Human Reproduction, Vol. 19, No. 1, 77-80,
January 2004
© 2004 European Society of Human Reproduction and Embryology
Comparison between the sublingual and oral route of misoprostol for pre-abortion cervical priming in first trimester abortions
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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BACKGROUND: Misoprostol has been used for achieving cervical priming before suction evacuation (SE) by the oral or vaginal route, although both routes have their shortcomings. We evaluated the efficacy of the sublingual versus oral route of misoprostol for cervical priming before SE. METHODS: A prospective clinical trial was carried out in 100 women with a period of gestation of between 6 and 12 weeks who were sequentially allocated to two groups of 50 each. Both groups received 400 µg of misoprostol 3 h prior to SE by either the sublingual or the oral route. RESULTS: Demographically, both groups were similar. For all periods of gestation, sublingual misoprostol significantly improved cervical dilation (P < 0.001) with a reduction in duration of surgery (P = 0.024) compared with the oral route. Mean (±SD) pain scores for the sublingual and oral groups were similar (2.6 ± 1.4 versus 3.5 ± 1.1). No major complications occurred in either of the two groups. CONCLUSION: the sublingual route is an effective alternative to oral administration of misoprostol for cervical dilation. To the best of our knowledge, this is the first study to compare the efficacy of the sublingual versus the oral route of misoprostol for cervical priming before SE.
Key words: cervical priming/misoprostol/oral/sublingual/suction evacuation
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Introduction |
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The traditional method for termination of early pregnancy has been via surgical dilation of the cervix, followed by evacuation by suction aspiration performed under anaesthesia or sedation. It is an effective method with a success rate of >95% (Child et al., 2001
). As with any other surgical procedure, it is also associated with slight risks from anaesthesia and surgery. Medical abortion has been investigated as a non-invasive option for early abortions as it avoids the risk of anaesthesia and surgical trauma to the cervix, uterus and other organs. The disadvantages of medical abortion are that medical supervision and follow-up is of utmost importance, and that the longer time that it takes leads to prolonged bleeding, which causes anxiety for the patient. More importantly, medical abortion should be attempted only if the patient has access to 24 h emergency services, which makes it unsuitable for many rural areas. 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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Following institutional ethical approval, written informed consent was obtained from 100 women requesting first trimester abortion of pregnancy. They were enrolled in this prospective clinical trial carried out at the Family Planning Services of a tertiary care hospital in India during March and April 2002. The inclusion criterion was young healthy women with a period of gestation of between 6 and 12 weeks. Gestational age was estimated clinically and was confirmed by ultrasonography in cases where there was any doubt. Patients with a history of previous uterine surgery, allergy or contraindications to prostaglandins, infection, haemoglobin <9 g%, intrauterine contraceptive device (IUCD) in situ, uterine anomaly and chronic maternal illness were excluded. Patients selected for the study were sequentially allocated to two groups of 50 each. Patients recruited for the study were told to self-administer 400 µg of misoprostol at 7 a.m. at home on the day of scheduled surgery. They were to self-administer the drug by either the oral or sublingual route as advised by the recruiting investigator on the basis of sequential allocation. Patients were told to report to the hospital at 9.30 a.m. on the day of surgery. On the day of surgery, SE was carried out by the operating surgeon, who was different from the recruiting investigator, on the basis of the time of arrival of patients at the hospital and not necessarily in the order of allocation. Therefore, the operating surgeon who was blinded to the route of misoprostol administration could not predict the route of administration during surgery.
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 Hegar’s 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 Karman’s 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 0–10 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, 4–6 moderate pain, and 7–10 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 7–10 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 Mann–Whitney 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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No significant difference was observed between the two treatment groups with respect to age, parity, gestational age, religion, socio-economic profile and number of previous abortions (Table I). Pre-operatively, of the 50 patients who were given sublingual or oral misoprostol, 20 (40%) versus 18 (36%) had spotting or slight bleeding 1–2 h after ingestion of misoprostol, and 11 patients (22%) versus 10 (20%) complained of mild spasmodic pain. None of them had heavy bleeding or passage of the conceptus through the vagina during the waiting period. No patient reported any nausea, vomiting or diarrhoea, during the pre-operative period. Three patients (6%) in the sublingual group compared with two (4%) in the oral group developed fever, within 2–3 h after administration of misoprostol.
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A single experienced investigator conducted all the cases of SE. During SE, five (10%) patients in the sublingual group compared with seven (14%) in the oral group were given a paracervical block for mechanical cervical dilation, as these patients had a cervical dilation less than that required for that particular gestational age. The initial cervical dilation of both groups ranged from 0 to 12 mm (Table II), with the sublingual group having a significantly higher median (±SD) value than the oral group (10 ± 2.8 versus 8 ± 2.3 mm, respectively, P < 0.001). The volume of blood loss varied from 8 to 31 ml at different periods of gestation in the sublingual group compared with 8–33 ml in the oral group (Table II). The duration of surgery ranged from 2 to 6 min for the sublingual group compared with 2.5–9 min for the oral group (Table II), with the sublingual group having a lower overall mean operating time (P = 0.024). For the operating surgeon, operative ease was greater in the sublingual group where five patients required mechanical cervical dilation as compared with seven in the oral group.
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No major complication occurred in either of the two groups. The majority of patients in both the sublingual and oral misoprostol groups who already had good cervical dilation felt mild pain (90% versus 86%) during surgery. The mean pain score (Table III) of the sublingual group was 2.6 ± 1.4, compared with 3.5 ± 1.1 in the oral group (P = NS).
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Post-operatively, side effects were noted in both groups. Their profile is depicted in Table IV. The incidence of nausea was 2% versus 4% in the sublingual compared with the oral group. Bleeding per vaginum was within normal limits in both groups. There was no incidence of any episode of diarrhoea or vomiting noted in any patient during our study. Three (6%) subjects in the sublingual group compared with two (4%) in the oral group developed hyperthermia and shivering which was managed by cold sponging and injectable acetaminophen.
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Patient acceptability of sublingual misoprostol as compared with the oral route was similar in our study (96% versus 98%). When questioned regarding the route of administration, 98% patients stated that they would opt for the oral route in preference to the sublingual route if the option were available. Three patients (6%) found the taste of sublingual misoprostol unpleasant. Thirty-six patients out of 100 had a history of previous abortion (using mechanical cervical dilation), and all of them were more satisfied by this method compared with the previous experience.
During follow-up at 7–10 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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Due to lack of evidence from large randomized studies, consensus has not been drawn regarding the optimal dose, time interval and route of administration of misoprostol for pre-abortion cervical priming. The vaginal route has been found to be more beneficial than the oral route (Lawrie et al., 1996
; Zieman et al., 1997; Danielsson et al., 1999) probably due to a constant absorption leading to an accumulating plasma level with fewer gastrointestinal side effects. Vaginal absorption of misoprostol is inconsistent with large individual variations. Sometimes remnants of tablets can be obtained from the vagina hours after its administration. Therefore, although used widely, the vaginal route may not be the ideal route of administration for clinical practice.
On the other hand, misoprostol is rapidly absorbed through the vascular buccal mucosa completely within 10–15 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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Acute Pain Management Guideline Panel (1992) Pain Control After Surgery: A Patient’s Guide. AHCPR Pub. No. 92-0021 US Department of Health, Agency for Health Care Policy and Research Public Health Service, Rockville, MD.
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Submitted on May 28, 2003; resubmitted on August 19, 2003; accepted on September 17, 2003.
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