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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Objective  To compare the effectiveness of vaginal misoprostol administered 6 or 12 hourly for second trimester pregnancy termination.

Design  A randomised controlled trial.

Setting  University teaching hospital.

Sample  Two hundred and seventy-nine pregnant women at gestations between 14 and 26 weeks undergoing pregnancy termination.

Methods  Women were randomised to receive 600-μg misoprostol tablets vaginally either every 6 hours or every 12 hours until abortion occurred.

Main outcome measures  Induction–abortion interval, success rate within 24 and 48 hours and adverse effects.

Results  There was no significant difference in the median induction to abortion interval 6 hours (16 hours) and 12 hours (16 hours; P= 0.80). The total dose of misoprostol was higher in the 6-hour group (1800 vs 1200 μg). The cumulative abortion rates within 24 hours were 74% and 67% and within 48 hours 94% and 92%, in the 6- and 12-hour groups, respectively. Fever was more common in the 6-hour group (53%) versus the 12-hour group (31%; P < 0.001). The incidence of nausea, vomiting, diarrhoea, severe bleeding and abdominal pain were similar.

Conclusions  Misoprostol (600 μg) administered at 12-hour intervals was associated with fewer adverse effects and was as effective as a 6-hour interval.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Progress in the field of fetal diagnosis has resulted in an increased number of second trimester pregnancy terminations. Mifepristone, a progesterone receptor antagonist, is effective in shortening the induction to abortion interval when used in combination with prostaglandins, but it is expensive.1,2

Recent reports have demonstrated that misoprostol, a synthetic prostaglandin E1 analogue, is a promising alternative prostaglandins.3–7 It is stable at room temperature and widely available, but its adverse effects, such as fever, nausea, vomiting and abdominal pain, are still of concern. Efforts to optimise the doses and interval to maximise effectiveness and minimise complications are therefore important.

Since 1995, we have been investigated the role of vaginal misoprostol for term labour induction, termination of pregnancy in first and second trimester and tried to find optimum regimen for the use of misoprostol.8–13 Our previous findings suggested that 600 μg of misoprostol is more effective than 200 and 400 μg8,9 but no advantage was found from increasing misoprostol to 800 μg,10 which was associated with a significant increase in fever (71% with 800 μg and 27% with 600 μg).10

This study is focussed primarily on adjusting the interval between doses. Zieman et al.14 demonstrated that the plasma level of misoprostol reached the peak slowly (80 minutes) after vaginal administration and the level was sustained up to 4–6 hours. The objective of this trial was to test our hypothesis that reducing the interval between doses from 12 to 6 hours would achieve a higher abortion rate within 24 hours with shorter induction to abortion interval.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

The study was carried out at the university tertiary care hospital. The protocol was approved by Hospital Ethics Committee. Women with live pregnancies between 14 and 26 weeks of gestation undergoing induced abortion for various indications according to criteria agreed upon by the Department Ethical Committee were recruited. Termination of pregnancy was not offered beyond 22 weeks of gestation apart from lethal fetal conditions.

The gestational age was confirmed by ultrasound measurement in all women. If dates were uncertain or if postmenstrual age differed from ultrasound examination by more than one week, the gestational age assigned by ultrasound was used. Exclusion criteria included unstable cardiac disease, recent severe asthmatic attack, severe hepatic or renal impairment and ruptured membranes. Women who fulfilled the entry criteria were counselled and given details of the trial. Written informed consent was obtained from each participant.

The women were randomly allocated by computer-generated number (Epi info version 6; World Health Organization, Geneva, Switzerland) to receive vaginal misoprostol 600 μg either every 6 hours or every 12 hours until abortion occurred. The assignments were put into sealed envelopes, which were opened when the women were recruited. This was an open study; both investigators and women knew the doses and the assigned time interval. The side effects including nausea, vomiting, diarrhoea, severe bleeding and fever (temperature ≥38°C) were recorded. Pulse rate, blood pressure and body temperature were monitored every 4 hours. Two oral tablets of 500-mg paracetamol or parenteral pethidine 100-mg analgesia were provided at 4 hourly intervals if required for pain. Two tablets of paracetamol were also provided every 4 hours if the body temperature was ≥38°C followed by wet sponge if necessary.

The induction to abortion interval was defined as the time taken from the initial insertion of misoprostol until expulsion of the fetus. Oxytocin was not given to accelerate placental expulsion. If the placenta appeared complete, no further interventions were undertaken. If the placenta was incomplete or failed to be expelled after 1 hour, an evacuation of uterus was carried out under general anaesthesia. Complete abortion was defined as the expulsion of both the fetus and the placenta without operative intervention. The amount of blood loss during abortion was assessed clinically. If abortion did not occur following the final dose of misoprostol at the end of 48 hours, they continued with the same regimen. If a woman failed to abort after five days, intravenous high concentration of oxytocin was added 6 or 12 hours after the last dose. Women were observed in the ward for a minimum of 6 hours following the complete expulsion. All women were given a follow up appointment within two weeks of termination.

On the basis of our previous study,10 it would be beneficial to reduce the dose interval from every 12 hours to every 6 hours if we can achieve a success rate at 48 hours of 93% and within 24 hours of 82%. One hundred and thirty-eight women were needed in each group to have the power of 80% and alpha error of 0.05 (two sided). These calculations were based on delivery within 24 hours. Continuous variables were analysed with unpaired t test and Mann–Whitney U test. Categorical variables were analysed with the χ2 test. P < 0.05 was considered as statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

This study was performed between December 2000 and December 2003. A total of 280 women, 140 each, were recruited (Fig. 1). One woman in the 12-hour group was excluded because of leaking amniotic fluid before misoprostol administration. There were no significant differences between groups in age, gestation, parity and history of caesarean section (Table 1).

image

Figure 1. Trial protocol.

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Table 1.  Baseline characteristics. Values are presented as n (%) or mean [SD].
 Every 6 hours (n= 140)Every 12 hours (n= 140)
Age (years)29 [7.9]30 [7.5]
Gestation (weeks)19 [2.4]19 [2.4]
Nulliparae70 (50)73 (52)
Previous caesarean section19 (14)10 (7.1)

Adverse effects are shown in Table 2. All three women who needed blood transfusion had underlying β-thalassaemia haemoglobin E disease.

Table 2.  Adverse effects after misoprostol administration. Values are presented as n (%).
 Every 6 hours (n= 140)Every 12 hours (n= 139)P
Nausea14 (10)8 (5.8)0.19
Vomiting12 (8.6)6 (4.3)0.15
Diarrhoea55 (39)48 (35)0.41
Temperature ≥38°C74 (53)43 (31)<0.001
Chill26 (19)15 (11)0.07
Intramuscular analgesia47 (34)39 (28)0.32
Blood loss >500 mL4 (2.9)3 (2.2)0.71
Blood transfusion2 (1.4)1 (0.7)0.57

The characteristics of the abortion process are shown in Table 3. The cumulative success rate in the whole group under 18 weeks was not significantly different. Above 18 weeks, the success rate within 24 hours was 76 (74%) in the 6-hour group and 64 (61%) in the 12-hour group (P= 0.049).

Table 3.  Characteristics of abortion. Values are presented as median (25, 75 centiles) or n (%).
 Every 6 hours (n= 140)Every 12 hours (n= 139)P
Induction–abortion interval (hours)
Primigravidae17 (12, 31)20.5 (13, 32)0.33
Multigravidae14.6 (11, 24)12.7 (11, 22)0.46
Whole group15.8 (12, 26)16.0 (12, 30)0.80
 
Abortion within 24 hours
Primigravidae50 (71)41 (56)0.06
Multigravidae53 (76)52 (79)0.67
Whole group103 (74)93 (67)0.22
 
Abortion within 48 hours
Primigravidae64 (91)67 (92)0.94
Multigravidae67 (96)61 (92)0.42
Whole group131 (94)128 (92)0.63
 
Complete abortion rate101 (72)93 (67)0.34

Figure 2 shows the survival analysis from the misoprostol administration time to fetal delivery in the 6- and 12-hour groups. All women in both groups aborted within five days using intravaginal misoprostol alone. The longest induction to abortion interval (woman in the 6-hour group) was 121 hours and 32 minutes. However, abortion occurred before oxytocin was added. The median amount of misoprostol administered in the 6-hour group (1800 μg; range 600–13200 μg) was significantly more than in the 12-hour group (1200 μg; range 600–4800 μg, P < 0.001). The 25, 75 centiles in the 6-hour group were 1200, 2850 and in the 12 hour group were 600, 1800, respectively.

image

Figure 2. Survival plot for induction to abortion interval.

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In the 6-hour group, 84 women (60%) returned for the follow up. Three women had dilatation and curettage for incomplete abortion and one woman had endometritis, which was successfully treated with oral doxycycline and metronidazole. In the 12-hour group, 71 women (51%) returned for the follow up; there were no complications in these women.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Jain et al.15 compared 200-μg vaginal misoprostol applied 6 to 12 hourly for second trimester pregnancy termination. They found no difference in the induction to delivery time but their small number did not have adequate statistical power. On the other hand, Wong et al.16 had sufficient numbers to compare 400-μg vaginal misoprostol applied every 3–6 hours. They found every 3 hours was more effective than every 6 hours.

The objective of this study was to evaluate two regimens of misoprostol that by reducing the dose interval from 12 hours to 6 hours might increase abortion rate within 24 hours and reduce the induction to abortion interval. We measured the induction to fetal delivery interval instead of the time from start to placental delivery because our primary aim was to deliver the fetus without having to resort to surgery. Also, delay of placental delivery might not be related to the effect of misoprostol. We continued to apply the same treatment until the fifth day because, from our previous study of 172 women, all aborted within five days using 600-μg intravaginal misoprostol alone every 12 hours.9 However, the results demonstrated the same to be effective between the 6- and 12-hour intervals. There was no significant difference in the abortion rate within 24 and 48 hours, the induction to abortion interval and the complete abortion rate. When we looked at the cumulative success abortion rates in women with gestational age less than 18 weeks and those 18 weeks or over, we found that in the 18 weeks and over, misoprostol applied every 6 hours had a better success rate within 24 hours than the 12 hourly application, but the difference was only slight if one took into consideration the total dose used and the adverse effects. The incidence of fever was significantly higher with the 6 hourly interval. This might result from the higher amount of total misoprostol that the women received. We believe that using only one uterotonic agent at a time would help reduce the chance of uterine rupture because this study included 29 women with previous caesarean section of which six women had more than one.17

Although the half life of misoprostol is 80 minutes, pharmacokinetic studies show that the peak plasma level after vaginal administration dropped slightly at the end of 4 hours.14,18 This might result from the difference in the rate of absorption due to misoprostol tablets not being prepared for vaginal use. Interpatient variations because of local effect influencing drug absorption can be expected for both plasma misoprostol levels and uterine activity.14,18 Our results revealed that vaginal administration of misoprostol every 12 hours is as effective as every 6 hours. This prolonged uterine stimulation may result in part from a direct effect of misoprostol on uterine contraction and slow absorption of misoprostol administered vaginally. This long lasting effect of misoprostol concurs with the Bugalho et al.19 report in which a single dose of 200-μg misoprostol can induce second trimester abortion in most women. Developing vaginal preparation of misoprostol should benefit the patient in terms of consistency of drug effect. This study was not designed to evaluate delayed complications and no conclusion about delayed complications can be drawn. Hence, the low follow up was due in part to being a tertiary care hospital. Many women were referred from other parts of the country and failed to return.

In conclusion, vaginal administration of 600-μg misoprostol every 12 hours is an effective regimen for medical termination of second trimester pregnancy. Reducing the drug interval to 6 hours does not enhance success rate of abortion but increases adverse effect instead.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References
  • 1
    Ashok PW, Templeton A. Nonsurgical mid-trimester termination of pregnancy: a review of 500 consecutive cases. Br J Obstet Gynaecol 1999;106: 706710.
  • 2
    Bartley J, Baird DT. A randomised study of misoprostol and gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy. BJOG 2002;109: 12901294.
  • 3
    Akoury HA, Hannah ME, Chitayat D, et al. Randomized controlled trial of misoprostol for second-trimester pregnancy termination associated with fetal malformation. Am J Obstet Gynecol 2004;190: 755762.
  • 4
    Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002;186: 470474.
  • 5
    Jain JK, Mishell DR. A comparison of misoprostol with and without laminaria tents for induction of second trimester abortion. Am J Obstet Gynecol 1996;175: 173177.
  • 6
    Jain JK, Mishell DR. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second trimester pregnancy. N Engl J Med 1994;331: 290293.
  • 7
    Wong KS, Ngai CS, Wong AY, Tang LC, Ho PC. Vaginal misoprostol compared with vaginal gemeprost in termination of second trimester pregnancy. Contraception 1998;58: 207210.
  • 8
    Herabutya Y, O-Prasertsawat P. Second trimester abortion using intravaginal misoprostol. Int J Gynaecol Obstet 1998;60: 161165.
  • 9
    Herabutya Y, Chanrachakul B, Punyavachira P. Vaginal misoprostol in termination of second trimester pregnancy. J Obstet Gynaecol Res 2000;26: 121125.
  • 10
    Herabutya Y, Chanrachakul B, Punyavachira P. Second trimester pregnancy termination: a comparison of 600 and 800 micrograms of intravaginal misoprostol. J Obstet Gynaecol Res 2001;27: 125128.
  • 11
    Herabutya Y, Chanrachakul B, Punyavachira P. Induction of labor with vaginal misoprostol for second trimester termination of pregnancy in the scarred uterus. Int J Gynaecol Obstet 2003;83: 293297.
  • 12
    Herabutya Y, O-Prasertsawat P, Pokpirom J. A comparison of intravaginal misoprostol and intracervical prostaglandin E2 gel for ripening of unfavorable cervix and labor induction. J Obstet Gynaecol Res 1997;23: 369374.
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    Herabutya Y, O-Prasertsawat P. Misoprostol in the management of missed abortion. Int J Gynaecol Obstet 1997;56: 263266.
  • 14
    Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90: 8892.
  • 15
    Jain JK, Kuo J, Mishell DR. A comparison of two dosing regimens of intravaginal misoprostol for second trimester termination. Obstet Gynecol 1999;93: 571575.
  • 16
    Wong KS, Ngai CS, Yeo ELK, Tang LCH, Ho PC. A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum Reprod 2000;15: 709712.
  • 17
    Herabutya Y, Chanrachakul B, Punyavachira P. Induction of labor with vaginal misoprostol for second trimester termination of pregnancy in the scarred uterus. Int J Gynecol Obstet 2003;83: 293297.
  • 18
    Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PYK, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93: 275280.
  • 19
    Bugalho A, Bique C, Almeida L, Faundes A. The effectiveness of intravaginal misoprostol (Cytotec) in inducing abortion after eleven weeks of pregnancy. Stud Fam Plann 1993;24: 319323.

Accepted 11 May 2005