Ekerhovd, E. MD, PhD; Radulovic, N. MD; Norström, A. MD, PhD
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.
Address reprint requests to: Erling Ekerhovd, MD, PhD, Sahlgrenska University Hospital, Department of Obstetrics and Gynecology, Göteborg University, Göteborg, SE-413 45, Sweden; E-mail: email@example.com.
Financial support was provided by the Foundation of Handlanden Hjalmar Svensson and the Göteborg Medical Society.
Received August 16, 2002. Received in revised form October 3, 2002. Accepted October 17, 2002.
OBJECTIVE: To compare the efficacy of 400 μg of misoprostol with that of 1 mg of gemeprost as cervical priming agents when administered vaginally 3 to 4 hours before first-trimester vacuum aspiration abortion.
METHODS: In a prospective controlled trial 90 nulliparous women who requested termination of pregnancy before 12 weeks' gestation were randomized to receive vaginally either misoprostol or gemeprost for cervical priming. The force to dilate the cervix was measured by the use of a cervical tonometer connected to Hegar dilators from 3 to 10 mm. The main outcome measures were baseline cervical dilation; the peak force to dilate the cervix at 8, 9, and 10 mm; and the cumulative force to dilate the cervix to 10 mm.
RESULTS: Baseline cervical dilation did not differ significantly between the women who received misoprostol and those who were treated with gemeprost. Neither the peak force required to dilate the cervix at 8, 9, and 10 mm nor the cumulative force to dilate the cervix to 10 mm showed any significant difference between the two groups.
CONCLUSION: Vaginally administered misoprostol (400 μg) is as effective as gemeprost (1 mg) for cervical priming 3 to 4 hours before surgical termination of first-trimester pregnancies.
Dilation of the uterine cervix in first-trimester surgical termination of pregnancy is associated with intraoperative complications such as cervical lacerations and uterine perforation. Cervical priming before surgery has been shown to reduce this risk, especially in nulliparous women. 1–4 Gemeprost (Cervagem; Aventis Pharma, Stockholm, Sweden), a vaginally administered prostaglandin E1 analogue of 1 mg, is one of the most commonly used cervical priming agents, with several studies having shown its efficacy. It is marketed with an optimal time interval between intravaginal administration and surgical dilation of 3–5 hours. However, gemeprost is expensive and unstable and requires refrigeration for storage
Misoprostol (Cytotec; Pharmacia AB, Stockholm, Sweden), another prostaglandin E1 analogue, marketed for prevention and treatment of gastric ulcers, has proved to induce cervical softening before first-trimester surgical termination of pregnancy. 5–7 Misoprostol can be administered either orally or vaginally. It is inexpensive, has a long shelf life, does not require refrigeration, and is widely available, being registered in more than 80 countries. Despite the fact that several studies have shown that misoprostol is an effective cervical priming agent, it is not licensed for preoperative cervical ripening.
Several studies have examined the route of administration, dose of misoprostol, and interval between administration and surgery. 8–12 It has been concluded that vaginal administration of misoprostol seems to be more effective than oral administration. 9,10 High doses of misoprostol (600–800 μg) are not well tolerated, mainly because of abdominal pain caused by prostaglandin-induced contractions of the uterine body. 9,13,14 On the other hand, a low dose of 200 μg of misoprostol seems to be less effective than 400 μg. 8 An interval of more than 6 hours between administration of misoprostol and surgical dilation increases the incidence of side effects, such as abdominal pain and vaginal bleeding. 5 Taken together, it has been suggested that 400 μg of misoprostol vaginally 3 to 4 hours before surgery provides optimal dilation with minimal side effects. 8–12
Our purpose was to compare the priming effect of 1 mg of gemeprost with that of 400 μg of misoprostol when the agents were administered vaginally 3 to 4 hours before suction curettage in nulliparous women.
MATERIALS AND METHODS
The study was approved by the human medical ethics committee of Göteborg University. A total number of 90 Scandinavian women of 8–12 weeks' gestation requesting surgical termination of pregnancy between April 2000 and December 2001 agreed to participate in the study. Included were only healthy, nulliparous women of at least 18 years of age with a viable intrauterine singleton pregnancy of 8–12 weeks' gestation, confirmed by transvaginal ultrasonography. Exclusion criteria were symptoms or signs of a threatened miscarriage and any kind of disease, defined as daily use of medication.
Three to 4 days before the operation routine medical history, physical medical examination, transvaginal ultrasonography, and cervical sampling for Chlamydia trachomatis were done by one of the gynecologists at our clinic. After informed consent, the participating women were randomly allocated to one of two groups by opening sequentially numbered, sealed, opaque envelopes that had been prepared with random number tables. The envelopes were opened by the research nurse. Forty-five women were assigned to receive 1 mg of gemeprost as preoperative cervical priming, whereas the other 45 women were allocated to have pretreatment with 400 μg of misoprostol.
Three to 4 hours before vacuum aspiration, the medication was placed into the posterior vaginal fornix by the nurse. At the operating theater, the vagina was cleansed by the assisting nurse to remove any remaining medication. Neither the participating women nor the operating physician were aware of the preoperative medication, and one and the same physician performed all the operations. The baseline dilation of the cervix and the peak force (N) required to dilate the cervix to 10 mm were measured. Dilation was done with a cervical tonometer (Figure 1) connected to graduated Hegar dilators from 3 to 10 mm. 15 The peak force required to enter the internal cervical os with each successive dilator was registered. Baseline cervical dilation was defined as the first dilator to produce a peak force of more than 5 N. The cumulative force required to dilate the cervix was calculated by summing the peak forces produced by each dilator up to 10 mm. After dilation, the uterus was evacuated with a suction curette in accordance with the standard procedure of the clinic. Syntocinon, 10 U administered intravenously, was given routinely at the beginning of the suction curettage to reduce blood loss. All registered clinical data were stored until accomplishment of the study and then analyzed by an independent statistician.
A sample size of 60 women in two groups, estimated by the Altman nomogram, 16 would yield 80% power at the 5% significance level of detecting a standardized difference of 0.75 N in the cumulative force required to dilate the cervix. For statistical comparison of the two groups, the Fisher nonparametric permutation test was used. The distribution of the variables are given as mean ± standard deviation and range. All significance tests were two tailed and conducted at the 5% significance level.
All 90 women recruited were found compliant and were included in the trial. No positive tests for C trachomatis were found. There were no significant differences in mean age, gestational age, and priming-to-operation interval between the two groups of women. Side effects after application of a dilating agent, mainly lower abdominal pain, were minor, and none of the women required analgesics.
Patient characteristics and intraoperative findings are presented in Table 1. The baseline cervical dilation in the gemeprost group did not differ significantly from that of the misoprostol group (P = .58). Likewise, the peak forces needed to dilate the cervix at 8, 9, and 10 mm were similar in the two groups (Ps = .75, .73, and .97, respectively). The cumulative force required to dilate the cervix to 10 mm showed huge interindividual differences, but no significant difference was found between the two groups (P = 61).
All 90 pregnancy interruptions were uneventful. Although not specifically studied in the present trial, none of the women had an estimated intraoperative blood loss of more than 350 mL. No complications were reported at postoperative control.
It is well known that complications due to difficult or inadequate dilation of the cervix can be reduced by preoperative cervical priming. The need for safe pregnancy interruptions makes it highly desirable to find simple methods to effect a safe and easily performed uterine evacuation at low costs. Various prostaglandin preparations, including misoprostol and gemeprost, have previously been shown to facilitate cervical dilation, thereby reducing the risks of iatrogenic complications. Several studies that examined various doses and premedication time intervals have concluded that administration of 400 μg of misoprostol vaginally 3 to 4 hours before surgery provides optimal dilation with minimal side effects. 8–12 The marketed dosage and premedication time interval for gemeprost is 1 mg 3–5 hours before surgery.
We performed a MEDLINE search for the key word “misoprostol” in combination with one of the following key words: “cervical ripening,” “gemeprost,” and “abortion.” All studies reported in English and published from January 1994 to June 31, 2002 were evaluated. Based on this search, only two studies have previously compared the clinical effects of vaginal misoprostol and gemeprost as pretreatment regimens before vacuum aspiration. El-Refaey and coworkers 13 demonstrated that 600 μg of misoprostol 2–4 hours before surgical evacuation led to an increase in the baseline cervical dilation, reduction in mechanical force required to dilate the cervix, and reduction in blood loss relative to 1 mg of gemeprost. However, other studies have shown that high doses of misoprostol (600–800 μg) are less well tolerated than the 400-μg regimen, causing side effects such as abdominal pain and vaginal bleeding. 9,12
Henry and Haukkamaa 17 studied the effect of 4 to 5 hours of cervical priming with 200 μg of misoprostol compared with 1 mg of gemeprost for at least 3 hours before vacuum aspiration. They found no significant difference in cervical dilation between the two groups, but misoprostol was associated with fewer side effects than gemeprost. Because most first-trimester surgical abortions are carried out in outpatient clinics, it was speculated that a shorter treatment time interval with 400 μg of misoprostol would be more practical in clinical work.
In the present study cervical resistance was objectively measured by the use of a cervical tonometer connected to graduated Hegar dilators from 3 to 10 mm. By this method the baseline cervical dilation; the peak force to dilate the cervix at 8, 9, and 10 mm; and the cumulative force required to dilate the cervix to 10 mm did not differ significantly when either 400 μg of misoprostol or 1 mg of gemeprost were administered 3 to 4 hours before surgery. The observation that misoprostol is as effective as gemeprost when dilation to 10 mm is performed is clinically important. When vacuum aspiration is performed in gestational weeks 10–12, cervical dilation up to 10 mm is normally necessary. The cervical priming effect of 400 μg of misoprostol when the uterine cervix has to be dilated to 10 mm has not been examined before. The present study demonstrates that the effect of 400 μg of misoprostol administered vaginally 3 to 4 hours before surgery is comparable to that of 1 mg of gemeprost, even when dilation to 10 mm is needed.
In addition, it appears clear that cervical priming with 400 μg of misoprostol for 3 to 4 hours is associated with minimal side effects. Thus, typical prostaglandin side effects such as nausea and lower abdominal pain were minor, and none of the women required analgesics. This observation is in agreement with previous studies showing that pretreatment with 400 μg of misoprostol for 3–5 hours is not associated with serious side effects. 8,11,12 This fact is important because it has previously been demonstrated that higher doses of misoprostol (600 and 800 μg) for 2 hours were associated with significantly more abdominal pain and even fever. 12 In that study it was also shown that a shorter priming interval of 2 hours failed to achieve optimal cervical dilation.
Another important consideration is that misoprostol tablets are easy to administer. In the present study the priming agents were inserted into the vagina by the research nurse to standardize the study procedure. In our outpatient clinic vaginal self-administration of 200 μg of misoprostol 10–12 hours before evacuation has been practiced on a regular basis in more than 3000 women since 1995. During these years, self-administration has always been conducted after preabortion counseling, clinical examination, transvaginal ultrasonography, and chart documentation performed by a gynecologist. However, several of the women have experienced lower abdominal pain, vaginal bleeding, and even abortion during this premedication interval. Studies in which vaginal misoprostol has been used in doses from 200 μg to 1000 μg over 12 hours before vacuum aspiration have demonstrated that an increasing dosage and time interval before evacuation are associated with an increase in side effects. 18 It therefore seems clear that both clinical priming effect and side effects are dose and time dependent.
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