Misoprostol moistened with acetic acid or saline for second trimester pregnancy termination: a randomized prospective double-blind trial

Bulent Yilmaz1,3, Sefa Kelekci1, Ibrahim Egemen Ertas1, Serkan Kahyaoglu1, Murat Ozel1, Necdet Sut2 and Nuri Danisman1

1 Zekai Tahir Burak Women’s Health Education and Research Hospital, Department of Obstetrics and Gynaecology, Ankara and 2 Department of Biostatistics, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey

3 To whom correspondence should be addressed at: Camlitepe Mahallesi, Taskent Sokak, 26/8, Kurtulus, 06600, Ankara, Turkey. E-mail: drbulentyilmaz{at}yahoo.com


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: This study was conducted to evaluate the efficacy and side effects of a new regimen of 800 µg misoprostol administered intravaginally every 6 h up to a maximum of three doses in 24 h for second trimester pregnancy termination. METHODS: A total of 66 women seeking termination of second trimester pregnancy (30 fetal structural anomaly, six chromosomal abnormality and 30 fetal death) were randomly assigned to one of two treatment groups: (i) intravaginal misoprostol moistened with 3 ml of 5% acetic acid in group A (n = 33); or (ii) intravaginal misoprostol moistened with 3 ml of saline in group B (n = 33). RESULTS: The overall median (range) induction–abortion interval was 10 h (2–46) [10 h (4–35) in 36 live fetuses and 9 h (2–46) in 30 dead fetuses, P = 0.515]. All of the patients in both groups aborted within 48 h (100% success rate). The median (range) induction–abortion interval revealed a significantly faster delivery time (P < 0.001) in group A [8 h (2–24)] than in group B [14 h (3–46)]. CONCLUSIONS: This new regimen of 800 µg of vaginal misoprostol every 6 h for a maximum of three doses in 24 h was an effective alternative method for second trimester abortion. In addition, misoprostol moistened with acetic acid was significantly more effective than misoprostol moistened with saline.

Key words: acetic acid/blood pressure/misoprostol/saline/second trimester pregnancy termination


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Abortion-related complications increase significantly as gestational age increases. Induction of abortion after 14 weeks of gestation is associated with a sharp rise in the rate of complications and in the consequent medical costs (Ngai et al., 2003Go). In addition, compared with women whose abortions were performed at or before 8 weeks of gestation, women whose abortions were performed in the second trimester were significantly more likely to die of abortion-related causes (Bartlett et al., 2004Go).

Various methods, including dilatation and evacuation, oxytocin infusion and amnioinfusion of hypertonic saline or urea, have been used previously for second trimester abortion and intrauterine death. There has been a recent worldwide trend towards alternative methods such as misoprostol use for second trimester abortion.

Misoprostol, a synthetic 15-deoxy-16-hydroxy-16-methyl analogue of naturally occurring prostaglandin E1, is marketed for use in the prevention and treatment of peptic ulcer disease. It is inexpensive and can be stored at room temperature. Although not registered for such use, misoprostol has been widely used in obstetrics and gynaecology for cervical priming, medical abortion and induction of labour. Various doses, routes and protocols for medical termination of second trimester pregnancy have been investigated (Ngai et al., 2000Go; Jain and Mishell, 2001Go; Dickinson and Evans, 2003Go; Feldman et al., 2003Go; Akoury et al., 2004Go).

Previous studies have demonstrated greater efficacy with vaginal misoprostol versus oral administration (Gilbert and Reid, 2001Go; Bebbington et al., 2002Go). The pharmacokinetics of the two routes of administration differ, with a slower absorption and longer onset of action for the vaginal route (Ziemann et al., 1997Go). Nonetheless, drug absorption after vaginal administration varies widely (Ziemann et al., 1997Go; Tang et al., 2002Go) and this may be due to the medium in which it is placed.

In a previous study (Ziemann et al., 1997Go), particulate remnants of misoprostol were identified at the time of repeat dosing. Others have also revealed the incomplete dissolution of the tablets (Zalanyi, 1998Go; Singh et al., 1999Go; Whitecar et al., 1999Go). To overcome this problem, various investigators have used a tablet moistened either with normal saline (Mishell et al., 1998Go; Creinin et al., 1999Go; Wiebe, 2001Go; Gilles et al., 2004Go) or with acetic acid (Ficicioglu et al., 1996Go; Singh et al., 1999Go; Sanchez-Ramos et al., 2002Go; Kelekci et al., 2004Go) to increase its success rate, but they reported contradictory results.

The aim of this randomized prospective controlled double-blind trial was to evaluate both the efficacy and side effects of 800 µg of misoprostol moistened either with acetic acid or with saline and subsequently administered intravaginally every 6 h up to a maximum of three doses in 24 h.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This prospective, double-blind, randomized, controlled trial was conducted between September 2004 and February 2005. Sixty-six healthy women seeking termination of second trimester pregnancy were progressively enrolled in the study. All subjects gave informed consent to participation in the study, which was approved by the institutional review board of Zekai Tahir Burak Women’s Health, Education and Research Hospital at Ankara.

After sonographic diagnosis of a fetal structural abnormality or intrauterine fetal death and detection of chromosomal abnormality, all patients, who were counselled by a perinatologist, genetic counsellor and the local ethics committee of our hospital, were offered termination of pregnancy.

Study inclusion criteria were: otherwise healthy women aged between 20 and 40 years old; a singleton, dead or live fetus at 14–24 weeks’ gestation with a complex fetal anomaly and/or abnormal fetal karyotype; with no cervical dilation and effacement; and haemoglobin ≥10 mg/dl. The exclusion criteria were: a known scarred uterus from either a previous Cesarean delivery or myomectomy whereby the endometrial cavity was entered; those with active bleeding; an allergy to prostaglandins; or in the case of ruptured membranes and vaginitis.

The women were randomly allocated to receive intravaginal 800 µg misoprostol (Cytotec 200 µg tablets, Ali Raif, Istanbul, Turkey) moistened either with 3 ml of 5% acetic acid (pH 2) in group A or with 3 ml of saline in group B. This was placed in the posterior vaginal fornix by a doctor (I.E.E.) at 6 h intervals for a maximum of three doses in 24 h, and repeated if delivery had not occurred within a maximum period of 48 h. No additional misoprostol dose was repeated if the patient was in the active phase of labour and had at least 70% cervical effacement with 2 cm opening.

Patients were divided into two groups using a computer-generated randomization (Random Numbers Generator Pro; Segobit Software trial version) each consisting of 33 patients. Assignments were placed in sealed, serially numbered, opaque envelopes which were opened when the women were recruited. The patients and the research team were blinded to the solution used to moisten the misoprostol, except for the doctor (I.E.E.) who had given the misoprostol to patients and therefore was aware of the treatment allocation. This doctort ultimately did not assess treatment outcome, which was evaluated by another doctor (B.Y.).

Patients who were willing to participate in the study were informed that they would follow a pharmacological procedure to terminate pregnancy. Subjects were also informed about the benefits, adverse effects and possible risks. They were told that in the case of failure to abort completely, a surgical or other pharmacological method for abortion would be performed.

Before the start of therapy, a blood sample was taken to determine haemoglobin, blood group and Rh factor. The blood pressure (BP), pulse and adverse effects of misoprostol were recorded every 4 h during treatment. BP was measured with the auscultatory method from the right antecubital artery with regard to Korotkoff sound five by the same nurse. Antiemetics were administered as indicated. Pethidine hydrochloride 50 mg (Aldolan, Liba Laboratuarlari A.S., Istanbul, Turkey) was given for pain relief if women requested it.

After abortion, all patients received 20 IU of oxytocin in 1000 ml of physiological serum at an infusion rate of 125 ml/h as in the previous study (Feldman et al., 2003Go). We determined that the products of gestation (fetus and placenta) had been successfully removed by transvaginal ultrasound to establish that the abortion was complete (GE Logic 200, NY). Any retained products of the placenta (not delivered spontaneously 1 h after delivery of the fetus) were curetted clean with a sharp uterine curette.

The main outcome measures were: induction–abortion interval (time from placement of the first dose of misoprostol until the time of expulsion of the fetus); successful abortion (defined as delivery within 48 h); the total number of doses (how many times 800 µg misoprostol was given for induction); the number of retained placentas; and haemoglobin decrease (a blood sample was taken 12 h after abortion). Secondary outcome measures were the side effects of the medication including nausea, vomiting, diarrhoea, chills and fever (temperature >38°C).

There was no literature on which to base sample size calculation. Therefore, using information from our pilot study (15 women in each group), the sample size was estimated with the assumption of a type I error ({alpha}) of 0.05 (with the use of a one-sided equivalence test), a power of 0.80 (1 – {beta}; type II error) and a 30% difference in outcome between the two groups, the sample size for each group in the study should be 31. We recruited 66 women in total; 33 in group A and 33 in group B.

The SPSS 11.0 (SPSS, Chicago, IL) statistical package was used for statistical analysis. The normality of distributions of variables was analysed by the Kolmogorov–Smirnov equality of distribution test. The independent samples t-test was used to determine the statistical significance of differences in normally distributed variables between groups; the paired t-test was used for determinaion of the statistical significance of differences between before and after values of variables in each groups. The {chi}2 and Mann–Whitney U-tests were used for determination of the statistical significance of differences in non-normally distributed variables between groups. The statistical significance of differences between before and after values of variables between groups was analysed using analysis of covariance (ANCOVA). A P-value of <0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Sixty-six women were enrolled for this study, 33 women in group A and 33 in group B. All of the patients completed the study except for one in group B, who wanted to discontinue the treatment due to excessive nausea and vomiting attacks after the first dose of misoprostol.

The distribution of patients’ age, body mass index, parity and gestational age was similar in both groups. Likewise, indications for termination of pregnancy and baseline haemoglobin values were not different between the groups (Table I).


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Table I. Patient characteristics

 

The characteristics of the abortion process and its relationship to misoprostol doses are shown in Table II. The overall median (range) induction–abortion interval was 10 h (2–46) [10 h (4–35) in 36 live fetuses and 9 h (2–46) in 30 dead fetuses, P = 0.515]. Fifty-seven of 65 patients (87.7%) delivered within 24 h. None of the patients required further interventions to effect delivery since all of them in both groups aborted within 48 h (100% success rate).


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Table II. Comparison of outcome measures between groups

 

The median induction–abortion interval revealed a faster delivery time in group A than in group B [8 h (2–24) and 14 h (3–46), respectively; P < 0.001]. All but one patient in group A (96.7%) and 25 (78.1%) in group B aborted within 24 h. The difference was statistically significant (P < 0.01). The total number of doses of misoprostol in group A was significantly fewer than in group B (P < 0.05). Delivery with the first dose of misoprostol occurred in 24 (70.6%) of the women in group A and 12 (37.5%) of the women in group B (P < 0.05). There was no statistically significant difference in terms of the mean haemoglobin decrease and the incidence of retained placenta between groups (Table II). Furthermore, considering analgesic requirements, 11 (%) and 10 (%) women had an i.m. aldolan injection in group A and B, respectively, and the difference was not statistically significant.

The numbers of patients with and without side effects including nausea, vomiting, fever, chills and diarrhoea were similar in the two groups (Table III).


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Table III. Incidence of side effects

 

Table IV shows the comparison of the BP of patients before and 4 h after the start of treatment. When the groups were ignored, there was a significant decrease in systolic (P < 0.001) and diastolic (P < 0.001) BP. Systolic and diastolic BP in group A were 119.3 ± 15.4 and 79.1 ± 10.2 mmHg at baseline and 105.2 ± 13.4 and 66.9 ± 10.2 mmHg 4 h after the initial dose of misoprostol, respectively. Baseline systolic and diastolic BP in group B was 117.5 ± 13.4 and 76 ± 11 mmHg, and 104.5 ± 14.1 and 67 ± 11.2 mmHg 4 h later, respectively. There was no significant inter-group difference with respect to systolic and diastolic BP at baseline and 4 h after the initial dose of misoprostol.


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Table IV. Overall blood pressure (BP) change in patients (n = 65)

 

There was one severe maternal complication in our study: a primigravid patient whose 23-week-old fetus had a neural tube defect aborted 32 h after the commencement of the first misoprostol dose moistened with saline. The placenta was retained and removed with difficulty using a sharp uterine curette, and postpartum haemorrhage was excessive. Baseline haemoglobin was 10.6 g/dl and it was 4.8 g/dl just 2 h after the removal of the placenta. We did not exclude this patient from the study, but her postpartum haemoglobin level was not included in the statistical analysis.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
To the best of our knowledge, this is the first clinical trial evaluating the efficacy and side effects of a new regimen where intravaginal 800 µg misoprostol moistened either with acetic acid or saline was given at 6 h intervals for a maximum of three dosages in 24 h for second trimester pregnancy termination.

This randomized prospective controlled double-blind study showed that this new regimen was very effective, as all of the women delivered in 48 h regardless of the method used. Moreover, the regimen of group A was significantly more effective in achieving delivery with a short induction–abortion interval (P < 0.001), in attaining abortion within 24 h (P < 0.01), and also in obtaining a higher delivery rate with the initial dose (P < 0.05) than the group B regimen. Furthermore, the total number of misoprostol doses was significantly lower in group A than in group B (P < 0.05). Nonetheless, the two groups revealed similar results with regard to retained placenta, side effects, haemodynamics of patients and mean decrease in haemoglobin.

Misoprostol has been widely used for induction of second trimester abortion and intrauterine death, which is a potentially hazardous procedure. Recent studies focus mainly on the optimization of misoprostol dosing regimens by comparing various dosages, dosing intervals and the route of administration. The dosage of misoprostol used ranged from 100 to 800 µg, with the dosing intervals ranging from 3 to 12 h. The efficacy of the misoprostol regimen improved when a higher dose (400–800 µg) was given at a shorter drug interval (3–4 h) (Ngai et al., 2003Go). Thus, the regimen of 800 µg misoprostol at 6 h intervals was used in this study.

Successful termination was generally considered to be the expulsion of the fetus within 48 h. In our study, the overall success rate was 100% with 10 h (4–35) median induction–abortion interval in live pregnancies and the abortion rate within 24 h was 89.4%. It has been reported that the successful abortion rate within 48 h of a regimen of 400 µg vaginal misoprostol every 6 h (same frequency but half the dose we used) in second trimester abortion was 75.7%, the abortion rate within 24 h was 60.8%, and the mean induction–abortion interval was 43.4 ± 64.8 h (Wong et al., 2000Go). Other authors using misoprostol doses of 800 µg every 12 h (same dose but twice the frequency as ours) for second trimester termination of pregnancy achieved a 91% complete abortion rate and the majority of subjects (85.6%) aborted within 24 h, with mean expulsion times of 12.1 ± 3.5 h for the fetus and 13.2 ± 3.8 h for the placenta (Carbonell et al., 2004Go).

Misoprostol tablets are not prepared for vaginal use, and local factors in vaginal usage may play an important role in its efficacy. Since it is desirable to achieve a constant plasma profile, it is important to develop a preparation or medium that would ensure more complete dissolution of the vaginal misoprostol tablet in order to achieve optimal efficacy. Misoprostol tablets are known to liquefy better in acidic medium (Karim et al., 1989Go; American Hospital Formulary Service Drug Information, 1998Go).

The impact of moistening misoprostol tablets administered intravaginally has been assessed by several studies. It was found that moistened misoprostol tablets were more effective for medical termination of early pregnancy than dry tablets (Wiebe, 2001Go). Likewise, others reported that using intravaginal misoprostol moistened with saline solution resulted in a higher success rate of early pregnancy termination (Mishell et al., 1998Go).

In contrast, in a randomized multicentre trial, moistened misoprostol tablets were compared with dry misoprostol tablets which were administered intravaginally for medical abortion after methotrexate (Creinin et al., 1999Go). The authors concluded that tablet moistening before vaginal administration did not significantly improve efficacy. Similarly, a recent randomized controlled trial demonstrated that the expulsion rate was not improved by saline solution-moistened misoprostol in first trimester pregnancy failure (Gilles et al., 2004Go).

In addition, others investigated whether misoprostol dissolved in acetic acid was more effective than misoprostol dissolved in water, and the authors concluded that use of acetic acid to dissolve vaginal misoprostol had not improved the efficacy in achieving successful cervical dilatation for pre-abortion cervical priming (Singh et al., 1999Go). In a similar study, however, it was revealed that intravaginal usage of misoprostol moistened with acetic acid was significantly more effective in pre-abortion cervical priming than misoprostol moistened with normal saline (Kelekci et al., 2004Go). In our present study, misoprostol tablets moistened with acetic acid were more effective in second trimester termination of pregnancy when compared with misoprostol moistened with saline.

It was observed in our study that the overall incidences of side effects were nausea 26.1%, vomiting 20%, diarrhoea 21.5%, fever 27.6% and chills 38.5%. Those reported in a recent study, in which 800 µg misoprostol doses were given every 12 h intravaginally to terminate pregnancies within 12–20 weeks gestation, were 23.4, 32.7, 54.3, 21.9 and 77.7%, respectively (Carbonell et al., 2004Go). Another study (Wong et al., 2000Go) using 400 µg vaginal misoprostol every 6 h for termination of second trimester pregnancy between 14 and 20 weeks showed that the frequencies of side effects were nausea 12.2%, vomiting 10.8%, fever 12.2% and diarrhoea 2.7%. Thus, when the frequency was doubled using the same dose, incidences of side effects were decreased (our study versus that of Carbonell et al., 2004Go). However, when the dose was decreased by half at the same frequency, incidences of side effects were even higher (our study versus that of Wong et al., 2000Go). This means the longer the dose interval, the less the side effects.

Arachidonic acid metabolites such as prostaglandins of the E series have effects on BP. Nonetheless, the only randomized, placebo-controlled clinical trial in the literature was investigating the effect of misoprostol (prostaglandin E1 agonist) on BP in 15 essential hypertensives to characterize the effects of a 400 µg oral dose (Kailasam et al., 1994Go). The authors concluded that oral misoprostol had exerted a modest but transient antihypertensive effect. However, haemodynamic evaluation of all patients in the present study showed that systolic and diastolic BP decreased significantly (both P < 0.001).

Vaginal pH might affect the pharmacokinetics of vaginally administered misoprostol (Gunalp et al., 2000). Unfortunately, the vaginal pH of the patients was not measured in this study. However, patients with rupture of membranes and those with vaginitis where vaginal pH may be changed were not included in this study.

In conclusion, in this small study, it was shown that, regardless of the method used, the regimen of vaginal misoprostol 800 µg every 6 h for a maximum of three doses in 24 h was an effective alternative method for second trimester abortion. In addition, misoprostol moistened with acetic acid was significantly more effective than misoprostol moistened with saline.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors would like to thank Selma Yörükan, MD, from Hacettepe University Faculty of Medicine, Deparment of Physiology, whose native language is English, for the final professional linguistic revision of the manuscript.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on February 21, 2005; resubmitted on May 6, 2005; accepted on June 16, 2005.





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