Misoprostol efficacy in second and third trimester pregnancy terminations

Objective

Retrospective analysis and evaluating reliability and efficiency of misoprostol in 87 cases having pregnancy termination by using vaginal misoprostol between 12 and 35 weeks’ gestation.

Methods

The present study was conducted at Celal Bayar University, Gynecology and Obstetrics Clinic, Perinatology unit between January 2006 and November 2008. A total of 87 cases attended at the Celal Bayar University Medical Faculty, Obstetrics and Gynecology Clinic, Perinatology unit between January 2006 and November 2008 and underwent pregnancy termination at more than 12 weeks gestation were included in the present study. 8 cases having uterine scars due to previous cesarean section and 79 cases having no previous uterine surgery were retrospectively analyzed. In all the cases, the induction agent administered was vaginal misoprostol. In cases having previous cesarean delivery, following the initial dose of 200 µg between 12-24 weeks’ gestation and 100 µg at more than 24 weeks’, misoprostol was administered 200 µg every 4 hours for a period of 24 hours until contractions started. In cases having no uterine scar, following the initial dose of 400 µg between 12-24 weeks’ and 200 µg after 24 weeks’, misoprostol was added 400 µg and 200 µg every 4 hours for a period of 24 hours, respectively. If contractions did not start, the same dose scheme was repeated after a 12 hours resting period and, if needed, an additional method was used.

Results

53 cases (60.9%) were nulliparous and 34 cases (39.1%) were multiparous. 49 out of 87 (56%) cases were between 12 and 20 weeks’ gestation, while 38 (44%) cases were at more than 20 weeks’gestation. The median induction-to-termination interval which was 28.5 h (1-137 h) for all the cases was 30.8 h in nulliparous cases and 24.8 h in multiparous cases, and no statistically significant difference was detected (p=0.32). In 16 cases (18%) duration of pregnancy termination was over 48 h. In 10 cases (11.5%) pregnancy termination was achieved by using an additional method. Compared to the cases having no uterine scar, additional methods were used significantly more in cases having previous cesarean delivery (25% versus 10%; p=0.000). Complications developed in 2 nulliparous cases (2.3%): fever and hemorrhage in one case and hemorrhage in one case. 1 case underwent cesarean section due to hemorrhage. No uterine rupture was observed in the cases.

Conclusion

Using vaginal misoprostol is a fairly safe, efficient and non-invasive method in second and third trimester pregnancy termination. However, studies with wider series are needed to assess reliability of using misoprostol in cases with uterine scarring.

Keywords

Misoprostol, termination of pregnancy, induction, second and third trimester

Introduction

In recent years, prostaglandins and its analogs have been widely used for medical termination of pregnancy in obstetrics practice. Today, increasing antenatal diagnosis of fetal malformations with prenatal ultrasonography and serum screening tests (1) and labor induction in 15% of all pregnancies (2) increase use of prostaglandin for this purpose. Also, increasing number of cesarean deliveries (3) and pregnancy termination due to medical indications increase use of prostaglandin analogs in patients with a history of previous cesarean. Pregnancy termination by using prostaglandins and its analogs provide a safe alternative to surgical termination (4). Misoprostol is a synthetic prostaglandin E1 analog used in prophylaxis and treatment of gastroduodenal ulcers, and its usage in pregnancy is contraindicated due to its uterotonic effect (5). Basic aims in the second and third-trimester pregnancy terminations are achieving a safe, effective, inexpensive and fast termination with minimum adverse effects. Owing to these, using misoprostol for induction is very common although it is not licensed in many countries (6). Misoprostol is a cheap drug that does not require special transfer and storage conditions as other prostaglandin analogs used previously. It can be administered orally and causes less gastrointestinal adverse effects. Recently, it has been used to induce labor in live term fetuses too (7). However, more uterine tacyhsystole (8) and uterine rupture when administered vaginally in the second trimester pregnancy terminations in women having a history of cesarean section (9) prevent elimination of concerns about this drug. Although there are increasing number of publications demonstrating that misoprostol is safe in the second trimester pregnancy termination in cases having uterine lower segment transverse incision (10), real incidence of uterine rupture is not known. In this retrospective study, our aim was to evaluate the safety and efficacy of using intravaginal misoprostol in inducing of the second and third trimester pregnancy terminations.

Methods

In the present study, retrospective analysis were performed on 87 cases whose pregnancies were terminated by vaginal misoprostol at more than 12 weeks gestation due to maternal or fetal indications at Celal Bayar University Gynecology and Obstetrics Clinic Perinatology Unit between January 2006 and November 2008. Parity, gestation week, obstetric history, presence of uterine scar, requirement of additional method, indications, induction-to-termination interval and delivery complications were recorded for all the cases. After getting the approval of Celal Bayar University, Medical Faculty, Perinatology Committee for termination of pregnancies, all the patients were informed on the issue that misoprostol is not licensed for pregnancy terminations and asked to sign an informed consent form that includes detailed information on complications.
Vaginal misoprostol protocol to be used for termination was determined according to the gestational week and presence of uterine scar. 1x200 µg misoprostol was placed in the posterior vaginal fornix in pregnancies having uterine scar due to previous cesarean section while 2x200 µg misoprostol was used in cases having no uterine scar at less than 24 weeks gestation. During the first 24 hours following the initial dose, vaginal misoprostol administration at initial dose was repeated every 4 hours until uterine contractions started. Before misoprostol administration at more than 24 weeks gestation in pregnancies with live fetuses, fetocide was performed by intracardiac lethal dose potassium chloride administration under ultrasonographic guidance. Then, 1x100 µg and 1x200 µg vaginal misoprostol was started in cases having uterine scar and cases without uterine scar, respectively. When contractions did not start, 1x200 µg misoprostol was administered every 4 hours. If contractions did not start at the end of the first 24 hours, dose scheme appropriate to the characteristics of the cases in both groups were repeated the same way after a 12 hours rest period. When pregnancy termination was not completed after 48 hours following the initial misoprostol administration, an additional method was used. Additional methods included using oxytocin, foley catheter in cervical channel and traction or termination of pregnancy by cesarean section. Epidural analgesia was used for pain management when requested by the cases.
Following vaginal misoprostol administration, vital signs and adverse effects observed in the cases were recorded every 4 hours. In cases having fever was equal to or more than 38.5C, 1gr paracetamol and, if needed, cold compress were used. When required, 10 mg metoclopramide or 50 mg cyclizine were administered as antiemetic agents every 8 hours. While induction-to-termination interval was defined as the time that elapsed from the initial misoprostol administration until fetal expulsion, the need to use an additional method for termination was defined as failure of misoprostol. 1 hour was allowed for placenta removal after fetal expulsion. Patient was examined carefully by ultrasonography to see whether complete removal of fetus and placenta was achieved. When incomplete termination was suspected or findings of rest placenta were present, surgical evacuation of the uterus was planned, and all the cases were followed for bleeding control at delivery service for 2 hours. All women were called for controls 1 month after termination.
All the data obtained from the cases were evaluated using SPSS (15.0 for Windows) program. In statistical evaluations Mann-Whitney U test was used for continuous variables and chi-square test was used for categorical variables. P<0.05 was considered as statistically significant.

Results

In this study, results obtained from 87 women having termination between 12 and 35 weeks’ gestation in a 3 years period were analyzed. Table 1 shows the characteristics of the women who underwent vaginal misoprostol induced termination at the second and third trimesters and Table 2 shows termination indications.
53 cases (60.9%) were nulliparous and 34 cases (39.1%) were multiparous. While no significant difference was observed between nulliparous and multiparous cases with respect to induction to termination interval (p=0.32), required total misoprostol dose was significantly higher in nulliparous women (p=0.019). Treatment results are given in Table 3. In 49% of the cases, termination was achieved in the first 24 hours. While the ratio of nulliparous women terminating within 24 hours after misoprostol administration was 52%, the ratio of multiparous women terminating within 24 hours was 44%. Pregnancy was terminated within 36 hours in 63% of the cases while termination was achieved within 48 hours in 70% of the cases. All the terminations were completed in 4 days. Only in one case, termination was not achieved despite using an additional method to misoprostol induction, and cesarean section was used for delivery. In the said case having in utero mort fetus at 17 weeks’ gestation, termination was tried to be achieved vaginally using other also additional methods due to bleeding, but upon failure, cesarean decision was taken after 55 hours.
In 90.8% of the cases (n=79), there was no uterine surgery history while 9.2% had previous cesarean section. 3 cases out of those having previous cesarean section were at more than 24 weeks’ gestation. Additional methods were required in 11.5% (n=10) of all the cases. 7 of the cases requiring additional methods were nulliparous, 3 were multiparous and there were two previous cesarean section cases among them. Both of these 2 cases having previous cesarean section and in whom additional methods were used for pregnancy termination were at more than 24 weeks’ gestation; and foley catheter was inserted in cervical channel in 1 of them being at 28 weeks’ gestation. The other case was at 34 weeks’ gestation and her pregnancy was terminated using oxytocin additionally. Additional method was used when termination was not achieved when 48 hours elapsed after vaginal misoprostol administration and beginning of induction. Only in one case, additional method was used before 24 hours due to bleeding and oxytocin was added for termination in this case. Surgical evacuation of uterus due to placental retantion was needed in none of the cases.
Mean induction to termination interval was 31.3 hours in cases at more than 24 weeks’ gestation while the said interval was 27.7 hours in those at less than 24 weeks’ gestation; and there was no significant difference (p=0.62). In 2 cases at more than 24 weeks’ gestation, termination was achieved by using an additional method; however no complications developed in these cases. Among all patients, complications after induction by misoprotol were observed in 2 cases. One case had hemorrhage while the other had both fever and hemorrhage. Both of these cases were at less than 24 weeks’ gestation and nulliparous. Pregnancy was terminated by cesarean section in one of these cases while oxytocin was used for termination in the other case. Table 4 shows a comparison of cases at more than 24 weeks’ and less than 24 weeks’ gestation with regard to induction to termination intervals and complication rates.

Discussion

Misoprostol has been widely used in induction of pregnancy terminations during the second and third trimesters (6). However, there exist a great range of variation in its administration route, frequency and dose. Misoprostol providing a noninvasive regimen for termination of pregnancy offers many advantages such as oral, rectal, sublingual or vaginal administration, low cost, stability at room temperature; and different doses of misoprostol have been shown to be effective (11). However, effective minimum dose, either orally or vaginally, for labor induction or pregnancy termination with minimum adverse effects both for fetus and mother in case of presence of a live fetus should be evaluated in further studies (7,12). There exist no standard regimen scheme neither for induction of labor in the third trimester nor for pregnancy termination in the second and third trimesters.
Pregnancies were terminated by vaginal misoprostol induction in 88.5% of our cases; however, in 11.5% of the cases an additional method was required along with misoprostol. Chawdhary et. al. (13) compared mifepristone oral followed by vaginal misoprostol (RU 486) with misoprostol alone for pregnancy terminations during first trimester and found that mifepristone oral followed by vaginal misoprostol provides a better success rate with fewer complications. They reported a success rate of 94% with combined mifepristone and vaginal misoprostol and 86% with only vaginal misoprostol. However, they stated that misoprostol alone was not as successful as combined regimen due to some limitations of their study. In a retrospective analysis of 252 cases, Mazouni et al. (14) showed a 99.2% success by combined vaginal misoprostol and mifepristone administration in pregnancy terminations at more than 15 weeks’ gestation. In a study where they used a combination of misoprostol and mifepristone, Tang et al. (15) showed that sublingual administration was more effective than oral administration. In another study where they used only misoprostol (16), they reported a success rate of 95% in vaginal administration and 91% success rate in sublingual administration after 48 hours. Similarly, in a retrospective study, Goh et al. (17) achieved termination of pregnancy at between 12 and 24 weeks’ gestation by vaginal misoprostol with later addition of mifepristone, if required, and reported that termination was completed 97.9% and 99.5% after 24 and 36 hours from the beginning of termination respectively. Mifepriston is an antagonist of progesterone receptor and it has been shown that using mifepristone before analogue in second trimester pregnancy terminations with prostaglandin analogue decreases the time that elapses from the initial administration of prostaglandin until fetus expulsion (18). This antigestagen sensitizes the pregnant uterus to exogenous prostaglandin. However, misoprostol is more commonly used in developing countries as it is cheap and requires no special storage conditions compared to mifespristone which is an expensive and requires special storage conditions. Bhattacharjee et al. (19) compared sublingual and vaginal administration of misoprostol in second trimester pregnancy terminations and found that both of the methods were equally effective. The failure rate was 9.42% after 48 hours in vaginal administration, which is a consistent with the results (9.5%) of Wong et al.(20) but higher than the rate (5%) reported by Tang et al.(16). While misoprostol was initially administered orally, today vaginal administration is preferred. Pharmokinetic studies showing that systemic bioavaliability of vaginally administered misoprostol is three times higher than that of misoprostol administered orally supports its vaginal administration (21). Behrashi et al. (22) compared oral and vaginal misoprostol administration in second trimester pregnancy terminations and found that vaginal administration of misoprostol resulted in a higher success rate with no significant differences in induction to delivery time and complications rates between vaginal and oral administration. By vaginal administration of misoprostol, in our study, we obtained a success rate of 85% in pregnancies at less than 24 weeks and 93.7% in those at more than 24 weeks, which makes a total success rate of 88.5%. In our study, termination was achieved within 48 hours in 70% of the cases. Except one case, all the pregnancies were terminated in 96 hours. Our results are not as high as those of the clinic studies reporting very high success rates; however, when compared to that of Tang et al. (16), we used lower doses of misoprostol and observed fewer complications. Tang et al. (16) found that incidence of fever increased significantly in vaginal administration and there existed no significant difference between sublingual and vaginal administration with respect to other complications. They reported that this could have resulted from the higher bioavaliability of repeated vaginal misoprostol. As a result, Tang et al. stated that vaginal misoprostol should the first choice but sublingual administration could be used as an alternative. In our study, we observed fever in 1 case and hemorrhage in 2 cases. Compared to multiparous women, the total misoprostol dose used for termination was significantly higher in nulliparous women and although there was no statistically significant difference with respect to mean induction-to-termination interval between nulliparous and multiparous women, it was longer in nulliparous women. These results are consistent with the results of the previous studies reporting a difference between responses of nulliparous and multiparous women to induction agents (17, 23). Goh et al. (17) stated that this could be resulted from the difference between cervical compliances of two groups. Goh et al. reported that, compared to nulliparous women, surgical evacuation of uterus was twice more in multiparous women and stated that the same result had been obtained in some previous studies too. Goh et al. completed termination surgically if bleeding was more than 500 ml during fetus or placenta removal. Bartley et al. (24) stated that more efficient establishment of pregnancy in multiparous women might cause this. 37% of our cases were at more than 24 weeks’ gestation, and mean induction-to-termination interval was moderately longer in these cases. Mozouni et al. (14) showed in their analysis that when terminations were achieved by misoprostol and mifepristone, pregnancies at more than 24 weeks’ gestation were associated with longer induction interval and higher morbidity. However, with respect to morbidity in pregnancies at more than 24 weeks’ gestation, results of our study differ from that of Mazouni et al. 8 of the 10 cases requiring additional method for termination were at less than 24 weeks’ gestation and similarly 2 cases having complications were at less than 24 weeks’ gestation too. However, compared to our study, Mazouni et al. (14) studied significantly more cases in their analysis.
Today, clinicians do not use a standard protocole in using misoprostol for pregnancy terminations. There is no consensus with respect to the administartion way, dose and frequency as there is a few number of well planned randomized controlled trials on this subject. It has been found that vaginal administration is more effective than oral administration, possibly because of accumulation at plasma levels and causes less gastrointestinal complications (21,25). However, there is a variability in the absorption of vaginally administered misoprostol among different individuals. For this reason, sublingual administration is favored; there may be variability in the absorption among different individuals but it has been reported that it reaches high serum peak concentrations by rapid absorption (26). Tang et al. (16) reported in their study that patients prefer sublingual administration.
In pregnancies at more than 12 weeks’ gestation, pregnancy terminations are carried out by medical methods rather than surgical procedures. Morbidity is lower in termination achieved by medical methods (4), and genetic analysis of fetus is possible. Adverse effects of prostaglandins are related mainly dose. However, various administration methods, dose schemes and intervals related to misoprostol make it hard to compare data. In our study, complications were observed in only 2 cases and both of these cases were nulliparous. Requirement of higher misoprostol dose in nulliparous women may lead to this result. Sanches-Ramos et al. (9, 27) showed in a study and meta-analysis that use of misoprostol increases risk of tachysystole and hyperstimulation without causing negative perinatal outcomes. Dodd et al. (6) found that use of misoprostol causes adverse effects at a low rate in the second and third trimester pregnancies; however, they showed that data were not sufficient to evaluate rare but life threatening complications such as uterine rupture. It has been drawn attention to the fact that history of cesarean section is not a contraindication for using misoprostol but there exist an increased risk of uterine rupture regardless of the gestational week (8). In a retrospective analysis of 91 cases, Aslan et al (28) showed that induction of delivery with misoprostol causes a two fold increased risk of uterine rupture in women with previous cesarean section and they stated that one should be careful with respect to maternal reliability.
In our study we obtained a success rate of 88.5% by misoprostol in second and third trimesters pregnancies and termination was achieved by using an additional method in 11.5% of the cases. Among those where an additional method was used, in only one case, we had to terminate pregnancy by cesarean section due to hemorrhage. Our complication rate (2.3%) was rather low. With respect to failure of misoprostol, although some of which report lower rates (16), our results are in consistency with many studies in the literature (19, 20, 22). Taking these data into consideration, we can say that misoprostol is highly effective and reliable in second and third trimester pregnancy terminations.
Although number of cases with a history of cesarean section is low in our study, no complications related to misoprostol were observed in these cases. Additional methods were used two times more in terminating pregnancies of cases having history of cesarean section but these additional methods did not increase the risk of complications.

Conclusion

For standard usage of misoprostol in the future, detecting optimal dose and optimal administration method should be the most important concern of the studies. Thus, evaluation of rare complications such as uterine rupture would be more objective and satisfactory. Once optimal dose and intervals are detected, further studies involving larger samples and multiple centers are required.

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	File/Dsecription
	Table 1. Characteristics of the study group.
	Table 2. Indications for termination.
	Table 3. Treatment results of women having termination by misoprostol during the second and third trimester.
	Table 4. Complication rates and abort intervals in pregnant women having an abortion between 12 and 24 and > 24 weeks’ gestation.