1 Department of Reproductive Biomedicine, National Institute of Health and Family Welfare and 2 Department of Obstetrics and Gynecology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
3 To whom correspondence should be addressed at: Department of Reproductive Biomedicine, National Institute of Health and Family Welfare, New Mehrauli Road, Munirka, New Delhi 110067, India. e-mail: pikeesaxena{at}hotmail.com
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Abstract |
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Key words: cervical priming/misoprostol/oral/sublingual/suction evacuation
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Introduction |
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In this study, we used 400 µg of sublingual or oral misoprostol (Misoprost, Cipla Ltd, Patalganga, India) for pharmacological cervical dilation in order to decrease the risk of injury and to achieve additional beneficial effects such as a reduction in the short- and long-term complications, amount of blood loss, pain intensity and duration of surgery, and to improve operative ease for the surgeon. Recently, misoprostol has been used for cervical priming before suction evacuation (SE) administered via the vaginal or oral route. The vaginal route has been found to be more effective but has a poorer patient acceptability compared with the oral route.
To date, we have found no evidence of a published randomized study comparing the sublingual versus oral route of misoprostol administration for first trimester surgical termination of pregnancy. The aim of the current study was therefore to compare the efficacy of sublingual versus oral misoprostol for cervical dilation during first trimester SE.
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Materials and methods |
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A total of 128 patients were assessed for eligibility. Of these, 28 patients were excluded from the study as 19 of them did not meet the inclusion criteria, six refused to participate and three were found to have high blood pressure.
After taking a thorough history, a complete physical and pelvic examination was done. Routine investigations including haemoglobin, urine analysis, blood group and Rhesus antigens were carried out.
Pre-operatively, side effects associated with misoprostol including pain, nausea, vomiting, diarrhoea, fever, shivering and bleeding per vaginum were recorded.
Intra-operatively, the amount of cervical dilation before performing SE was measured using Hegar dilators. The dilators were passed through the cervix in descending order starting with size 12. The largest Hegars dilator passing through the internal os without resistance was regarded as the dilation achieved. If the cervix had a dilation which was appropriate or more for that period of gestation, no further dilation was performed (Singh et al., 1998). In patients with insufficient dilation, a paracervical block was given in order to facilitate dilation and to reduce pain perception (Stubblefield, 1998
). SE was done by using the appropriate size of Karmans cannula, which was followed by curettage. The duration of surgery was measured from the start of dilation until the end of curettage. Intra-operative fluid loss was measured with a graduated cylinder as the volume of total uterine aspirate, after sieving away the products of conception (Singh et al., 1998
). The appropriate amount of liquor for that period of gestation was subtracted from the amount measured in order to calculate the amount of actual blood loss (Singh et al., 1998
). Pain intensity was measured during surgery after completion of curettage and prior to insertion of an IUCD, tubal ligation or laparoscopic sterilization. Recordings were made on a 010 numeric scale where the severity at the extreme left of the scale was considered as 0, i.e. no pain, and that at the extreme right of the scale was considered as maximum, i.e. 10. To simplify our results, scores between 0 and 3 were considered to be mild pain, 46 moderate pain, and 710 severe pain (requiring injectable analgesics) (Acute Pain Management Guideline Panel, 1992
).
Any cervical or uterine injuries ranging from superficial cervical laceration to an ascending cervical tear, uterine perforation or injury to any other intra-abdominal organs was noted. All patients underwent IUCD insertion or laparoscopic sterilization during the same sitting by choice.
Post-operatively, the incidence of nausea, vomiting, diarrhoea, fever, shivering and bleeding per vaginum was noted. As a routine, all patients received analgesics for 2 days and antibiotics for 5 days at discharge from the hospital.
Follow-up was done twice, first after 710 days and subsequently after 1 month or the first menstrual period. Any unscheduled hospital visit was noted.
The difference in pre-operative cervical dilation was the main outcome indicator for the calculation of sample size. Sample size was estimated using the method described by Meinert (1986), with the assumption of
error as 0.05 with a power of 0.95. The second indicator was a 50% difference in successful cervical dilation of at least 8 mm between the two routes. By this method, the sample size for each route group should be 27. Assuming a 20% default at follow-up, a sample size of 50 patients in each group was selected; therefore, the total sample size was 100.
Statistical analysis was done using the BMDP 7.0 analytical program (Biomedical Data Processor, Statistical Software, Los Angeles, CA). The median initial dilation of the case and control groups was compared using the MannWhitney non-parametric test. The significance of all other parameters was evaluated using the Student t-test. A P-value of 0.05 was considered as significant.
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Results |
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During follow-up at 710 days or after 1 month, none of these patients had any major complaints and their pelvic examination revealed no abnormality.
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Discussion |
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On the other hand, misoprostol is rapidly absorbed through the vascular buccal mucosa completely within 1015 min (Tang et al., 2002b). Recently a few pilot studies have been performed on the use of sublingual misoprostol for medical termination of pregnancy (Tang and Ho, 2001
; Tang et al., 2002b
) and it has been found to be a very effective and convenient route of administration.
Only one study conducted so far has evaluated the effect of sublingual misoprostol for cervical ripening before SE (Saxena et al., 2003) where it was found to be very eficacious. Tang et al. (2002a)
have compared the pharmacokinetics of misoprostol by the sublingual, oral and vaginal route, and the vaginal route with addition of water. They found that sublingual misoprostol achieved significantly higher peak serum concentrations (574.8 ± 250.7 pg/ml) than oral (287.7 ± 144.3 pg/ml; P < 0.01) or vaginal (125.2 ± 53.8 pg/ml) routes. The time to peak was similar in both the sublingual (26.0 ± 11.5 min) and oral groups (27.5 ± 14.8 min) and was significantly shorter than that in both vaginal groups. The area under the misoprostol acid concentration versus time curve up to 360 min was also significantly higher with the sublingual route (743.7 ± 291.2 pg/h/ml) compared with the oral (402.8 ± 151.6 pg/h/ml; P = 0.05) and vaginal (433.7 ± 182.6 pg/h/ml) routes. This probably explains the significantly higher cervical dilation for all periods of gestation in our study.
Oral misoprostol is a safe drug, which is being used for treatment of peptic ulcers without any serious reported side effects (Zieman et al., 1997). Misoprostol, a prostaglandin E1 analogue, binds to myometrial cells causing strong myometrial contractions leading to softening and dilation of the cervix. This results in separation of the conceptus from the uterine wall, thereby initiating the abortion process before SE. For these reasons, ease of dilation improves while operative blood loss and duration of surgery are reduced.
Out of a total of 50 patients in each group, three (6%) in the sublingual group and four (8%) in the oral group did not respond to misoprostol in terms of dilation of the cervix. The lack of response in 7% of our patients may have been due to the lack of EP-3/EP-2 prostanoid receptors (Okanlomo and Ngotho, 1999). These receptors are specific for misoprostonic acid, the diesterified derivative of misoprostol which is the active metabolite producing a biphasic effect (Okanlomo and Ngotho, 1999
). These receptors are known to increase in number with increasing gestational age. It is of paramount importance to explain to these women that pregnancy termination is mandatory and continuation of pregnancy may be associated with VIth and VIIth nerve palsies associated with a limb reduction defect or arthrogyposis congenital multiplex (Okanlomo and Ngotho, 1999
).
In cases of SE, misoprostol is required only for cervical priming. Long lasting and continuously increasing levels of misoprostol are not required as they are in cases of medical abortion. Therefore, a route which provides a faster and a higher plasma level is preferable. In fact, further studies should be done to evaluate whether dose and time interval of sublingual misoprostol can be reduced further without compromising its efficacy.
In conclusion, the sublingual route of misoprostol is preferable because of a high systemic concentration due to avoidance of first pass-metabolism in the liver, resulting in many beneficial effects as discussed above. At the same time, the unwanted gastrointestinal side effects are reduced to some extent compared with oral administration (El-Rafaey and Templeton, 1994).
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References |
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Submitted on May 28, 2003; resubmitted on August 19, 2003; accepted on September 17, 2003.