Original Research

Vaginal Misoprostol Compared With Buccal Misoprostol for Termination of Second-Trimester Pregnancy A Randomized Controlled Trial Ragip A. Al,

MD,

and Omer E. Yapca,

MD

OBJECTIVE: To compare the efficacy of vaginal misoprostol with buccal misoprostol for second-trimester termination of pregnancies. METHODS: In a randomized trial, we compared 400 micrograms vaginal and buccal misoprostol every 3 hours for up to six doses for induction of labor at 13–24 weeks of gestation with a live fetus and intact membranes. Women who had a uterine scar were excluded from the study. The primary outcome of the study was induction-to-abortion interval. Based on a two-tailed a of 0.05, we planned to include 65 patients per group to detect a 50% difference in the primary outcome with a power of 80%. RESULTS: From January 2014 to December 2014, 172 women were screened and 130 were randomized: 65 vaginal and 65 buccal misoprostol. Characteristics of patients were similar between groups. Patients administered vaginal misoprostol compared with buccal misoprostol had a shorter induction-to-abortion interval (25617 hours compared with 40629 hours, P5.001) and a higher abortion rate within both 24 hours (41 [63%] compared with 27 [42%] P5.014) and 48 hours (59 [91%] compared with 44 [68%], P5.001). Complete abortion rates were similar in both groups (vaginal 51 [78%] compared with buccal 54 [83%]). The incidence of side effects was similar for both groups. The perceived pain was higher in the buccal group, but the small difference did not appear to be clinically meaningful. From the Department of Obstetrics and Gynecology, Atatürk University Faculty of Medicine, Erzurum, Turkey. Corresponding author: Ragip A. Al, MD, Cigdem Mah, 1561. Sokak, Segmen sitesi A Blok No 7/25, 06530 Cankaya, Ankara, Turkey; e-mail: [email protected] gmail.com. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15

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CONCLUSION: Vaginal compared with buccal misoprostol administration has a shorter induction-toabortion interval for second-trimester termination of viable pregnancies. However, both administration routes are equally effective for induction of termination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02048098. (Obstet Gynecol 2015;126:593–8) DOI: 10.1097/AOG.0000000000000946

LEVEL OF EVIDENCE: I

T

ermination of second-trimester pregnancy consists of 10–15% of induced abortions worldwide.1 Misoprostol is the drug of choice as a single agent for medical termination of second-trimester pregnancy because of its high efficacy, low cost, and ease of use.2,3 The ideal dosing regimen of misoprostol is uncertain at present. It can be administered by vaginal, sublingual, oral, or buccal routes for medical abortion. Vaginal misoprostol is more effective than the oral route in the second trimester.4,5 Sublingual misoprostol has comparable effectiveness and safety with the vaginal route.2,6 In the only published study comparing vaginal with buccal administration, the median times from induction to abortion were similar for both groups.7 Direct comparison of the two routes was limited, however, because both groups receiving an initial dose of vaginal misoprostol. Successful outcomes were reported with buccal misoprostol for first-trimester abortion.8 It has a lower peak plasma concentration than all other routes and produces a uterine response similar to vaginal administration.9,10 The efficacy of misoprostol varies depending on the cause of termination. It is more effective for intrauterine fetal demise, with a shorter induction-todelivery interval, than when it is administered for termination of ongoing pregnancy.5,11,12 Women with

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premature rupture of membranes (PROM) also constitute a different group, in whom the process of labor has started before induction. To this end, a randomized trial comparing buccal misoprostol with vaginal misoprostol as a single agent for the management of second-trimester abortion with a live fetus and intact membranes was conducted.

MATERIALS AND METHODS The study was an open-label, randomized clinical trial carried out at Ataturk University Hospital between January 2014 and December 2014. Approval was obtained by the institutional review board of the Ataturk University Faculty of Medicine before the beginning of the study. Women admitted to the hospital for secondtrimester medical abortion because of fetal abnormality or maternal medical complications were eligible for inclusion if they had a live singleton fetus at 13–24 weeks of gestation, no uterine contractions, and a Bishop score less than 5. Women were excluded if they had a history of prostaglandin allergy, a scar on the uterus, a uterine abnormality, or PROM. Gestational age was determined either on the basis of certain menstrual date confirmed by ultrasonography or by ultrasound dating if the menstrual dates were uncertain or differed more than 7 days from ultrasonography. Premature rupture of membranes was diagnosed by history, physical examination, or placental alpha microglobulin-1 biomarker test. All eligible women admitted to the hospital during the study period were invited to participate in the study; those who gave informed consent were consecutively enrolled. At enrollment, medical history, hemoglobin (Hb) level, and Rh-antigen status were assessed and a physical examination including Bishop scoring was performed. Cervical length was measured by transvaginal ultrasonography. All participants then were randomly assigned to either vaginal or buccal induction treatment. Randomization was performed by means of a computerized random number generator in single blocks. Group allocation was predetermined by a physician who was not involved in the study before patient enrollment and placed in consecutively numbered and sealed opaque envelopes. When a woman was recruited into the study, she was given a sequential study number according to the sequence of entry into the study. The principal investigator was contacted and opened the sealed envelope bearing the study number of the participant for the purpose of treatment allocation. Women were randomized to receive 400 micrograms buccal misoprostol or 400 micrograms vaginal

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misoprostol every 3 hours for up to six doses until delivery took place. Vaginal tablets were introduced with moisture. Women in the buccal group were instructed to place tablets between their teeth and buccal wall and let them completely dissolve without chewing or swallowing whole. The treatment was withheld if the patient had strong uterine contractions. If abortion had not occurred within 24 hours after the beginning of the treatment, a second course of 400 micrograms misoprostol every 3 hours up to six doses was administered by the initially assigned route. If abortion had not occurred within 48 hours after the beginning of the study, it was considered a treatment failure, and the primary physician and the woman were then given the option to choose from other induction methods or to continue the protocol. Investigators, nursing stuff, and resident physicians were involved in patient care. Inductions took place in the obstetrics ward. Blood pressure, pulse rate, temperature, and side effects were recorded every 3 hours by the nursing stuff. Diclofenac sodium (75 mg intramuscularly) and metoclopramide (10 mg intramuscularly) were provided for pain and nausea according to patient request. We applied a standard treatment protocol for the management of the third stage of labor. Once fetal expulsion occurred, all participants received highdose oxytocin, 20 units in 1,000 mL of isotonic saline at 100 mL per hour, until delivery of the placenta. Spontaneous expulsion of the placenta was awaited up to 2 hours after the delivery of the fetus. If the placenta was delivered spontaneously, it was examined to check whether the abortion was complete. If necessary, exploration and evacuation of the uterus were performed. If the placenta was not expulsed within 2 hours, it was removed with Winter placental forceps and blunt curettage. Curettage is not performed routinely. Patients were discharged 24 hours after abortion if there were no complications. At discharge, Hb level was assessed. The pain related to treatment was evaluated by visual analog scale (VAS) scoring. The intensity of perceived pain is a highly subjective experience and can vary from one individual to another. The subjective experience of pain is profoundly modulated by past experience and future expectations about a nociceptive stimulus.13 Because participants might have had delivery or abortion experiences before the study, we assessed both expected and perceived pain from the procedure. The expected pain from the procedure was measured just after the randomization process, and perceived pain was recorded 12 hours after the placenta and fetus had been completely removed. We

Misoprostol for Second-Trimester Termination

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planned to perform this assessment with the Face Pain Scale–Revised.14 However, we faced some challenges in the understanding and acceptance of the scale by the patients. We changed it to a VAS after five patients had been recruited. The pain scores of these five patients were included in our analysis. The primary outcome measure of the study was the induction-to-abortion interval. It was defined as the interval between the time of administration of the first dose of misoprostol to the time when the fetus was delivered. Secondary outcome measures were abortion rate at 24 and 48 hours, requirement for another intervention, expected and perceived pain VAS scores, rate of complete abortion, number of misoprostol doses, difference in Hb level measured at the entry of the study and after the delivery, side effects, and maternal complications during the hospitalization period. Complete abortion was defined as expulsion of both the fetus and placenta completely without instrumental assistance. Diarrhea was defined as more than three episodes of loose bowel movements. Fever was defined as body temperature of 38°C or more. Abortion rates were calculated according to expulsion time of the fetus. Sample size calculations were based on the induction-to-abortion interval. Systemic bioavailability of buccal misoprostol was reported close to oral misoprostol, and both were lower than that of vaginal misoprostol.9,10 The effect size was estimated from previous studies that compared vaginal misoprostol with oral misoprostol using similar doses and dose intervals as the current study.15,16 Based on a twotailed a of 0.05, it was determined that 65 patients

per group were required to detect a 50% difference in the mean induction-to-abortion interval with a power of 80%. The analysis was based on the intention-to-treat principle. The statistical software used for analysis were Sample Power 3.0 and SPSS 20.0. The Kolmogorov-Smirnov test was used to check normality of distributions. The data were analyzed with the Student’s t test and Mann-Whitney U test for continuous variables and Pearson x2 test or Fisher’s exact test for categorical variables. Comparison of perceived pain between the groups was also performed with analysis of covariance adjusting for expected pain scores. All the test were two-sided and P values ,.05 were considered statistically significant.

RESULTS One hundred seventy-two women requesting secondtrimester termination of pregnancy were screened. A total of 130 eligible patients were recruited the study. All patients completed the study and were included in the analysis (Fig. 1). Maternal age, gravidity, parity, primigravidity, gestational age, cervical length, Bishop score, predelivery Hb level, and expected pain VAS scores were not different between the groups (Table 1). The mean induction-to-abortion interval was shorter in the vaginal group compared with the buccal group (25617 hours compared with 40629 hours respectively, P5.001). In the vaginal group, abortion rate at 24 hours (vaginal 41 [63%] compared with buccal 27 [42%], P5.014) and 48 hours (vaginal Assessed for eligibiity (n=172)

Enrollment

Recruited and randomized (n=130)

Excluded (n=42) Did not meet inclusion criteria: 37 Previous cesarean delivery: 10 Intrauterine exitus: 17 Premature rupture of membranes: 10 Declined to participate: 5

Allocation Randomized and received vaginal misprostol (n=65) Follow-up

Randomized and received buccal misprostol (n=65)

Treatment failed, received another induction method* (n=3)

Treatment failed, received another induction method* (n=15) Analyzed, vaginal misprostol (n=65)

Analysis

Analyzed, buccal misprostol (n=65)

Fig. 1. Flowchart showing recruitment (based on Consolidated Standards of Reporting Trials). The analyses were performed according to the intention-to-treat principle. *Included in analysis. Al. Misoprostol for Second-Trimester Termination. Obstet Gynecol 2015.

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Misoprostol for Second-Trimester Termination

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Table 1. Maternal Characteristics

Characteristic Maternal age (y) Gravidity Parity Primigravida Gestational age (wk) Cervical length (mm) Bishop score Prelabor hemoglobin (g/dL) Expected pain VAS score

Vaginal Misoprostol (n565)

Buccal Misoprostol (n565)

P

2967 2 (1, 10) 1 (0, 9) 19 (29) 1863 3963 2 (0, 4) 12.561.3

2767 2 (1, 11) 1 (0, 6) 21 (32) 1864 3962 2 (0, 4) 12.961.1

.108 .673 .514 .704 .501 .407 .314 .072

4.861.8

4.661.7

.401

VAS, visual analog scale. Data are mean6standard deviation, median (minimum, maximum), or n (%) unless otherwise specified.

59 [91%] compared with buccal 44 [68%], P5.001) was significantly higher (Table 2). A total of 18 (14%) patients for whom treatment failed were given other induction methods (Table 2). In the vaginal group, three (5%) patients had extraamniotic Foley catheters applied with 400 micrograms sublingual misoprostol. In the buccal group, eight (12%) patients continued treatment by 400 micrograms vaginal misoprostol and seven (11%) by Foley catheter with 400 micrograms vaginal misoprostol. The remaining nine (7%) patients for whom treatment Table 2. Treatment Outcomes

Characteristics Induction-toabortion time (h) Abortion in 24 h Abortion in 48 h No. of misoprostol doses Complete abortion Other induction methods Postpartum Hb (g/dL) Change in Hb (g/dL) (pre–post) Packed red cell transfusion Perceived pain (VAS score)

Vaginal Group (n565)

Buccal Group (n565)

P

25617

40629

.001

41 (63) 59 (91) 3 (1, 14)

27 (42) 44 (68) 5 (1, 18)

.014 .001 ,.001

51 (78) 3 (5)

54 (83) 15 (23)

.504 .002

11.861.4

11.861.5

.964

0.6 (21, 4.3)

0.8 (20.8, 4.4)

.107

2 (3) 6.661.6

2 (3) 7.361.4

1 .01

Hb, hemoglobin; VAS, visual analog scale. Data are mean6standard deviation, n (%), or median (minimum, maximum) unless otherwise specified.

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failed chose to continue treatment with the initially assigned induction method. The complete abortion rates were similar between the groups (vaginal 51 [78%] compared with buccal 54 [83%], P5.504) (Table 2). Prelabor Hb level, postpartum Hb level, and the difference between prelabor and postpartum values were not different between the two groups. Two patients had packed red blood cell transfusion in both of groups: postpartum Hb concentration fell below 8 g/dL in two patients in the vaginal group and two women in the buccal group had a retained placenta with significant hemorrhage. The perceived pain was higher in the buccal arm than the vaginal arm (Table 2). The mean difference between the buccal arm and vaginal arm was 0.7 (95% confidence interval 0.17–1.12). Expected pain was significantly related perceived pain (F54.4, P5.038, r50.18). Perceived pain was still higher in the buccal group when comparisons between the groups were performed after adjustment for expected pain (F57.9, P5.006, partial h250.059). The median number of misoprostol doses given was higher in the buccal group. Side effects were similar between the two groups (Table 3). At least one side effect was observed in all of the patients. Fifty-five (84%) women in the vaginal group and 61 (94%) in the buccal group had more than one side effect (P5.09).

DISCUSSION The results of our study indicate that 400 micrograms vaginal misoprostol administered every 3 hours is equally effective and has a shorter induction-toabortion interval for second-trimester termination of viable pregnancies than buccal misoprostol given at the same dose and dosing interval. The rates of side effects and complete abortion were similar in both administration routes. We chose the most common regimen used for vaginal misoprostol to ensure comparability of the Table 3. Side Effects

Nausea Dizziness Fatigue Headache Fever and chills Diarrhea Vomiting

Vaginal Group (n565)

Buccal Group (n565)

16 12 19 15 19 3

16 16 20 24 28 3 2

(25) (18) (29) (23) (29) (5) 0

(25) (25) (31) (37) (43) (5) (3)

P 1 .393 .848 .085 .1 1 .094

Data are n (%) unless otherwise specified.

Misoprostol for Second-Trimester Termination

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study with other studies. The success of vaginal misoprostol at 24 hours and 48 hours was similar to the previous report.17–21 The mean induction-todelivery time for vaginal misoprostol was similar to some previous reports; however, it was longer than the other studies.17–21 The time interval for buccal misoprostol was also longer than two previous reports.22,23 These differences may be the result of difference in patient characteristics between previous studies and the current one. The current study does not include women with intrauterine fetal demise or PROM in contrast to the other reports. Minor side effects were common as reported previously and at a similar rate in both groups.18,24 We found that perceived pain was higher in the buccal group than that of the vaginal group. This finding is somewhat unexpected because the mean peak serum level of the vaginal route was reported to be approximately half the buccal one.9 It may be related to a longer induction time in the buccal arm. A longer induction-todelivery time causes a longer duration of pain and exposes the women to side effects for a longer time and may be more traumatic emotionally. However, the difference between pain scores that was statistically significant is unlikely to be of clinical significance. A minimum of a 1.3-cm (range 1.0–1.7 cm) difference on the VAS represents the smallest measurable change in acute pain severity that is clinical important.25 There is no evidence that the operative intervention rate for incomplete abortion differs by the route of misoprostol.2 In the current study, all women received standardized management of the third stage of labor. The operative intervention rate was similar for both groups and was approximately 20%, as reported in previous studies in which the third stage was managed similarly.26–28 This study has a number of strengths. Cervical length, Bishop scores, rate of primigravidity, and gestational age were similar between groups. As potential confounders, women who had intrauterine fetal demise or PROM were not included in the study. The results of this study may not be applicable to these groups. The study has a limitation on the secondary outcomes. The findings related to complete abortion rate, change in Hb level, transfusion rate, pain, and side effects of the study should be interpreted with caution because the study is not specifically powered to assess these outcomes. The greater bioavailability of vaginal misoprostol probably explains the results of the current trial. Meckstroth et al9 compared the serum pharmacokinetics of misoprostol with vaginal compared with

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buccal (400 micrograms) administration in pregnant women. Systemic bioavailability of vaginally administered misoprostol computed by area under the curve of serum concentration across time was two times higher than that of the buccal route. Although vaginal misoprostol is the most effective one, women prefer the oral and sublingual routes because these routes are more convenient, less painful, and give more privacy.17–19,29 However, long induction-to-delivery times are unacceptable to most women. A combined regimen including both the vaginal and buccal routes improves patient acceptability and the efficacy of buccal misoprostol. Ellis et al7 found no significant difference between the vaginal and buccal routes after an initial vaginal dose and both regimens were highly acceptable. It seems to be better to use vaginal misoprostol for the first dose followed by repeated doses of buccal misoprostol. It has been shown by randomized studies that use of oral mifepristone 24–48 hours before misoprostol administration significantly shortens the induction-todelivery interval, reduces the total misoprostol dose, and increases the success rate.22,23 However, it is not available in most countries, including Turkey. The long induction intervals with misoprostol used alone provide additional compelling evidence about the need to have access to mifepristone for secondtrimester induction. REFERENCES 1. Harris LH, Grossman D. Confronting the challenge of unsafe second-trimester abortion. Int J Gynaecol Obstet 2011;115:77–9. 2. Wildschut H, Both MI, Medema S, Thomee E, Wildhagen MF, Kapp N. Medical methods for mid-trimester termination of pregnancy. The Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD005216. DOI: 10.1002/14651858. CD005216.pub2. 3. Second-trimester abortion. Practice Bulletin No. 135. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:1394–406. 4. Bebbington MW, Kent N, Lim K, Gagnon A, Delisle MF, Tessier F, et al. A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination. Am J Obstet Gynecol 2002;187:853–7. 5. Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002;186:470–4. 6. Cabrera Y, Fernández-Guisasola J, Lobo P, Gámir S, Alvarez J. Comparison of sublingual versus vaginal misoprostol for second-trimester pregnancy termination: a meta-analysis. Aust N Z J Obstet Gynaecol 2011;51:158–65. 7. 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. 8. Kulier R, Kapp N, Gülmezoglu AM, Hofmeyr GJ, Cheng L, Campana A. Medical methods for first trimester abortion. The

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Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD002855. DOI: 10.1002/14651858.CD002855.pub4.

between 13 to 20 weeks. Aust N Z J Obstet Gynaecol 2008; 48:165–71.

9. Meckstroth KR, Whitaker AK, Bertisch S, Goldberg AB, Darney PD. Misoprostol administered by epithelial routes: drug absorption and uterine response. Obstet Gynecol 2006;108: 582–90.

20. Tang OS, Lau WN, Chan CC, Ho PC. A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy. BJOG 2004;111: 1001–5.

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21. Dickinson JE, Evans SF. A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality. Obstet Gynecol 2003;101:1294–9.

11. Jain JK, Kuo J, Mishell DR Jr. A comparison of two dosing regimens of intravaginal misoprostol for second-trimester pregnancy termination. Obstet Gynecol 1999;93:571–5. 12. Jain JK, Mishell DR Jr. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290–3. 13. Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective experience of pain: where expectations become reality. Proc Natl Acad Sci U S A 2005;102:12950–5. 14. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain 2001;93:173–83. 15. Akoury HA, Hannah ME, Chitayat D, Thomas M, Winsor E, Ferris LE, et al. Randomized controlled trial of misoprostol for second-trimester pregnancy termination associated with fetal malformation. Am J Obstet Gynecol 2004;190:755–62. 16. Behrashi M, Mahdian M. Vaginal versus oral misoprostol for second-trimester pregnancy termination: a randomized trial. Pak J Biol Sci 2008;11:2505–8. 17. Wong KS, Ngai CS, Yeo EL, Tang LC, Ho PC. A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum Reprod 2000;15:709–12.

22. Kapp N, Borgatta L, Stubblefield P, Vragovic O, Moreno N. Mifepristone in second-trimester medical abortion: a randomized controlled trial. Obstet Gynecol 2007;110: 1304–10. 23. 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;118:601–8. 24. Bracken H, Ngoc NT, Banks E, Blumenthal PD, Derman RJ, Patel A, et al. Buccal misoprostol for treatment of fetal death at 14–28 weeks of pregnancy: a double-blind randomized controlled trial. Contraception 2014;89:187–92. 25. Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27: 485–9. 26. Feldman DM, Borgida AF, Rodis JF, Leo MV, Campbell WA. A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination. Am J Obstet Gynecol 2003;189:710–3. 27. Ramsey PS, Savage K, Lincoln T, Owen J. Vaginal misoprostol versus concentrated oxytocin and vaginal PGE2 for secondtrimester labor induction. Obstet Gynecol 2004;104:138–45.

18. von Hertzen H, Piaggio G, Wojdyla D, Nguyen TM, Marions L, Okoev G, et al. Comparison of vaginal and sublingual misoprostol for second trimester abortion: randomized controlled equivalence trial. Hum Reprod 2009;24:106–12.

28. Dickinson JE, Jennings BG, Doherty DA. Mifepristone and oral, vaginal, or sublingual misoprostol for second-trimester abortion: a randomized controlled trial. Obstet Gynecol 2014; 123:1162–8.

19. Bhattacharjee N, Saha SP, Ghoshroy SC, Bhowmik S, Barui G. A randomised comparative study on sublingual versus vaginal administration of misoprostol for termination of pregnancy

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Vaginal Misoprostol Compared With Buccal Misoprostol for Termination of Second-Trimester Pregnancy: A Randomized Controlled Trial.

To compare the efficacy of vaginal misoprostol with buccal misoprostol for second-trimester termination of pregnancies...
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