Department of Obstetrics & Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong
1 To whom correspondence should be addressed at: Department of Obstetrics & Gynaecology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. Email: cwcchan{at}graduate.hku.hk
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Abstract |
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Key words: misoprostol/nitric oxide donor/sodium nitroprusside/surgical termination of pregnancy
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Introduction |
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Nitric oxide (NO) synthase has been identified in the human cervix, and it is ascribed a role as the final mediator of cervical ripening (Chwalisz and Garfield, 1998). Local application of NO donors induced cervical ripening associated with ultrastructural and functional changes in guinea-pigs (Chwalisz et al., 1997
). Morphologic changes in the cervix have also been described in human (Ekerhovd et al., 2002
; Piccinini et al., 2003
). The effectiveness of NO donors in cervical priming before surgical termination of first trimester pregnancies in human has been inconsistent. Some showed advantage over placebo (Thomson et al., 1997
, 1998
, 1999), while others did not (Li et al., 2003
). All these studies used preparations originally designed for oral administration. Drug absorption may be different and incomplete if given vaginally. A recent study showed that intracervical application of sodium nitroprusside (SNP) gel exerted a favourable dilatatory effect over placebo on the cervix without affecting the blood pressure or increasing the incidence of severe migraine headaches commonly reported to be associated with NO donors use (Facchinetti et al., 2000
). In this study, the number of subjects involved was only 36. Thus conclusions could not be drawn on the safety and tolerability of intracervical SNP gel.
The current study was undertaken to investigate the efficacy of intracervical SNP gel in cervical priming prior to suction evacuation for termination of first trimester pregnancies. The primary objective was to compare the efficacy of intracervical SNP gel and vaginal misoprostol in cervical priming. Baseline cervical dilatation, duration of operation, blood loss during the operation and incidence of side effects were compared as secondary objectives.
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Materials and methods |
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Transvaginal ultrasound scan was performed to confirm intrauterine pregnancy, the number of fetus(es) and the stage of gestation. Patients were randomly assigned to 400 µg vaginal misoprostol and intracervical placebo gel, or 10 mg intracervical SNP gel and two vaginal vitamin B6 tablets 3 h before the suction evacuation procedure. The gels were prepared by the pharmacy in batches once every 2 weeks. Prefilled syringes contained either 10 mg SNP gel in 0.5 ml hydroxyethylcellulose gel or an equivalent volume of hydroxyethylcellulose gel alone. The potency of the SNP gel was analysed 1 month after preparation to ensure potency. The gels were packed in black opaque plastic bags individually and stored at 4 °C. The drugs were administered by the research nurse under the supervision of C.C.W.C. The cervix was exposed with a speculum. The syringe tip was introduced into the cervical canal via the external os and the gel was then expelled. The misoprostol or placebo tablets were inserted into the posterior vaginal vault after removing the speculum. The patients and the surgeon were blinded to the treatment group that the patients were assigned to.
Just before, and at 1, 2 and 3 h after administration of the medications, blood pressure was measured with an automatic device with the patients in the supine position. A record of undesirable events including headache, vomiting, diarrhoea, palpitation, abdominal pain, use of analgesia, vaginal bleeding and fever was completed at 3 h after administration of the medications by duty nurses. Pain was assessed objectively using a 10-point visual analogue scale, with 1 denoting no pain and 10 denoting excruciating pain.
The operation was performed under local anaesthesia with Fentanyl 25 µg and Midazolam 2 mg intravenously by two experienced gynaecologists (C.C.W.C., C.F.L.). Additional Fentanyl was given on request by the women, and the dose was recorded. The baseline cervical dilatation and cumulative force required to dilate the cervix from 4 to 9 mm were measured with a tonometer coupled to Hegar dilators as described previously (Ngai et al., 1995a,b
, 1996
). The baseline cervical dilatation was taken as the first dilator to produce a peak force above 5 Newtons (N). The forces required to dilate the cervix from 4 to 9 mm was recorded and the cumulative force calculated. Further cervical dilatation, if necessary, was performed. The uterus was evacuated using Karman suction curette. Blood loss during the operation was measured as the total volume in the suction bottle after sieving off the products of gestation. Pain during the operation was again assessed immediately after the end of the operation using the same 10-point visual analogue scale by a theatre nurse. Complications including excessive bleeding, cervical damage, uterine perforation and retained products of gestation were described in detail in the patient's record.
The patients were seen again 8 weeks after the abortion. Adverse events such as pelvic infection, incomplete evacuation and Asherman's Syndrome were recorded.
Statistical analysis
The primary outcome measure was the cumulative force required to dilate the cervix from 4 to 9 mm. The secondary outcome measures included the baseline cervical dilatation, changes in blood pressure, duration of operation, operative blood loss, incidence of side effects and pain. The cumulative force required to dilate the cervix from 4 to 9 mm after administration of vaginal misoprostol was 30 ± 15 N (mean± SD) (El Refaey et al., 1994). We assumed that if the cumulative force required to dilate the cervix from 4 to 9 mm after administration of sodium nitroprusside fell within half an SD (i.e. ±7.5 N), sodium nitroprusside could be considered as effective as vaginal misoprostol in priming the cervix. To fulfil such an assumption, the number of subjects required in each group was 89 to give a power of 90% at the 5% significance level. Hence a total of 200 patients were recruited.
Continuous variables were expressed as mean±SD. Categorical variables were expressed as number (%). The cumulative force required to dilate the cervix from 4 to 9 mm and the baseline cervical dilatation in both groups were compared using two-sided MannWhitney U test. A sub-group analysis on these two parameters was performed for primiparous and multiparous patients. Incidences of side effects were compared by Chi-square test. Differences were considered significant when the P-value was <0.05.
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Results |
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Discussion |
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The other factor that can affect the effectiveness of NO donors is the timing of administration. In most of the previous studies, the NO donor was given 3 h before the operation because this is the usual time interval for the misoprostol to exert its effect. Furthermore, the peak plasma levels of IMN are achieved within 2 h after oral administration (Abshagen, 1992). Changes in the cervical ultrastructure similar to those seen during spontaneous cervical ripening began at 3 h (Piccinini et al., 2003
). Nevertheless, the morphological change, together with the increased levels of many inflammatory mediators in the cervix, persisted at 10 h (Ekerhovd et al., 2002
). Vaginal IMN administration in pregnant women in the late third trimester also showed that the peak levels were still not achieved at 6 h (Bates et al., 2003
). Extrapolating these findings will lead to a postulation that a longer drug-to-operation time interval will be more beneficial. This theory has been refuted by our previous study which showed that a drug-to-operation interval of up to 6 h did not confer any benefit (Li et al., 2003
).
The initial enthusiasm about NO donors was stimulated by their relative lack of side effects as compared to prostaglandin analogues and hence their potential to replace the later. No change in blood pressure was noted in two previous studies of smaller sample sizes (Thomson et al., 1998; Facchinetti et al., 2000
). Our study is the largest randomized controlled trial ever reported. With 200 women involved in the study, we showed a very rapid drop in both the SBP and the DBP, occurring as soon as 1 h after the SNP gel administration. The DBP recovered at 2 h after the drug, with the SBP lagging behind until the difference between the two groups almost disappeared at the end of the third hour. The observed changes in blood pressure was a proof that SNP gel was absorbed very quickly from the genital tract and it had not lost its potency. In addition, significantly more patients in the SNP gel group complained of nausea, palpitation and dizziness. Headache was more common in the SNP gel group, although the difference did not reach statistical significance. All these symptoms were related to decrease in the blood pressure. The side effect profiles of misoprostol were very different from that of SNP gel, with abdominal pain being the most common complaint. From our data, SNP gel did not appear to have fewer side effects than misoprostol.
In conclusion, we failed to show equivalence in terms of the cumulative force required to dilate the cervix from 4 to 9 mm between SNP gel and misoprostol treatment to the cervix prior to suction termination of first trimester pregnancy. The baseline cervical dilatation, duration of operation and operative blood loss were in favour of misoprostol. The overall incidence of side effects was similar between the two groups.
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Acknowledgements |
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References |
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Submitted on September 9, 2004; accepted on November 19, 2004.
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