Intracervical sodium nitroprusside versus vaginal misoprostol in first trimester surgical termination of pregnancy: a randomized double-blinded controlled trial

C.C.W. Chan1, O.S. Tang, E.H.Y. Ng, C.F. Li and P.C. Ho

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Results from small-scale randomized studies on the effectiveness of different preparations of nitric oxide donors in cervical priming before first trimester termination of pregnancies are not consistent. We compared sodium nitroprusside gel to misoprostol, the standard agent for cervical priming in this randomized double-blinded controlled trial. METHODS: Two hundred pregnant patients between 8 to 12 weeks admitted for surgical termination of pregnancy were recruited. They were randomized into either 400 µg vaginal misoprostol and intracervical placebo gel, or 10 mg intracervical sodium nitroprusside gel and placebo tablets 3 h before the procedure. The baseline cervical dilatation and cumulative force required to dilate the cervix from 4 to 9 mm were measured with a tonometer. Blood pressure was measured and side effects were assessed. RESULTS: The cumulative force to dilate the cervix from 4 to 9 mm was significantly higher in the sodium nitroprusside group, and the difference remained when a sub-group analysis was performed according to parity. Baseline cervical dilatation, duration of operation and operative blood loss were all in favour of misoprostol. Transient drop in blood pressure was observed after sodium nitroprusside treatment. CONCLUSIONS: Intracervical sodium nitroprusside is not as effective as misoprostol in cervical priming.

Key words: misoprostol/nitric oxide donor/sodium nitroprusside/surgical termination of pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Suction evacuation of the uterus remains one of the management options for termination of first trimester pregnancies. Various cervical priming agents have been evaluated and proven to be effective, including prostaglandins. Misoprostol, a prostaglandin E1 analogue, has been shown to decrease the cumulative force required to dilate the cervix (El-Refaey et al., 1994Go; Ngai et al., 1996Go, 1999Go). It can also reduce some of the serious complications associated with the operation. The major disadvantage with misoprostol is its ability to stimulate uterine contractions at the same time, hence inducing crampy abdominal pain. Fever and gastrointestinal side effects are usually self-limiting but may cause discomfort. There is a need to develop a potent cervical priming agent with fewer side effects.

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, 1998Go). Local application of NO donors induced cervical ripening associated with ultrastructural and functional changes in guinea-pigs (Chwalisz et al., 1997Go). Morphologic changes in the cervix have also been described in human (Ekerhovd et al., 2002Go; Piccinini et al., 2003Go). 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., 1997Go, 1998Go, 1999), while others did not (Li et al., 2003Go). 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., 2000Go). 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The study was approved by the Joint Institutional Review Board of the University of Hong Kong and the Hospital Authority. Primiparous or multiparous patients admitted for termination of first trimester pregnancy between 8 to 12 weeks by suction evacuation of uterus under local anaesthesia at Queen Mary Hospital were invited to join the study. Exclusion criteria were: (a) previous uterine surgery, (b) known allergy to sodium nitroprusside or misoprostol, (c) any chronic diseases requiring medication, (d) language barrier and hence unable to understand the consent form, (e) age<18 years. All patients gave their written consent to join the study. Patients were randomly assigned to either treatment group immediately after recruitment. Randomization was performed by serially numbered and sealed envelopes prepared according to a randomization table by a research nurse. Patients were randomized separately according to their parity status.

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., 1995aGo,bGo, 1996Go). 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., 1994Go). 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 Mann–Whitney 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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Two hundred patients with a mean age of 27.0 years (range 18–45) were recruited between May 2003 to July 2004, with 100 being primiparous and 100 being multiparous. These patients were randomized into the two treatment groups with 100 in each group. All patients completed the study and underwent surgical termination of pregnancy. The baseline characteristics of the patients in both groups were comparable (Table I).


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Table I. Baseline characteristics and operative findings

 
The baseline cervical dilatation was significantly higher in the group to be treated with misoprostol. When a subgroup analysis was performed, the difference remained significant for the multiparous group but not for the primiparous group (Table I). The cumulative force to dilate the cervix from 4 to 9 mm was significantly lower in the misoprostol group, and the difference remained even when the analysis was limited to either primiparous or multiparous patients. The force required to dilate the cervix at each stage of the dilatation is shown in Figure 1. The duration of operation was significantly longer in the SNP gel group, and the blood loss during the operation was also higher in this group. The pain scale was comparable between the two groups (Table I).



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Figure 1. The mean force (N) required to dilate the cervix at each stage of cervical dilatation. *P<0.05 between the two groups (Mann–Whitney U test).

 
The incidences of various side effects are summarized in Table II. Fifty-nine patients in the SNP gel group and 64 patients in the misoprostol group complained of at least one side-effect, but the difference was not significant (Chi-square test, P=0.467). Abdominal pain was the most common side effect. Almost half of the patients in the misoprostol group had this complaint and this was significantly higher than that in the SNP gel group. A quarter of the patients in the SNP gel group complained of nausea. Nausea, palpitation and dizziness were significantly more common in the SNP gel group. The incidences of other side effects including vaginal bleeding, headache, fever and vomiting were similar between the two groups. Significant drops in both systolic blood pressure (SBP) (Figure 2) and diastolic blood pressure (DBP) (Figure 3) were noticed in the first hour after SNP gel administration. A gradual recovery was noticed in the second and third hour in both SBP and DBP, although the SBP remained marginally lower in the SNP gel group at the end of the third hour after drug administration.


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Table II. Side effect profiles

 


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Figure 2. Changes in systolic blood pressure (SBP) (mmHg) with respect to time after administration of the two different cervical priming agents. *P<0.05 between the two groups (Mann–Whitney U test).

 


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Figure 3. Changes in diastolic blood pressure (DBP) (mmHg) with respect to time after administration of the two different cervical priming agents. *P<0.05 between the two groups (Mann–Whitney U test).

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Early studies investigating NO donors in different forms as potential agents for cervical priming before suction evacuation to terminate first trimester pregnancies showed that vaginal administration, either in the form of isosorbide mononitrate (IMN) or glyceryl trinitrate, were better than placebo but less effective than prostaglandin analogues (Thomson et al., 1997Go), even when a higher dose was used (Thomson et al., 1998Go). When combined with misoprostol, vaginal IMN did not seem to exert any synergistic effect (Ledingham et al., 2001Go). We compared vaginal IMN versus misoprostol and placebo in a previous study but failed to show any effect after vaginal IMN (Li et al., 2003Go). Inconsistency in drug absorption may explain the discrepancy. In all these studies, the non-proprietary IMN tablets initially intended for oral administration were administered vaginally. NO donors in vaginal paste or gel form may allow better drug absorption. Intracervical application of a self-prepared SNP gel has been studied in a small-scale randomized controlled trial and this preparation significantly lowered the force required to dilate the cervix (Facchinetti et al., 2000Go). However, it is important to test this preparation against a current standard for cervical priming. In this study, we failed to demonstrate equivalence in terms of the cumulative force required to dilate the cervix to 9 mm between the SNP gel and misoprostol, one of the recommended standard agents for cervical priming. SNP gel was also inferior to misoprostol in terms of the duration of the operation and the operative blood loss. A placebo group was not included in the study as it would have been unethical to perform suction termination of pregnancy without cervical priming.

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, 1992Go). Changes in the cervical ultrastructure similar to those seen during spontaneous cervical ripening began at 3 h (Piccinini et al., 2003Go). Nevertheless, the morphological change, together with the increased levels of many inflammatory mediators in the cervix, persisted at 10 h (Ekerhovd et al., 2002Go). 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., 2003Go). 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., 2003Go).

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., 1998Go; Facchinetti et al., 2000Go). 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.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This investigation received financial support from the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction, World Health Organization.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Bates CD, Nicoll AE, Mullen AB, Mackenzie F, Thomson AJ and Norman JE (2003) Serum profile of isosorbide mononitrate after vaginal administration in the third trimester. BJOG 110, 64–67.[ISI][Medline]

Chwalisz K, Shao-Qing S, Garfield RE and Beier HM (1997) Cervical ripening in guinea-pigs after a local application of nitric oxide. Hum Reprod 12, 2093–2101.[Abstract]

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Ekerhovd E, Weijdegard BS, Brannstrom M, Mattsby-Baltzer I and Norstrom A (2002) Nitric oxide induced cervical ripening in the human: Involvement of cyclic guanosine monophosphate, prostaglandin F2{alpha}, and prostaglandin E2. Am J Obstet Gynecol 186, 745–750.[CrossRef][ISI][Medline]

El Refaey H, Calder L, Wheatley DN and Templeton A (1994) Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet 343, 1207–1209.[CrossRef][ISI][Medline]

Facchinetti F, Piccinini F and Volpe A (2000) Chemical ripening of the cervix with intracervical application of sodium nitroprusside: a randomized controlled trial. Hum Reprod 15, 2224–2227.[Abstract/Free Full Text]

Ledingham MA, Thomson AJ, Lunan CB, Greer IA and Normal JE (2001) A comparison of isosorbide mononitrate, misoprostol and combination therapy for first trimester pre-operative cervical ripening: a randomised controlled trial. BJOG 108, 276–280.[CrossRef][Medline]

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Ngai SW, Yeung KC, Lao T and Ho PC (1995b) Oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration in women in the sixth to twelfth week of gestation. Contraception 51, 347–350.[CrossRef][ISI][Medline]

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Ngai SW, Chan YM, Tang OS and Ho PC (1999) The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial. Hum Reprod 14, 2139–2142.[Abstract/Free Full Text]

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Thomson AJ, Lunan CB, Ledingham M, Howat RC, Cameron IT, Greer IA and Norman JE (1998) Randomised trial of nitric oxide donor versus prostaglandin for cervical ripening before first-trimester termination of pregnancy. Lancet 352, 1093–1096.[CrossRef][ISI][Medline]

Submitted on September 9, 2004; accepted on November 19, 2004.





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