British Journal of Obstetrics and Gynaecology March 1999, Vol 106, pp. 266-269

Vaginal misoprostol for pre-abortion cervical priming: is there an optimal evacuation time interval?

*Kuldip Sin@ Associate Professor/Senior Consultant, *Y. F. Fong Registral; *R. N. V. Prasad Professor and Senior Consultant, **F. Dong Medical Biostatistician

*Department of Obstetrics and Gynaecology, National University Hospital, Singapore; **Biostatistics Consultancy Unit, National University of Singapore Medical Institute

Objective To determine the optimal evacuation time interval in the use of vaginal misoprostol for cervi-

Design Prospective double-blind randomised study.

Setting Fertility Control Centre, National University Hospital, Singapore.

Methods Sixty healthy nulliparous women requesting legal termination of pregnancy between 6 and 11 weeks of gestation were randomly allocated to either the 400 pg or 600 pg misoprostol group. Vacuum aspiration was performed after three hours in the 400 pg group and at the end of two hours in the women given 600 pg misoprostol. Using Hegar's dilator, degree of cervical dilatation before operation was measured. Other parameters assessed included the amount of additional dilatation required (if < Hegar 8), pre-operative and intra-operative blood loss, and associated side effects.

For the 600 pg group, only five women (16.7%) achieved a cervical dilatation of 2 8 nun, compared with 28 women (93.3%) in the 400 pg group. Using the 400 pg misoprostol group as a baseline, the odds ratio was 0.014 (95% CI 0.003-0.080) for 600 pg for successful pre-operative cervical dilatation of 2 8 mm. The mean cervical dilatation for 400 and 600 pg misoprostol was 8.1 mm and 6.6 mm, respectively ( P < 0.001). Despite the shorter evacuation time interval of two hours, the 600 pg dose was associated with an increase in side effects such as vaginal bleeding, abdominal pain and a fever of > 38-0"C. However, other than abdominal pain, no significant differ- ences in the frequency of these side effects were shown.

Conclusion Use of 400 pg misoprostol with a minimal evacuation time interval of three hours still appears the optimal dosage and evacuation time for cervical priming before fiist trimester termination of pregnancy.

cal priming before first trimester termination of pregnancy.

Results

INTRODUCTION Cervical priming before vacuum aspiration of first trimester unwanted pregnancies in nulliparous women is an important pre-requisite in reducing the risks of cer- vical injury and uterine perforation that are often associ- ated with mechanical cervical dilatation of a nulliparous cervix'.'. Misoprostol, a synthetic 15 deoxy-16 hydroxy 16-methyl analogue of naturally occurring prostaglandin E,, used for the prevention and treatment of peptic ulcers, has been used in several treatment regi- mens with varying degree of success for pre-abortion cervical ~ r i m i n g ~ - ~ . In a previous study the authors have shown that the optimal clinical dosage of intra-vaginal misoprostol for pre-abortion cervical priming is 400 pg, administered three to four hours before vacuum aspira-

Correspondence: Professor K. Singh, Department of Obstetrics and Gynaecology, National University Hospital, Lower Kent Ridge Road, Singapore 119074.

tion in first trimester nulliparae'. This is associated with minimal side effects and risks to the women.

Since first trimester vacuum aspiration is increasingly performed as an outpatient or day surgery basis, it would appear that a shorter evacuation time interval would be more acceptable for cervical priming. This would ensure that the vacuum aspiration could be per- formed earlier and the women observed for a reasonable time interval before returning home. Thus the aim of this study was to determine whether a higher dose of 600 pg of vaginal misoprostol administered with a shorter interval of two hours before vacuum aspiration would be as effective as the previously determined opti- mal dose of 400 pg administered three hours before vac- uum aspiration.

METHODS Sixty healthy pregnant nulliparous women between 6 and 11 weeks of gestation requesting legal termination of

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VAGINAL MISOPROSTOL FOR PRE-ABORTION CERVICAL P R I M I N G 267

a first trimester pregnancy were recruited for the study. The gestational age was determined by reliable men- strual history and confirmed either by pelvic examina- tion or ultrasound. Their pre-operative baseline haemoglobin was also estimated, and only women with a pre-operative haemoglobin of > 10 g/dL were recruited. Informed consent was obtained from all women.

The study was double blind and the women were ran- domised to either the 400 pg or 600 pg misoprostol dosage groups. Randomisation was achieved by the opening of one of 60 sequentially numbered, sealed envelopes prepared using random number tables. Since termination of pregnancy was performed on a day surgery basis, the women were admitted on the morning of the procedure, having fasted overnight. During vagi- nal examination on the morning of surgery, the appro- priate dose of misprostol pre-packed in a plastic foil was opened and inserted into the posterior vaginal fornix by a doctor who was not one of the surgeons assessing the treatment outcome. No premedication was given, but the women were told that should they experience pain, analgesics were available. In addition, their blood pres- sure, pulse rate, temperature and the occurrence of side effects, such as abdominal pain, vaginal bleeding, nau- sea, vomiting, fever and diarrhoea before the vacuum aspiration, were recorded. The severity of abdominal pain experienced by the women was assessed using a three-point response scale: no pain; minimal or moder- ate pain requiring no analgesics; and severe pain requir- ing analgesics. Pre-operative blood loss was approximately estimated by measuring blood from the vagina in a measuring cylinder. The degree of soaking of the sanitary pad was also noted.

Vacuum aspiration was performed under general anaesthesia after two hours when the 600 pg dose was administered, and after three hours when the dose was 400 pg. As it was not possible to perform every opera- tion exactly on the hour, arrangements were made to perform every vacuum aspiration within 15 minutes of the schedule timing. Vacuum aspirations were per- formed in all women by one of the two designated sur- geons (K.S. and Y.F.F.) to reduce individual variation. The randomisation schedule was unknown to the sur- geons. Pre-operative douchng of the vagina with water to cleanse any particulate remains of the misoprostol tablets helped to minimise knowledge by the surgeons of dosage used.

The degree of cervical dilatation before vacuum aspi- ration was measured by passing Hegar dilators in a descending order starting with Hegar 12. The size of the largest Hegar dilator that could be passed into the cervi- cal 0s without resistance was recorded as the cervical dilatation achieved. If the cervix had dilated to at least 8 mm, no further dilatation was performed and the preg- nancy was evacuated with a size 8 vacurette.

Other parameters that were assessed during the opera- tion included the amount of further dilatation required (if < Hegar 8) to permit passage of the suction vacurette, and intra-operative blood loss. Intra-operative blood loss was taken as the volume of the total uterine aspirate after sieving away the products of conception measured with a measuring cylinder.

At the end of the procedure the uterus was curetted clean with a small sharp uterine curette. Following the operation, the women were kept in hospital for three to four hours before discharge. For all women, the prod- ucts of conception were confirmed histologically. They attended a follow up six weeks later when a pelvic examination was performed and their haemoglobin level was checked.

The difference in pre-operative cervical dilatation was used as the main outcome indicator in the calcula- tion of the sample size. The sample size was estimated using two assumptions: firstly, using the method described by Meinert’ and Fisher and Van Belle* with the assumption of a type I error of 0.05 and a power of 0.95, and secondly a 50% difference in successful cervi- cal dilatation of 2 8 mm between the doses studied. Using both methods, the sample size for each dosage group in the study was calculated as 27. Assuming a 10% default at follow up, the number chosen was 30; therefore total sample size was 60.

Statistical analyses were performed using the Stu- dent’s t test, Fisher’s exact test and the Mann-Whitney U test. Variables that were normally distributed were presented as mean and standard error of the mean (SEM). Differences in the age of women, gestational age, and the pre-operative and post-operative haemoglobin levels were compared using the Student’s t test. The mean cervical dilatation was compared using the Mann-Whitney U test. In addition, odds ratios with 95% confidence interval were calculated for successful cervical dilatation (defined as a cervical dilatation of 2 8 mm after cervical priming) between the two dosage groups. The frequency of pre-operative side effects were compared with Fisher’s two-tailed exact test. The study was approved by the local ethical committee.

RESULTS The two treatment groups were similar in relation to maternal age and gestational age (Table 1). None of the women aborted during the interval between misoprostol administration and the scheduled time of evacuation of the uterus. Only five (16.7%) of the women who had received 600 pg misoprostol for a time interval of two hours achieved a cervical dilatation of 2 8 mm, com- pared with 28 (93.3%) who had received 400 pg miso- prostol for a time interval of three hours. Using the 400 pg dose as a baseline, the odds ratio was 0.014

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268 K. S l N G H E T A L

Table 1. Patient characteristics. Values are given as mean (SEM).

Misoprosto1400 pg (n = 30)

Misoprosto1600 pg (n = 30) P

Age (years) 22.2 (0.7) 22.1 (0.8) 0.950 Gestation (weeks) 7.8 (0.3) 1.7 (0.3) 0.862 Pre-operative Hb (g/dL) 12.2 (0.2) 12.2 (0.2) 0.893 Post-operative Hb (g/dL) 12.4 (0.2) 12.3 (0.2) 0.484

(95% CI 0.003-0.080) for 600 pg misoprostol for suc- cessful pre-operative cervical dilatation of 2 8 mm. The mean cervical dilatation for 400 pg and 600 pg miso- prostol was 8.1 and 6.6 mm, respectively (P < 0.001). The mean pre-operative and intra-operative blood loss was noted to be higher with 600 pg of misoprostol, but the difference was not statistically significant (Table 2).

More women experienced vaginal bleeding, abdomi- nal pain and had a fever of more than 38.0”C in the 600 pg group, compared with the 400 pg group (Table 3). However, only the incidence of women expe- riencing abdominal pain was statistically significant (P < 0.001). None of these women experienced severe pain requiring analgesia for pain relief.

At the follow up visit of six weeks, all women in the study had resumed their menses. None had any persis- tent or delayed side effects and there was no significant difference in the haemoglobin levels pre- and post-oper- atively in both groups (Table 1).

DISCUSSION

The success of cervical priming associated with the use

of vaginal misoprostol increases with both dosage and evacuation time interval””. In our previous study it was shown that only 23.3% of women receiving 200 pg of misoprostol achieved a successful dilatation at an evac- uation time interval of three to four hours, whereas the use of higher dosages of 400,600 or 800 pg of vaginal misoprostol was significantly more effective in achiev- ing a pre-abortion cervical dilatation of 2 8 mm at simi- lar evacuation time intervals’. Furthermore, we had also showed that there was no significant difference among the 400,600 or 800 pg in terms of achieving a success- ful cervical dilatation6. Instead, increasing the dose of vaginal misoprostol was associated with significantly more pre-operative side effects and intra-operative blood loss6.

The results of this preliminary study clearly demon- strates that the evacuation time interval is as important as the dosage used. Despite a larger dose, only 16.7% of women given 600 pg achieved a successful cervical dilatation of 1 8 mm when the evacuation interval was two hours, whereas the use of 400 pg with an evacuation time interval of three hours was significantly more effective in achieving a pre-operative cervical dilatation

Table 2. Intra-operative findings in two treatment groups. Values are given as n (%) or mean [SEMI.

Misoprosto1400 pg (n = 30)

Misoprosto1600 pg (n = 30) P

Cervical dilatation 1 8 mm 28 (93.3) 5 (16.7) < 0.001 * Mean cervical dilatation (mm) 8.1 [0.1] 6.6 [0.2] < 0.001 Re-operative blood loss (mL) 1.5 [0.6] 2.3 [0.8] 0.459 Intra-operative blood loss (mL) 88.3 [4.6] 94.0 [4.8] 0.6 12

*OR (95% Cl) = 0.014 (0@03-0~080).

Table 3. Side effects associated with different dosages of misoprostol. Values are given as n (%).

Misoprostol 400 pg (n = 30)

Misoprosto1600 pg (n = 30) P

Vaginal bleeding 6 (20.0) 8 (26.7) 0.761

Fever > 38°C 0 (0.0) 3 (10.0) 0.237

*OR (95% CI) = 10.3 (2641.4).

Abdominal pain 3 (10.0) 16 (53.3) < 0.001*

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of 2 8 mm and also a statistically significant greater mean baseline cervical dilatation (Table 2).

Despite the shorter evacuation time interval of two hours, the larger 600 pg dose of misoprostol was associ- ated with more side effects than those reported with the 400 pg dose with a longer evacuation time interval of three hours. Although only abdominal pain was shown to be significantly more common with the higher dose, there were three women who experienced a temperature of 238.0"C or more with this higher dose despite the shorter evacuation time interval.

CONCLUSION The results of this study confirms that the efficacy of vaginal misoprostol for cervical priming is both dose and time dependent. There appears to be a minimal evacuation time interval, and the results of our prelimi- nary study indicate this to be three hours. The use of 400 p,g misprostol vaginally with this evacuation time interval appears to be associated with mimimal side effects and risks to the woman. Increasing the dose to 600 pg with a shorter evacuation time interval failed to achieve the desired successful cervical dilatation of 2 8 mm and despite the shorter evacuation time interval was associated with more side effects in the women studied. However, we must concede that the sample size in this pilot study was too small to achieve the desired power to conclude this with confidence. A further evalu- ation using a larger sample size with adequate power to

evaluate the side effects would be important and forth- coming in the future.

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Received 26 June 1998 Returnedfor revision 21 October 1998 Accepted 18 November 199U

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