation. The review committee was blinded to the treatment assignments. Early termination of the study was not recommended.
3. Results 153 women were enrolled: 76 were randomly assigned to receive 100 mcg buccal misoprostol, and 77 to receive 200 mcg buccal misoprostol (Fig. 1). Most of the women were recruited at the study site in Vietnam (140 of 153). One woman assigned to the 100 mcg group was withdrawn after
189
the administration of 2 doses of misoprostol when she developed preeclampsia. One woman assigned to the 200 mcg arm was determined to be ineligible after enrollment due to a gestational age of 12 weeks. All women were included in the final outcome analysis. The average gestational age at time of demise was approximately 18 weeks (Table 1). No significant difference in maternal age, gestational age or parity between the two groups was present at the time of randomization. In almost all cases (100 mcg: 95.9% or 71/76; 200 mcg: 96.1% or 73/77) membranes were intact at the time of enrollment. There was a significant difference between the two groups in the number of women with recorded dilation at the time of enrollment (100 mcg: 6.6% or 5/76; 200 mcg: 0; p=.02): Five women in the 100 mcg study arm were dilated 1–1.5cm. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg (Table 2). Rates for both arms were well below the hypothesized efficacy rate of 95±5%. The difference between the two groups was statistically significantly different (RR: 0.68; 95% CI: 0.50–0.93; p=.03) (Table 2). In one case where the fetus and placenta were successfully expelled within the study period, tissue in the cervix was removed by forceps three days after discharge from the study. She was considered a treatment success.
Fig. 1. CONSORT Flow Diagram.
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Table 1 Background characteristics (n, %)
Age (y) Mean (SD) Range Primiparous Gestational age at time of demise (weeks) mean (SD) (range) Fetal age at time of demise 14–18 weeks 19–23 weeks 24–28 weeks Presentation at time of enrollment Chorioamnionitis at time of enrollment Vaginal bleeding Painful contractions Cervix dilated* (n, %) 1 cm 1.5 cm Membranes intact
100 mcg (n=76)
200 mcg (n=77)
p-value
25.6 (5.6) 17–41 55 (72.4)
25.8 (5.9) 16–47 60 (77.9)
.93 .43
18.4 (3.6) (14.14–28.0)
17.5 (3.4)(12.71–26.43)
.14
39 (51.3) 24 (31.6) 13 (17.1)
49 (63.6) 23 (29.9) 5 (6.5)
0 0 0 5 (6.6) 4 1 71 (95.9)
Most of the women (n=140) were recruited at the Vietnam study site. We analyzed the results from the Vietnam site separately in order to control for any inter-site differences. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 64.3% (45/70) of women receiving misoprostol 100 mcg and 81.4% (57/70) of women receiving misoprostol 200 mcg (Fischer’s exact p=.02). Among women with successful complete delivery of both fetus and placenta, delivery was achieved in a median of 20.8 hours (range: 5.67–47.00) with the 100 mcg regimen and 14.4 hours (range: 0.83–47.00) with the 200 mcg regimen (Fig. 2). There was a significant difference in the percent of women who delivered within 24 h in the two groups (100 mcg: 39.5% (30/76); 200 mcg: 64.9% (50/77); RR: 0.60; 95% CI: 0.44–0.84; p=.002) (Table 2). The rate of complete expulsion of the fetus alone also differed significantly across groups [100 mcg: 65.8% (50/ 76); 200 mcg: 84.4% (65/77); RR: 0.46; 95% CI: 0.25– 0.83]. A few women who successfully expelled the fetus then required interventions in addition to the single 200 mcg
0 0 0 0 (0)
.02
73 (96.1)
.97
dose to expel the placenta (100 mcg: 3 women; 200 mcg: 4 women) [RR: 0.75 (95% CI: 0.17–3.24) p=0.70]. Six women received treatment for bleeding or a suspected pelvic infection. Two women in the 200 mcg arm and one woman in the 100 mcg arm received oxytocin IV after expulsion of the fetus when bleeding reached 100–250 ml. One woman in the 100 mcg arm and one woman in the 200 mcg arm received presumptive treatment with antibiotics for a suspected infection. One woman in the 200 mcg arm had a continued hospitalization after discharge from the study as a “failure of expulsion.” As per the protocol, she then received the hospital’s standard of care for this indication including laminaria, pitocin and additional misoprostol to induce delivery. The woman delivered 96 hours after her discharge from the study. Rates of side effects in both study arms were low (Table 3). There was no significant difference between the two groups in vomiting, chills, headache, and pain. There were significantly more women who experienced diarrhea among those receiving 200 mcg misoprostol compared to those who received 100 mcg (100 mcg: 10.7% or 8/76; 200
Table 2 Delivery interval characteristics (n, %) 100 mcg (n=76)
200 mcg (n= 77)
RR (95% CI)
Fetal and placental expulsion within 48 hours with study drug alone
47 (61.8)
60 (77.9)⁎⁎
Fetal and placental expulsion within 24 hours with study drug alone
30 (39.5)
50 (64.9)
0.68 (0.50–0.92) p=.03 0.68 (0.44–0.84) p=.002
Induction to delivery interval among women with successful procedure (hours) Mean Median Range
23.9 (12.5) a 20.8 (5.67–47.00)
18.5 (11.9) b 14.4 (0.83–47.00)
⁎⁎ In one case, tissue was removed with forceps three days after delivery. a n=47. b n= 60.
p=.02
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4. Discussion
Fig. 2. Time from misoprostol administration to delivery of fetus and placenta. Survival curve of the percentage of pregnancies that were undelivered for each of the two study regimens. Log rank test p=.001.
mcg: 32.5% or 25/77; p=.001). In all cases, diarrhea was either mild or moderate. Analgesic usage was not significantly different between the two groups. Narcotic analgesia was required in 2.6% (or 2/76) of women in the 100 mcg group and 6.4% (or 5/77) of women in the 200 mcg arm (p=0.25). No woman received an epidural. Almost all women in both study groups were satisfied or very satisfied with the treatment (100 mcg: 76.7% or 56/73; 200 mcg: 89.5% or 68/76). Women in the lower dose arm were more likely to find the procedure unsatisfactory or very unsatisfactory (100 mcg: 21.9% or 16/73; 200 mcg: 7.8% or 6/77; RR: 1.61; 95% CI: 1.17–2.21; p=0.02). Most women found the pain associated with the induction less than or same as expected. While most women found the side effects acceptable, significantly more women in the 100 mcg arm found the side effects unacceptable or very unacceptable (100 mcg: 16.0% or 12/75; 200 mcg: 3.9% or 3/77) (RR: 1.73; 95% CI: 1.27–2.36; p=.012). Women in the 100 mcg arm were more likely to find the duration of treatment unacceptable or very unacceptable (100 mcg: 17.1% or 12/ 70; 200 mcg: 8.1% or 6/74; p=.09) and the length of the hospitalization the worst aspect of the procedure (100 mcg: 18.9% or 14/74; 200 mcg: 7.8% or 6/77; p=.06).
Table 3 Side effects as reported by woman after completion of treatment (n, %)
Diarrhea Nausea Vomiting Chills Headache Pain
100 mcg (n= 76)
200 mcg (n= 77)
p-value
8 (10.7) 14 (18.7) 7 (9.5) 19 (25.3) 13 (17.3) 68 (90.7)
25 (32.5) 18 (23.4) 12 (15.6) 16 (20.8) 17 (22.1) 72 (93.5)
.001 .56 .33 .57 .54 .56
Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. The use of 200 mcg of buccal misoprostol for the induction of labor between 14–28 weeks following intra-uterine fetal demise is more effective than 100 mcg, with women experiencing shorter induction to expulsion interval, and an increased chance expelling the fetus and placenta within 48 h of the start of the induction. Our result also is consistent with findings from a systematic review that found that lower (800 mcg or less) cumulative doses of misoprostol were associated with an increased chance of women not achieving vaginal birth within 24 h when compared with moderate doses (800–2400 mcg) of misoprostol [4]. Our study found that women’s satisfaction with the induction method and ability to tolerate side effects was likely related to the success and duration of the induction process. This finding echoes other studies that found the duration, rather than the route of drug administration, critical in determining acceptability to women [4]. Differences in the time to induction are thus highly clinically significant in this study, and the higher dose regimen is clearly preferable. The study has several limitations. Most of the women were recruited at the Vietnam study site (140 of 153). The results obtained in a single country, Vietnam, may not be generalizable. Pain management expectations and availability may differ in different settings. This study was also not powered to detect a difference in safety outcomes because major adverse events (e.g., uterine rupture, blood transfusion, infection) are rare. Indeed, no studies of misoprostol for this indication were powered to detect rates of rare occurrence of major events. Similar to prior research, no uterine ruptures occurred, and blood transfusion and/or treatment for suspected infection was infrequent. This study was designed as separate non-comparative efficacy trials. We estimated that the effectiveness of buccal misoprostol would be approximately 95% in both arms. The effectiveness of buccal misoprostol was much lower than anticipated, especially in the low dose arm (100 mcg: 61.8%; 200 mcg: 78.9%). Although not significantly different, due to the limited sample size, the women's gestation in the 200 mcg group was lower than in the 100 mcg group and may account for some of the observed difference in effectiveness between the two groups. Comparison of success rates across studies is difficult given variations in dose, route of administration, interval, study sample (i.e., some studies include both spontaneous intrauterine fetal demise and live fetuses or fetal demise at different gestational ages), and the use of oxytocin for augmentation. Still, the success rate in the 200 mcg of our study (78.9%) is lower than rate of successful evacuation of the fetus alone in previous studies of 200 mcg vaginal misoprostol for this indication (98.1%) [15]. Dickinson et al. found that evacuation of the placenta or placental fragments in the operating room occurred in over one-third (37.8%) of cases [15]. Our lower success rate may, in part, be a result of a
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more conservative study outcome (complete delivery of fetus and placenta) and a protocol that did not allow additional interventions for delivery of the placenta. A second study by the same authors comparing 3 dosages administered vaginally at 6 hours also found a high rate of placental retention in all three study arms (200 mcg:25%; 400 mcg: 42%; 600 mcg loading dose plus 200 mcg: 40.8%) [16,17]. If we consider delivery of the fetus alone the success rate in our study is slightly higher in both study arms (100 mcg: 65.8%; 200 mcg: 84.2%). A study comparing buccal versus vaginal misoprostol for induction of second trimester abortion found the two routes of administration equally effective [12]. Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. Induction of labor to effect the delivery of a demised fetus at 14–28 weeks with 200 mcg buccal misoprostol given every six hours is an effective and feasible approach that can be implemented in a wide variety of settings. Acknowledgments This study was funded by a grant from the Office of Orphan Products Development of the United States Food and Drug Administration. References [1] Cousens S, Blencowe H, Stanton C, Chou D, Ahmed S, Steinhardt L, et al. National, regional, and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis. Lancet 2011; 377(9774):1319–30. [2] Shulman LP, Lipscomb GH, Ling FW. Management of abnormal pregnancies. In: Paul M, Lichtenberg ES, Borgatta L, Grimes DA, & Stubblefield PG, editors. A Clinician’s Guide to Medical and Surgical Abortion. Castro Valley, CA: W.B. Saunders Company; 1999. [3] Romero R, Copel JA, Hobbins JC. Intrauterine fetal demise and hemostatic failure: the fetal death syndrome. Clin Obstet Gynecol 1985;28(1):24–31. [4] Dodd JM, Crowther CA. Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine fetal death. Cochrane Database Syst Rev 2010;4 CD004901.
[5] Vayrynen W, Heikinheimo O, Nuutila M. Misoprostol-only versus mifepristone plus misoprostol in induction of labor following intrauterine fetal death. Acta Obstet Gynecol 2007;86: 701–5. [6] Sharma D, Singhal SR, Poonam, Paul A, Kunika. Comparison of mifepristone combination with misoprostol and misoprostol alone in the management of intrauterine death: condensation - misoprostol and mifepristone combination is more effective than misoprostol alone in the management of intrauterine death. Taiwan J Obstet Gynecol 2011 Sep;50(3):322–5. [7] Royal College of Obstetricians and Gynaecologists (RCOG). Late intrauterine fetal death and stillbirth. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2010 Oct. 33 p. (Green-top guideline; no. 55). Accessed on January 7, 2013 at http://www.rcog. org.uk/files/rcog-orp/GTG%2055%20Late%20Intrauterine%20fetal% 20death%20and%20stillbirth%2010%2011%2010.pdf. [8] Carlan SJ, Blust D, O’Brien WF. Buccal versus intravaginal misoprostol for cervical ripening. Am J Obstet Gynecol 2002;186: 229–33. [9] Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening and induction of labor. Cochrane Database Syst Rev 2004;4 CD004221. [10] Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008;112:1303–10. [11] Ngoc NT, Shochet T, Raghavan S, Blum J, Nga NT, Minh NT, et al. Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion: a randomized controlled trial. Obstet Gynecol 2011 Sep;118(3):601–8. [12] Ellis SC, Kapp N, Vragpvoc O, Borgata L. Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion. Contraception 2010;81:441–5. [13] Tang OS, Schweer H, Seberth HW, Lee S, Ho PC. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17(2):332–6. [14] Meckstroth KR, Whitaker AK, Bertisch S, Goldberg A, Darney P. Misoprostol administered by epithelial routes. Obstet Gynecol 2006; 108(3):582–90. [15] Clark W, Shannon C, Winikoff B. Misoprostol for uterine evacuation in induced abortion and pregnancy failure. Expert Rev Obstet Gynecol 2007;2(1). [16] Dickinson JE, Godfrey ME, Evans SF. Efficacy of intravaginal misoprostol in second-trimester pregnancy termination: a randomized controlled trial. J Matern Fetal Med 1998;7:115–9. [17] Dickinson J, Evans S. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002:471–4.
Original research article
Buccal misoprostol for treatment of fetal death at 14–28 weeks of pregnancy: a double-blind randomized controlled trial☆,☆☆ Hillary Bracken a,⁎, Nguyen Thi Nhu Ngoc b , Erika Banks c , Paul D. Blumenthal d , Richard J. Derman e , Ashlesha Patel f , Marji Gold c , Beverly Winikoff a Buccal misoprostol for IUFD Research Group a Gynuity Health Projects, New York, NY 10010, USA Center for Research and Consultancy in Reproductive Health, 16D Luy Ban Bich. Tan thoi Hoa Tan Phu, Hochiminh City, Vietnam c Albert Einstein College of Medicine, Bronx, NY 10461, USA d Family Planning Services and Research, Stanford University, Stanford, CA 94305-5317, USA e Christiana Care Health System, Department of OB/GYN Research, Newark, DE 19718, USA f Department of Obstetrics and Gynecology, JH Stroger Jr. Hospital of Cook County, Chicago, IL 60622, USA Received 26 July 2013; revised 6 November 2013; accepted 15 November 2013
b
Abstract Objective: To assess whether buccal misoprostol is effective for the treatment of intrauterine fetal death. Study Design: This double-blind randomized trial was conducted at five tertiary-level hospitals in the United States and Vietnam. One hundred fifty-three women with an intrauterine fetal death at 14–28 weeks of pregnancy received either 100 mcg buccal misoprostol or 200 mcg buccal misoprostol every 6 h for a maximum of 8 doses. The main outcome measure was the fetal-placental delivery rate within 48 hours of prostaglandin commencement without any additional intervention. Results: Most of the women (140/153) were recruited at the study site in Vietnam. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg. The 200 mcg dose was significantly more effective than the 100 mcg dose at expelling the fetus and placenta within 48 h [RR 0.68 (95% CI: 0.50–0.92; p=.03)]. The mean time to expulsion was significantly shorter using the 200 mcg dose (18.5±11.9 h) than the 100 mcg dose (23.9±12.5 h) (p=.02). Most women in both groups found the procedure satisfactory or very satisfactory (100 mcg: 76.7% (56/73); 200 mcg: 89.5% (68/76) [RR 0.86 (95% CI: 0.74–1.00)]. Conclusion: Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. A 200 mcg dose is significantly more effective than 100 mcg for evacuating the uterus within 48h. The treatment is highly acceptable to women. Implications: Administration of 200 mcg buccal misoprostol every six hours is an effective and acceptable method to effect the delivery of a demised fetus at 14–28 weeks that can be feasibly implemented in a wide variety of settings. © 2014 Elsevier Inc. All rights reserved. Keywords: Buccal misoprostol; Intrauterine fetal demise
1. Introduction
☆
Conflicts of interest: The authors declare no conflicts of interest. Clinical Trial Registration: The study is registered with Clinical Trials.gov, NCT 00671060. ⁎ Corresponding author. Gynuity Health Projects, New York, NY 10010. Tel.: + 1 212 448 1230; fax: + 1 212 448 1260. E-mail address: [email protected] (H. Bracken). ☆☆
0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2013.11.014
Globally, access to healthcare and differing methodologies for the classification of fetal demise contribute to wide variation in rates of fetal death in utero [1]. Timely evacuation can both avoid emotional distress and reduce the possibility of developing disseminated intravascular coagulapathy (DIC) [2,3]. Intrauterine fetal demise (IUFD) may be managed surgically with dilatation and evacuation (D&E) or
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labor induction with a variety of products including vaginal placement of prostaglandin E2 vaginal suppositories, misoprostol and/or oxytocin. Surgery is often expensive, potentially dangerous in settings with limited resources or a lack of trained providers, and is more difficult as the pregnancy becomes more advanced. Induction with misoprostol is a safe and effective option particularly in low-resource settings. Unlike other prostaglandins, misoprostol is stable at room temperature and very inexpensive. A systematic review found vaginal misoprostol as effective as, or more effective than, other prostaglandin preparations (including gemeprost [Cervagem], prostaglandin E2, and prostaglandin F2 alpha) and oral misoprostol for induction of labor in the second or third trimester for women following fetal death [4]. Pretreatment with mifepristone appears to significantly reduce the time to expulsion and side effects when compared to misoprostol alone [5–7]. However, mifepristone is expensive and not available in many settings so a safe, effective misoprostol alone regimen is still a desirable treatment option. Studies of misoprostol alone for IUFD have examined different modes of administration (oral, vaginal and sublingual). The use of buccal misoprostol for this indication is less studied. Researchers have evaluated buccal routes for labor induction [8,9] and induction of first and second trimester abortion either alone or after pre-treatment with mifepristone [10–12]. Pharmacokinetic studies show that the buccal route results in a serum concentration curve similar in shape to the curve associated with vaginal administration, the most commonly used route for IUFD [13,14]. Buccal administration may also be more acceptable to women as it does not necessitate frequent vaginal exams [13]. Our study documented the efficacy and side effect profile of two regimens (100 mcg and 200 mcg) of buccal misoprostol. A 100 mcg tablet is the smallest dose commercially available in many settings and eliminates the need to cut or dissolve tablets in solution, which may result in inaccurate or variable dosing.
2. Methods This double-blind randomized trial was approved by the institutional review boards of Montefiore Medical Center, Stanford University, Stroger Hospital, Christiana Health System, the Huong Vuong Hospital in Ho Chi Minh City, Viet Nam and the Allendale Investigational Review Board, an independent review board. Women who sought medical care for possible fetal demise in pregnancies of between 14 and 28 weeks at the five hospitals from December 2008 to December 2011 were screened. Confirmation of fetal demise and final gestational age were determined by ultrasound. Women were excluded if they had known allergies or other contraindications to the use of misoprostol; placental abruption with active hemorrhage, complete placenta previa, extreme uterine structural anomalies, or other contradictions
to vaginal delivery of the fetus; presentation in active labor (moderate to severe contractions every 10 minutes or less); history of prior uterine incision; or four or more previous deliveries. All subjects provided written informed consent. At enrollment, a medical history and physical examination were performed. Women were randomized to one of two study groups. Both women and providers were blinded to the treatment allocation. The groups were created by Gynuity Health Projects using a simple randomization sequence generated by computer with blocks of 10. Randomization was stratified by study site. A research assistant prepared numbered and sealed randomization packets before beginning enrollment. Each packet contained eight individually labeled dose envelopes. Each woman was administered a randomization envelope containing two tablets (either Group 1: a 100 mcg misoprostol tablet with a placebo pill made to resemble a 100 mcg tablet, or Group 2: two 100 mcg misoprostol tablets). The woman was instructed to hold the tablets in her cheeks for 20 minutes, after which she swallowed any remaining medication. Study drug was administered at 6-hourly intervals, for a maximum of 8 doses (either 800 or 1600 mcg depending on treatment arm). A woman was not administered the next dose if she was experiencing active labor. If at 48 hours the fetus and placenta remained undelivered, the case was considered a failure for purposes of the study, and the woman was treated according to established practice at the facility including surgical termination, expectant management or repeating the induction. No prophylactic medications were used for management of the gastrointestinal side effects of misoprostol. Women remained in the hospital for the duration of treatment. Patients were monitored for basic vital signs as well as every two hours for pain, cervical dilation, uterine contractility, and signs of possible complications. Pain management was according to the standard practice at each facility. No cervical osmotic dilators or laminaria were administered prior to trial entry for cervical preparation. Women who expelled the fetus within the study period were provided with a single dose of 200 mcg buccal misoprostol after expulsion of the fetus for placental management. Patient acceptability was assessed in an exit interview conducted prior to hospital discharge when the woman was fully stable. Satisfaction with the procedure was measured using a validated five-point Likert scale. The primary outcome was the fetal-placental delivery rate within 48 hours of misoprostol commencement without any additional intervention. Rates of success were compared across study arms. We anticipated that given the pharmacokinetic profile of buccal administration, results would be similar to those found with vaginally administered misoprostol. A systematic review conducted by one of the study authors gave us no reason to think that either of the two treatment doses would be superior to the other [15]. Thus, we designed the study as a separate, non-comparative efficacy study. In order to have 80% power (alpha=.05) to demonstrate that each misoprostol regimen was 95%, ± 5%, effective, we calculated that we would need to enroll 73
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women with second-trimester fetal death in each arm of the study, or 146 women total. The sample size also provided 80% power (alpha=.05) to detect a significant difference between treatments should the treatment arms differ in effectiveness by a sizeable margin (i.e. ± 10%). Results for the two treatment arms are presented separately. Differences between the two groups were compared using the chi-square (or Fischer’s exact) and Student’s t-test for categorical and continuous variables, respectively. All analyses were performed using SPSS Version 19.0. Time to expulsion was analyzed by survival methods, i.e. Kaplan Meier and log rank test. The analysis was intent-to-treat. According to the protocol, the data and safety monitoring committee conducted one interim analysis when approximately two-thirds of the study sample (98 of 146 women) had completed participation. The review committee was blinded to the treatment assignments. Early termination of the study was not recommended.
3. Results 153 women were enrolled: 76 were randomly assigned to receive 100 mcg buccal misoprostol, and 77 to receive 200 mcg buccal misoprostol (Fig. 1). Most of the women were recruited at the study site in Vietnam (140 of 153). One woman assigned to the 100 mcg group was withdrawn after
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the administration of 2 doses of misoprostol when she developed preeclampsia. One woman assigned to the 200 mcg arm was determined to be ineligible after enrollment due to a gestational age of 12 weeks. All women were included in the final outcome analysis. The average gestational age at time of demise was approximately 18 weeks (Table 1). No significant difference in maternal age, gestational age or parity between the two groups was present at the time of randomization. In almost all cases (100 mcg: 95.9% or 71/76; 200 mcg: 96.1% or 73/77) membranes were intact at the time of enrollment. There was a significant difference between the two groups in the number of women with recorded dilation at the time of enrollment (100 mcg: 6.6% or 5/76; 200 mcg: 0; p=.02): Five women in the 100 mcg study arm were dilated 1–1.5cm. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg (Table 2). Rates for both arms were well below the hypothesized efficacy rate of 95±5%. The difference between the two groups was statistically significantly different (RR: 0.68; 95% CI: 0.50–0.93; p=.03) (Table 2). In one case where the fetus and placenta were successfully expelled within the study period, tissue in the cervix was removed by forceps three days after discharge from the study. She was considered a treatment success.
Fig. 1. CONSORT Flow Diagram.
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Table 1 Background characteristics (n, %)
Age (y) Mean (SD) Range Primiparous Gestational age at time of demise (weeks) mean (SD) (range) Fetal age at time of demise 14–18 weeks 19–23 weeks 24–28 weeks Presentation at time of enrollment Chorioamnionitis at time of enrollment Vaginal bleeding Painful contractions Cervix dilated* (n, %) 1 cm 1.5 cm Membranes intact
100 mcg (n=76)
200 mcg (n=77)
p-value
25.6 (5.6) 17–41 55 (72.4)
25.8 (5.9) 16–47 60 (77.9)
.93 .43
18.4 (3.6) (14.14–28.0)
17.5 (3.4)(12.71–26.43)
.14
39 (51.3) 24 (31.6) 13 (17.1)
49 (63.6) 23 (29.9) 5 (6.5)
0 0 0 5 (6.6) 4 1 71 (95.9)
Most of the women (n=140) were recruited at the Vietnam study site. We analyzed the results from the Vietnam site separately in order to control for any inter-site differences. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 64.3% (45/70) of women receiving misoprostol 100 mcg and 81.4% (57/70) of women receiving misoprostol 200 mcg (Fischer’s exact p=.02). Among women with successful complete delivery of both fetus and placenta, delivery was achieved in a median of 20.8 hours (range: 5.67–47.00) with the 100 mcg regimen and 14.4 hours (range: 0.83–47.00) with the 200 mcg regimen (Fig. 2). There was a significant difference in the percent of women who delivered within 24 h in the two groups (100 mcg: 39.5% (30/76); 200 mcg: 64.9% (50/77); RR: 0.60; 95% CI: 0.44–0.84; p=.002) (Table 2). The rate of complete expulsion of the fetus alone also differed significantly across groups [100 mcg: 65.8% (50/ 76); 200 mcg: 84.4% (65/77); RR: 0.46; 95% CI: 0.25– 0.83]. A few women who successfully expelled the fetus then required interventions in addition to the single 200 mcg
0 0 0 0 (0)
.02
73 (96.1)
.97
dose to expel the placenta (100 mcg: 3 women; 200 mcg: 4 women) [RR: 0.75 (95% CI: 0.17–3.24) p=0.70]. Six women received treatment for bleeding or a suspected pelvic infection. Two women in the 200 mcg arm and one woman in the 100 mcg arm received oxytocin IV after expulsion of the fetus when bleeding reached 100–250 ml. One woman in the 100 mcg arm and one woman in the 200 mcg arm received presumptive treatment with antibiotics for a suspected infection. One woman in the 200 mcg arm had a continued hospitalization after discharge from the study as a “failure of expulsion.” As per the protocol, she then received the hospital’s standard of care for this indication including laminaria, pitocin and additional misoprostol to induce delivery. The woman delivered 96 hours after her discharge from the study. Rates of side effects in both study arms were low (Table 3). There was no significant difference between the two groups in vomiting, chills, headache, and pain. There were significantly more women who experienced diarrhea among those receiving 200 mcg misoprostol compared to those who received 100 mcg (100 mcg: 10.7% or 8/76; 200
Table 2 Delivery interval characteristics (n, %) 100 mcg (n=76)
200 mcg (n= 77)
RR (95% CI)
Fetal and placental expulsion within 48 hours with study drug alone
47 (61.8)
60 (77.9)⁎⁎
Fetal and placental expulsion within 24 hours with study drug alone
30 (39.5)
50 (64.9)
0.68 (0.50–0.92) p=.03 0.68 (0.44–0.84) p=.002
Induction to delivery interval among women with successful procedure (hours) Mean Median Range
23.9 (12.5) a 20.8 (5.67–47.00)
18.5 (11.9) b 14.4 (0.83–47.00)
⁎⁎ In one case, tissue was removed with forceps three days after delivery. a n=47. b n= 60.
p=.02
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4. Discussion
Fig. 2. Time from misoprostol administration to delivery of fetus and placenta. Survival curve of the percentage of pregnancies that were undelivered for each of the two study regimens. Log rank test p=.001.
mcg: 32.5% or 25/77; p=.001). In all cases, diarrhea was either mild or moderate. Analgesic usage was not significantly different between the two groups. Narcotic analgesia was required in 2.6% (or 2/76) of women in the 100 mcg group and 6.4% (or 5/77) of women in the 200 mcg arm (p=0.25). No woman received an epidural. Almost all women in both study groups were satisfied or very satisfied with the treatment (100 mcg: 76.7% or 56/73; 200 mcg: 89.5% or 68/76). Women in the lower dose arm were more likely to find the procedure unsatisfactory or very unsatisfactory (100 mcg: 21.9% or 16/73; 200 mcg: 7.8% or 6/77; RR: 1.61; 95% CI: 1.17–2.21; p=0.02). Most women found the pain associated with the induction less than or same as expected. While most women found the side effects acceptable, significantly more women in the 100 mcg arm found the side effects unacceptable or very unacceptable (100 mcg: 16.0% or 12/75; 200 mcg: 3.9% or 3/77) (RR: 1.73; 95% CI: 1.27–2.36; p=.012). Women in the 100 mcg arm were more likely to find the duration of treatment unacceptable or very unacceptable (100 mcg: 17.1% or 12/ 70; 200 mcg: 8.1% or 6/74; p=.09) and the length of the hospitalization the worst aspect of the procedure (100 mcg: 18.9% or 14/74; 200 mcg: 7.8% or 6/77; p=.06).
Table 3 Side effects as reported by woman after completion of treatment (n, %)
Diarrhea Nausea Vomiting Chills Headache Pain
100 mcg (n= 76)
200 mcg (n= 77)
p-value
8 (10.7) 14 (18.7) 7 (9.5) 19 (25.3) 13 (17.3) 68 (90.7)
25 (32.5) 18 (23.4) 12 (15.6) 16 (20.8) 17 (22.1) 72 (93.5)
.001 .56 .33 .57 .54 .56
Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. The use of 200 mcg of buccal misoprostol for the induction of labor between 14–28 weeks following intra-uterine fetal demise is more effective than 100 mcg, with women experiencing shorter induction to expulsion interval, and an increased chance expelling the fetus and placenta within 48 h of the start of the induction. Our result also is consistent with findings from a systematic review that found that lower (800 mcg or less) cumulative doses of misoprostol were associated with an increased chance of women not achieving vaginal birth within 24 h when compared with moderate doses (800–2400 mcg) of misoprostol [4]. Our study found that women’s satisfaction with the induction method and ability to tolerate side effects was likely related to the success and duration of the induction process. This finding echoes other studies that found the duration, rather than the route of drug administration, critical in determining acceptability to women [4]. Differences in the time to induction are thus highly clinically significant in this study, and the higher dose regimen is clearly preferable. The study has several limitations. Most of the women were recruited at the Vietnam study site (140 of 153). The results obtained in a single country, Vietnam, may not be generalizable. Pain management expectations and availability may differ in different settings. This study was also not powered to detect a difference in safety outcomes because major adverse events (e.g., uterine rupture, blood transfusion, infection) are rare. Indeed, no studies of misoprostol for this indication were powered to detect rates of rare occurrence of major events. Similar to prior research, no uterine ruptures occurred, and blood transfusion and/or treatment for suspected infection was infrequent. This study was designed as separate non-comparative efficacy trials. We estimated that the effectiveness of buccal misoprostol would be approximately 95% in both arms. The effectiveness of buccal misoprostol was much lower than anticipated, especially in the low dose arm (100 mcg: 61.8%; 200 mcg: 78.9%). Although not significantly different, due to the limited sample size, the women's gestation in the 200 mcg group was lower than in the 100 mcg group and may account for some of the observed difference in effectiveness between the two groups. Comparison of success rates across studies is difficult given variations in dose, route of administration, interval, study sample (i.e., some studies include both spontaneous intrauterine fetal demise and live fetuses or fetal demise at different gestational ages), and the use of oxytocin for augmentation. Still, the success rate in the 200 mcg of our study (78.9%) is lower than rate of successful evacuation of the fetus alone in previous studies of 200 mcg vaginal misoprostol for this indication (98.1%) [15]. Dickinson et al. found that evacuation of the placenta or placental fragments in the operating room occurred in over one-third (37.8%) of cases [15]. Our lower success rate may, in part, be a result of a
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more conservative study outcome (complete delivery of fetus and placenta) and a protocol that did not allow additional interventions for delivery of the placenta. A second study by the same authors comparing 3 dosages administered vaginally at 6 hours also found a high rate of placental retention in all three study arms (200 mcg:25%; 400 mcg: 42%; 600 mcg loading dose plus 200 mcg: 40.8%) [16,17]. If we consider delivery of the fetus alone the success rate in our study is slightly higher in both study arms (100 mcg: 65.8%; 200 mcg: 84.2%). A study comparing buccal versus vaginal misoprostol for induction of second trimester abortion found the two routes of administration equally effective [12]. Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. Induction of labor to effect the delivery of a demised fetus at 14–28 weeks with 200 mcg buccal misoprostol given every six hours is an effective and feasible approach that can be implemented in a wide variety of settings. Acknowledgments This study was funded by a grant from the Office of Orphan Products Development of the United States Food and Drug Administration. References [1] Cousens S, Blencowe H, Stanton C, Chou D, Ahmed S, Steinhardt L, et al. National, regional, and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis. Lancet 2011; 377(9774):1319–30. [2] Shulman LP, Lipscomb GH, Ling FW. Management of abnormal pregnancies. In: Paul M, Lichtenberg ES, Borgatta L, Grimes DA, & Stubblefield PG, editors. A Clinician’s Guide to Medical and Surgical Abortion. Castro Valley, CA: W.B. Saunders Company; 1999. [3] Romero R, Copel JA, Hobbins JC. Intrauterine fetal demise and hemostatic failure: the fetal death syndrome. Clin Obstet Gynecol 1985;28(1):24–31. [4] Dodd JM, Crowther CA. Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine fetal death. Cochrane Database Syst Rev 2010;4 CD004901.
[5] Vayrynen W, Heikinheimo O, Nuutila M. Misoprostol-only versus mifepristone plus misoprostol in induction of labor following intrauterine fetal death. Acta Obstet Gynecol 2007;86: 701–5. [6] Sharma D, Singhal SR, Poonam, Paul A, Kunika. Comparison of mifepristone combination with misoprostol and misoprostol alone in the management of intrauterine death: condensation - misoprostol and mifepristone combination is more effective than misoprostol alone in the management of intrauterine death. Taiwan J Obstet Gynecol 2011 Sep;50(3):322–5. [7] Royal College of Obstetricians and Gynaecologists (RCOG). Late intrauterine fetal death and stillbirth. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2010 Oct. 33 p. (Green-top guideline; no. 55). Accessed on January 7, 2013 at http://www.rcog. org.uk/files/rcog-orp/GTG%2055%20Late%20Intrauterine%20fetal% 20death%20and%20stillbirth%2010%2011%2010.pdf. [8] Carlan SJ, Blust D, O’Brien WF. Buccal versus intravaginal misoprostol for cervical ripening. Am J Obstet Gynecol 2002;186: 229–33. [9] Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening and induction of labor. Cochrane Database Syst Rev 2004;4 CD004221. [10] Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008;112:1303–10. [11] Ngoc NT, Shochet T, Raghavan S, Blum J, Nga NT, Minh NT, et al. Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion: a randomized controlled trial. Obstet Gynecol 2011 Sep;118(3):601–8. [12] Ellis SC, Kapp N, Vragpvoc O, Borgata L. Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion. Contraception 2010;81:441–5. [13] Tang OS, Schweer H, Seberth HW, Lee S, Ho PC. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17(2):332–6. [14] Meckstroth KR, Whitaker AK, Bertisch S, Goldberg A, Darney P. Misoprostol administered by epithelial routes. Obstet Gynecol 2006; 108(3):582–90. [15] Clark W, Shannon C, Winikoff B. Misoprostol for uterine evacuation in induced abortion and pregnancy failure. Expert Rev Obstet Gynecol 2007;2(1). [16] Dickinson JE, Godfrey ME, Evans SF. Efficacy of intravaginal misoprostol in second-trimester pregnancy termination: a randomized controlled trial. J Matern Fetal Med 1998;7:115–9. [17] Dickinson J, Evans S. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002:471–4.
