Abstract

BACKGROUND

The copper intrauterine device (IUD) is a highly effective and safe contraceptive method, also in nulliparous women. However, insertion of an IUD through a narrow cervix may be technically difficult. Misoprostol has been shown to be effective for cervical priming in non-pregnant women prior to hysteroscopy.

METHODS

Eighty nulliparous women requesting an IUD were randomly allocated to receive sublingually 400 µg misoprostol and 100 mg diclofenac (misoprostol group) or 100 mg diclofenac alone (control group) 1 h prior to IUD insertion. Cervical dilatation was measured prior to insertion using Hegar pins. Ease of insertion was judged by the investigator. Pain, bleeding and side effects were recorded at insertion and until follow-up performed one month later.

RESULTS

Following treatment with misoprostol, insertion was significantly easier than in the control group [P = 0.039, difference 19.36%, confidence interval (CI) −0.013, 39.99]. Pain estimated on a visual analogue scale (1–10) showed no evidence of a difference between the groups. The overall distribution of side effects did not differ. However, shivering was more common in the misoprostol group (P = 0.0084, difference 23.27%, CI 6.64, 39.90).

CONCLUSIONS

Misoprostol facilitates insertion of an IUD, and reduces the number of difficult and failed attempts of insertions in women with a narrow cervical canal. The optimal regimen of misoprostol remains to be defined.

Introduction

The copper intrauterine device (IUD) is a highly effective contraceptive method, also in young or nulliparous women (WHO, 1987; Penney et al., 2004). Furthermore, the copper IUD is the most effective emergency contraceptive method available (Contraception Technology Update, 1995). Complications are not more common at insertion post-coitally at any time during the menstrual cycle than at routine insertion during or after the menstrual period. However, a disadvantage in nulliparous women is that the insertion of an IUD through a narrow cervix may be technically difficult and painful (Farmer and Webb, 2003). Failed insertion, complications and side effects are significantly more common among women who have no previous vaginal delivery. Nulliparous women have an increased risk of cervical problems and bradycardia. Complications include partial or total expulsion and following unintended pregnancy, pain, abnormal and heavy bleeding. Sometimes insertion has to be performed under general anaesthesia. The fear of painful insertion may make women hesitate to use an IUD. In lieu of using an IUD, women may prematurely request sterilization (and may regret it later), choose less effective or less convenient methods, or risk an unwanted pregnancy.

Misoprostol (Cytotec) is a prostaglandin (PG) E1 analogue commercially widely available and used to decrease the ulcerogenic effects of non-steroidal anti-inflammatory drugs (NSAID). Misoprostol is available in oral tablets and the dose used therapeutically is 400–800 µg daily. PG analogues are used for cervical dilatation prior to surgical abortion in order to avoid damage to the cervix and uterus due to a rigid cervix and to decrease the bleeding (Ngai et al., 1995,1999; Lawrie et al., 1996). Today, the PG analogue of choice is misoprostol. Misoprostol has also been shown to be a highly effective method for termination of first and second trimester pregnancy (WHO, 1987; Ngai et al. 2000) as well as for labour induction and post-partum haemorrhage (Bugalho et al., 2001; Alfirevic et al., 2002; Villar et al., 2002; Hofmeyr et al., 2005).

The effect of misoprostol is dependent of the route of administration. Oral administration of misoprostol is highly effective in terminating early pregnancy if the duration of amenorrhoea is <50 days. Thereafter, clinical data indicate that oral misoprostol is less effective (McKinley et al., 1993). However, if misoprostol (tablets for oral use) is administered vaginally the efficacy is increased and side effects decreased (El-Refaey et al., 1995). A possible reason for the more pronounced effect of vaginal misoprostol could be a slower uptake and metabolism and a more prolonged elevated plasma concentration compared with the oral route that allows development of uterine contractions (Gemzell-Danielsson et al., 1999). Although vaginal misoprostol has been shown to be more effective and with less side effects, oral administration is preferred by many women (Ngai et al., 2000).

A possible alternative is to administer misoprostol sublingually (Tang and Ho, 2001; Aronsson et al., 2004a). At sublingual administration the tablet is allowed to melt under the tongue and has usually melted and disappeared after 10–20 min. (Tang et al., 2002; Aronsson et al., 2004a). In case the tablet by mistake is swallowed too early the effect will be at least that following oral administration.

Pharmacokinetic studies as well as studies on uterine contractility in pregnant women indicate that sublingual administration of misoprostol results in a more rapid elevation of plasma levels compared with vaginal administration, a longer duration of elevated plasma concentration of the active misoprostol free acid compared with oral administration and development of uterine contractility similar to vaginal treatment (Tang et al., 2002; Aronsson et al., 2004b). Sublingual administration of misoprostol has been shown to be more effective also for cervical priming compared with oral administration (Aronsson et al., 2004a) and equally effective as vaginal administration (Hamoda et al., 2004; Tang et al., 2004).

Another possible indication for use of misoprostol is cervical priming prior to insertion of an IUD, which would be of benefit especially in nulliparous women with a narrow cervical canal. Misoprostol has been shown to be effective for cervical priming in non-pregnant women of fertile age. Previous studies have shown the benefit of misoprostol for cervical dilatation prior to hysteroscopy (Ngai et al., 1997; Thomas et al., 2002). Regimens of 400 micro;g misoprostol orally 3–12 h prior to surgery have been used with a significant effect on cervical resistance and diameter. In an earlier study, a PG F2α analogue given as a vaginal suppository 1 h prior to IUD insertion was shown to be well tolerated and to reduce nausea and syncope (Lauersen et al., 1982). A mean increase in cervical diameter of 2.14 mm was achieved.

The aim of the present study is to compare, in a randomized fashion, treatment with sublingual misoprostol plus diclofenac to diclofenac-alone given 1 h prior to insertion of an IUD and to evaluate the effect on cervical dilatation, side effects (i.e. nausea, diarrhoea, skin rash, fever/shivering, bradycardia, syncope), pain, bleeding and acceptability.

Materials and Methods

The study was conducted in the Department of Obstetrics and Gynaecology at the Karolinska University Hospital between September 2004 and July 2006.

Participants were recruited among women requesting a copper IUD insertion. The study included nulliparous women or women with no previous vaginal delivery admitted to the clinic for insertion of a copper IUD. All women were considered to be of good general health, over 18 years of age and willing and able to participate and to sign an informed consent. Exclusion criteria were any signs of genital infection, contraindications to misoprostol or a positive pregnancy test. The study was approved by the ethics committee at Karolinska Institutet.

Patients were randomly allocated to either treatment with misoprostol with diclofenac (a pain medication) (misoprostol group), or to only diclofenac (control group), by means of a computer-generated number table, and by using sealed opaque envelopes, numbered and used consecutively. A study nurse, not directly involved in the study, generated the computerized randomization list. Prior to enrolment, a written informed consent was obtained from the patient by the investigators. Women who met the inclusion criteria and not the exclusion criteria were assigned to trial group according to the randomization number by a study nurse. The randomization list was kept concealed from the investigators until the study was completed. The women received, after randomization, 400 µg (two tablets) of misoprostol sublingually and 100 mg diclofenac or 100 mg diclofenac-alone 1 h prior to the IUD insertion. In case of contraindications to NSAID two T. Citodon (paracetamol and codein) was given instead of diclofenac.

A nurse administered the allocated study medication 1 h prior to insertion of the IUD (Nova-T, Schering AG, Berlin). The study was conducted in a single-blinded fashion, the drug administered was unknown (blinded) to the investigating doctors (n = 4) and staff performing the insertion of the IUD, but not to the patients.

Cervical dilatation was recorded at the insertion of the IUD. The degree of dilatation was determined by whether or not Hegar dilators with a diameter of 4 mm or smaller could pass through the internal cervical os without resistance. Any resistance or need for dilatation was recorded, as well as the degree of difficulty of the IUD insertion judged as the resistance of the internal cervical os experienced by the investigator and classified as ‘easy’, ‘moderate’ or ‘difficult’. In addition, the investigators were asked to judge based on the ease or difficulty of insertion in each woman whether they believed that pretreatment with misoprostol had been given or not.

Pain was indicated by the woman on a visual analogue scale (VAS) graded from 0 to 10, 0 representing no pain at all and 10 worst possible pain imaginable. It was also noted how difficult the insertion had been, from the patients point of view. The general experience of the insertion was estimated by the patient as very ‘unpleasant’, ‘unpleasant’ or ‘very little unpleasant’. Side effects such as nausea, diarrhoea, skin rash, fever/shivering, bradycardia or syncope were recorded. In addition, women were asked to keep daily records of pain, bleeding and any side effects experienced until follow-up.

The patients returned for a follow-up visit one month after insertion of the IUD. At the follow-up visit a vaginal examination was performed, and the pain, side effects and bleeding diary was collected.

The main outcome of the study was the cervical resistance judged by the investigator. No previous study using misoprostol prior to IUD insertion has been published. We postulated that cervical dilatation would clinically correspond to level of difficulty of IUD insertion. Therefore, for calculation of the sample size, previous data on the effect of misoprostol for cervical priming was used. When the effect of misoprostol was studied in non-pregnant women the effect on cervical dilatation was found to be similar to the effect seen in pregnant women. In a previous study, the baseline cervical diameter in pregnant nulliparous women was 4.1 mm (SD 1.4) and increased to 7.4 mm (SD 2.0) after oral misoprostol administration (Ngai et al., 1995). In non-pregnant women baseline cervical diameter was 3.2 mm (SD 1.3) (Ngai et al., 1997). Based on these previous studies with samples sizes of 75 and 44 women, respectively, a sample size of 80 women was estimated to be enough to show a difference in ease of insertion between the groups.

Statistics

To evaluate the differences between the two groups with regard to cervical resistance indicated by difficulty or ease of insertion, judged by the investigator, the Fisher's Exact test was used (one-sided mid-P-value). The Fisher's Exact test (two-sided) or the chi-squared test was used for independent nominal data such as side effects and overall experience of the insertion. Continuous variables with a normal distribution such as age and BMI were presented as mean±SD. Comparison was made using the unpaired t-test. Discrete numerical variables such as number of previous pregnancies, dilatation of the cervical internal os, bleeding and pain were presented as medians and ranges and assessed for normality and comparison using the Mann–Whitney U-test. Results were considered statistically significant if P-value was <0.05.

Results

A total of 80 women were recruited to the study. All 80 women fulfilled the inclusion criteria and none of the exclusion criteria. The subjects in the two groups were comparable in age and BMI (Table 1). There were nine previous pregnancies in the misoprostol group and eight in the control group, all terminated during first trimester through spontaneous or induced abortion. Five women were given Citodon, all due to a previous medical history of asthma. Two of the women were in the misoprostol group and three in the control group.

Table 1:

Characteristics of study subjects

Characteristics Misoprostol group Control group  
Age (years) 22.7 (3.1) (18–36) 23.1 (2.9) (19–31) aP = 0.52 
BMI 21.4 (2.4) (17.9–25.7) 21.8 (2.8) (16.8–29.4) aP = 0.58 
Characteristics Misoprostol group Control group  
Age (years) 22.7 (3.1) (18–36) 23.1 (2.9) (19–31) aP = 0.52 
BMI 21.4 (2.4) (17.9–25.7) 21.8 (2.8) (16.8–29.4) aP = 0.58 

Results are presented as mean±SD and range.

aUnpaired t-test.

There were no failed insertions in the misoprostol group. One patient in the misoprostol group interrupted the insertion procedure before the IUD had been inserted. The insertions were performed in a standardized manner, to avoid differences between the inserters, and also to prevent differences depending on the anatomy of the uterus. A Schröder forceps was applied on the portio. Thereafter, dilatation was measured using Hegar pins. If necessary, dilatation was performed up to Hegar 4 mm. A uterine sound measurement was performed followed by the IUD insertion. The forceps can cause some pain, but decreases the risk of uterine perforation, particularly in an ante- or retroverted uterus. The patient who interrupted the procedure did so after the forceps had been applied, and there was no attempt made to introduce the Hegar pins, uterine sound or to insert the IUD. Two insertions failed in the controlled group, both due to a narrow cervix and failure to dilate (Fig. 1).

Figure 1:

Flow chart of the study

Figure 1:

Flow chart of the study

When dilatation was measured as Hegar 4 mm or less that could pass through the internal cervical os without resistance there was no evidence of a difference between the groups (median 4 mm following misoprostol and 4 mm in the control group (P = 0.44). However, when resistance was measured as ‘difficulty or ease of insertion’ there was a significant difference between the groups (P = 0.039, difference 19.36%, confidence interval (CI) −0.013, 39.99) (Table 2). The number of patients with a strong resistance of the internal cervical os judged as difficult insertions was three in the treatment group, compared with six in the control group. The insertion was estimated to be easy in 29 women in the misoprostol group compared with 22 in the control group, and intermediate or difficult in 10 patients compared with 18 in the control group. The investigators assumption was that 27 out of the 40 women in the misoprostol group and 20 out of the 40 women in the control group had received treatment with misoprostol.

Table 2:

Difficulty of IUD insertion, as estimated by the inserter

Estimation of difficulty of insertion Misoprostol group, n = 39 (%) Control group, n = 40 (%) 
Easy 29 (74.4) 22 (55.0) 
Intermediate or difficult 10 (25.6) 18 (45.0) 
Estimation of difficulty of insertion Misoprostol group, n = 39 (%) Control group, n = 40 (%) 
Easy 29 (74.4) 22 (55.0) 
Intermediate or difficult 10 (25.6) 18 (45.0) 

P = 0.039; Fisher's Exact test, mid-P-value. Degrees of freedom = 1.

Insertion was performed on cycle Day 1–7 for women with regular menses or withdrawal bleeding. There were no differences in the number of women with or without bleeding at insertion (28 and 29 women in the control and misoprostol group, respectively (P = 0.65). The median number of bleeding days after insertion was 4 in both groups (Table 3).

Table 3:

Comparisons between the study groups

 Misoprostol, n = 39 Control, n = 40 Significance 
Median dilatation of cervix 4 mm (0–4 mm) 4 mm (0–4 mm) P = 0.44, CI 0, 0 
Median VAS pain estimation 7 (2.5–10) 6.5 (0–10) P = 0.20, CI 0, 1.5 
Median no. of days with pain until follow-up 5 (1–20) 7 (0–28) P = 0.18, CI −4, 1 
Median no days with bleeding after insertion 4 (0–29) 4 (0–31) P = 0.96, CI −2, 1 
Median no. of days with bleeding until follow-up 10 (3–29) 15 (1–31) P = 0.11, CI −6, 1 
 Misoprostol, n = 39 Control, n = 40 Significance 
Median dilatation of cervix 4 mm (0–4 mm) 4 mm (0–4 mm) P = 0.44, CI 0, 0 
Median VAS pain estimation 7 (2.5–10) 6.5 (0–10) P = 0.20, CI 0, 1.5 
Median no. of days with pain until follow-up 5 (1–20) 7 (0–28) P = 0.18, CI −4, 1 
Median no days with bleeding after insertion 4 (0–29) 4 (0–31) P = 0.96, CI −2, 1 
Median no. of days with bleeding until follow-up 10 (3–29) 15 (1–31) P = 0.11, CI −6, 1 

Mann–Whitney U-test, median (range).

CI, confidence interval for difference between medians; VAS, visual analogue scale.

Side effects such as nausea, vomiting, diarrhoea, shivering and fever were recorded. Over all, there was no evidence of a difference between the groups in the distribution of side effects reported (P = 0.21) (Table 4). Twelve women reported shivering, 1 fever, 14 nausea and 12 diarrhoea in the misoprostol group whereas 3 women in the control group reported shivering, 0 fever, 17 nausea and 6 diarrhoea. There was a significant difference for shivering (P = 0.0084, difference 23.27%, CI 6.64, 39.90).

Table 4:

Number of patients with side effects

Side effects Misoprostol group, n = 39 (%) Control group, n = 40 (%) P-value 
Any side effect 23 (60.0) 18 (45.0) aP = 0.21 
Shivering 12 (30.8) 3 (7.5) aP = 0.0084 
Diarrhoea 12 (30.8) 6 (15.0) aP = 0.075 
Nausea 14 (35.9) 17 (42.5) aP = 0.55 
Vomiting 2 (5.1) 1 (2.5) bP = 0.62 
Side effects Misoprostol group, n = 39 (%) Control group, n = 40 (%) P-value 
Any side effect 23 (60.0) 18 (45.0) aP = 0.21 
Shivering 12 (30.8) 3 (7.5) aP = 0.0084 
Diarrhoea 12 (30.8) 6 (15.0) aP = 0.075 
Nausea 14 (35.9) 17 (42.5) aP = 0.55 
Vomiting 2 (5.1) 1 (2.5) bP = 0.62 

Degrees of freedom = 1.

achi-squared test.

bFisher's exact test.

The pain experienced by the woman was recorded on a VAS scale (0–10). There was no evidence of a difference between the groups. The median VAS scores were 7.0 (range 2.5–10) in the misoprostol group compared with 6.5 (range 0–10) in the control group (P = 0.20, CI 0, 1.5). The general experience of the insertion was estimated by the patient as very ‘unpleasant’, ‘unpleasant’ or ‘very little unpleasant’, and showed striking similarities between the groups with no evidence of a difference. In the misoprostol group, 17 patients found the procedure very unpleasant, 18 unpleasant and 4 very little unpleasant, compared with 13, 19 and 8 patients, respectively, in the control group (P = 0.39, degrees of freedom = 2, test).

Pain and bleeding during the first month after insertion were also comparable between the groups and showed no evidence of a difference. The median number of days with any pain reported was 5 (range 1–20) in the group treated with misoprostol and 7 (range 0–28) in the control group (P = 0.18, CI −4, 1, Mann–Whitney U-test).

The IUD was well tolerated in both groups. Five women declared they would not go through the insertion again, but 63 stated they would if necessary. Twelve women did not answer the question; the women with failed or interrupted insertion are also in this latter group. Of the five women who would not go though the insertion again, three were in the misoprostol group and two in the control group. Of the 63 women who were willing to go though the procedure again, 31 were in the misoprostol group and 32 in the control group. No post-insertion infection or expulsion occurred in the month of follow-up. Of the 77 successful IUD insertions, 75 patients returned for the follow-up visit one month after insertion, and 1 woman was contacted on the telephone while 1 woman was lost to follow-up.

Discussion

In the present study, priming of the cervix with misoprostol in addition to pain medication was compared with only pain medication prior to IUD insertion in nulliparous women. The difficulty of insertion was estimated in regard to the resistance of the cervix.

A facilitating effect of misoprostol on IUD insertion was found, with significantly less resistance of the internal cervical os and following technically less difficult insertions compared with the untreated controls. However, on the whole, the insertion of an IUD in nulliparous women was generally less complicated than expected. In fact, the inserters guessed that a total of 47 women had received treatment; 27 in the misoprostol group and 20 in the control group. This should indicate that the insertions were overall easier and more uncomplicated than had been anticipated.

There were very few failures to insert the IUD, only two insertions failed due to very narrow cervix in the control group. None of the insertions failed in the misoprostol group.

An IUD can be a safe and effective contraceptive alternative also for nulliparous women. Importantly, a smaller uterus does not reduce efficacy of an IUD, which does not differ between nulliparous and parous women (Duenas et al., 1996; Wildemeersch et al., 2005) and continuation rates with IUD in nulliparous women do not seem to be lower than continuation rates in parous women (Meirik et al., 2001).

Although failed insertion, complications and side effects are significantly more common among women who have no previous vaginal delivery there is no increased risk for infections or infertility following IUD use in nulliparous women (Luukkainen et al., 1979; Hubacher et al., 2001; Wildermeesch et al., 2003). Importantly, copper IUD use was not associated with tubal infertility in nulliparous women, but with a past Chlamydia infection (Hubacher et al., 2001). An increased risk of infections during the first month post-IUD insertion has been shown while infection rates thereafter remain low and constant for up to 12 years (Farley et al., 1992). In the present study there was no post-insertion infection recorded.

A possible advantage with the levonorgestrel releasing intrauterine system (LNG-IUS) with regard to infections is the effect on the cervical mucus which render it less permeable for sperms as well as for pathogens. The LNG-IUS has a lower reported rate of infections in nulliparous as well as fewer removals due to pelvic inflammatory disease (Andersson et al., 1994). Another important advantage with the IUS compared with combined oral contraceptive in nulliparous women is a higher continuation rate (Suhonen et al., 2004). A disadvantage with the LNG-IUS is the larger diameter of the IUS compared with the copper IUD. Therefore, the priming effect of misoprostol might be even more advantageous for LNG-IUS insertion. In the present study, a smaller copper IUD (Nova-T, Schering AG) was used which may have affected the results.

For estimation of cervical dilatation Hegar dilators were used. There was no significant difference in the number of women without resistance to the Hegar dilator with a diameter of 4 mm (cervical diameter 4 mm or more). However, when resistance was judged as ‘ease or difficulty of insertion’ there were a larger proportion of easy insertions in the misoprostol group. The difference in cervical dilatation might have been better estimated if the diameter had been measured as the largest Hegar pin that could pass through the cervical internal os. However, this measurement was not performed due to the possible risk of increased expulsion or infection rate with an unnecessary dilatation.

Our results are consistent with a report on IUD insertion in a small group of 11 nulliparous women following vaginal administration of 0.5 mg 15-ME-PGF2α. One hour following treatment cervical diameter was increased by 2–4 mm measured by Hegar pins. A majority of the patients experienced uterine contractions following administration of PG while few other side effects were recorded.

Due to its higher uterine specificity, low side effects and low cost misoprostol has come to replace other PGs for several indications in obstetrics and gynaecology. Misoprostol is highly effective for cervical dilatation in pregnant women and widely used off-label for this indication. The route of administration seems to be more important than the dose given. Following oral intake there is a rapid increase in plasma level which is short lasting. In contrast, vaginal treatment results in lower plasma levels with a later peak level but the elevation in misoprostol free acid is longer lasting (Zieman et al., 1997). Sublingual administration results in a rapid uptake similar to oral administration with the highest peak level and with sustained levels similar to vaginal treatment (Tang and Ho, 2001). Vaginal and sublingual administration has been shown to be more effective than oral misoprostol to induce cervical dilatation as well as uterine contractions in pregnant women (Aronsson et al., 2004b; Hamoda et al., 2004; Tang et al., 2004). The sublingual route was chosen based on the pharmacokinetic studies. Following administration of sublingual misoprostol there is a rapid increase in plasma levels of misoprostol free acid. It was hypothesized that this would also reflect in a shorter interval needed for cervical priming. However, oral administration and a longer priming interval may well be a better choice. In pregnant women the optimal interval for priming following oral and vaginal administration has been shown to be 3 h. For the sublingual route the optimal dose and interval remains to be investigated.

A potential advantage with the sublingual route is that sublingual administration of misoprostol is usually more acceptable to women than vaginal administration. It is easy to self-administer at home prior to admission to the hospital.

Misoprostol has also been shown to induce cervical dilatation in non-pregnant women when used prior to a hysteroscopy. In these studies the route of administration was oral (Ngai et al., 1997; Thomas et al., 2002).

Interestingly the height of the serum peak of misoprostol free acid following misoprostol intake seems to be associated with the side effects, while the sustained plasma levels are associated with development of uterine contractions. Thus sublingual administration shows more side effects than conventional oral or vaginal administration in pregnant women.

The distribution of side effects showed no evidence of a difference between the two groups in the present study. However, shivering was significantly more common in the misoprostol group.

Surprisingly, there was no reduction of pain experienced by the patients in the misoprostol group during the insertion, in spite of the decreased cervical resistance experienced by the inserter. The women were not blinded to the treatment, but the investigators were. This was due to the problem of finding an appropriate placebo-tablet to use sublingually. This could have introduced bias in the patient's experience of pain during the insertion; however, the drug misoprostol was explained to the patients as a potential facilitator, which possibly could make the insertion less difficult. In spite of this, the tendency was that the misoprostol group had a higher median value on the VAS scale (7.0 compared with 6.5 in the control group), although this showed no evidence of a difference.

The experience as a whole was also regarded as equally comfortable or uncomfortable by the two groups. The pain in the control group is likely to be related to the pain at insertion through a narrow cervical canal and induction of uterine contractions, while pain in the treatment group may be due to misoprostol induced uterine cramping. Based on the data from pregnant women it is likely that these side effects could be reduced by administering misoprostol vaginally and/or by reducing the dose.

Conclusions

The study shows that misoprostol can be used to facilitate the insertion of an IUD in nulliparous women with a narrow cervix. However, the majority of insertions were uncomplicated and the difficulties few in both groups. Shivering was more common in the misoprostol group, which should be considered before starting to treat on a routine basis. Probably this could be reduced by using the vaginal route of misoprostol administration. The optimal dose of misoprostol and priming interval remains to be defined.

Acknowledgements

The authors are grateful to research nurses Margareta Hellborg and Lena Elffors-Söderlund, Karolinska University Hospital, Stockholm, Sweden, for taking excellent care of the patients. The study was supported by grants from the Swedish Medical Research Council (2003-3869) and Stockholm city county/Karolinska Institutet (ALF).

References

Alfirevic
Z
Howart
G
Gaussmann
A
Oral misoprostol for induction of labour with a viable fetus (Cochrane Review)
Cochrane Database Syst Rev
 , 
2002
 
CD 001338
Andersson
K
Odlind
V
Rybo
G
Levonorgestrel-releasing and cupper-releasing (NovaT) IUDs during five years of use: a randomized comparative trial
Contraception
 , 
1994
, vol. 
49
 (pg. 
56
-
72
)
Aronsson
A
Helstrom
L
Gemzell-Danielsson
K
Sublingual compared with oral misoprostol for cervical dilatation prior to vacuum aspiration: a randomized comparison
Contraception
 , 
2004
, vol. 
69
 (pg. 
165
-
169
)
Aronsson
A
Bygdeman
M
Gemzell-Danielsson
K
Effects of misoprostol on uterine contractility following different routes of administration
Hum Reprod
 , 
2004
, vol. 
19
 (pg. 
81
-
84
)
Bugalho
Daniel
A
Faúndes
A
Cunha
M
Misoprostol for prevention of postpartum hemorrhage
Int J Gynecol Obstet
 , 
2001
, vol. 
73
 (pg. 
1
-
6
)
Data lacking to support antibiotics at IUD insertion
Contracept Technol Update
 , 
1995
, vol. 
16
 (pg. 
77
-
78
)
Duenas
JL
Albert
A
Carrasco
F
Aroca
JM
New methods of mathematical analysis for studies of intrauterine contraception
Eur J Obstet Gynecol Reprod Biol
 , 
1996
, vol. 
68
 (pg. 
143
-
146
)
El-Refaey
H
Rajasekar
D
Abdalla
M
Calder
L
Templeton
A
Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol
N Engl J Med
 , 
1995
, vol. 
332
 (pg. 
983
-
987
)
Farley
TM
Rosenberg
MJ
Rowe
PJ
Chen
JH
Meirik
O
Intrauterine devices and pelvic inflammatory disease: an international perspective
Lancet
 , 
1992
, vol. 
28
 (pg. 
785
-
788
)
Farmer
M
Webb
A
Intrauterine device insertion-related complications: can they be predicted?
J Fam Plann Reprod Health Care
 , 
2003
, vol. 
29
 (pg. 
227
-
231
)
Gemzell-Danielsson
K
Marions
L
Rodriguez
A
Spur
BW
Wong
PY
Bygdeman
M
Comparison between oral and vaginal administration of misoprostol on uterine contractility
Obstet Gynecol
 , 
1999
, vol. 
93
 (pg. 
275
-
280
)
Hamoda
H
Ashok
PW
Flett
GM
Templeton
A
A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion
Am J Obstet Gynecol
 , 
2004
, vol. 
190
 (pg. 
55
-
59
)
Hofmeyr
GJ
Walraven
G
Gulmezoglu
AM
Maholwana
B
Alfirevic
Z
Villar
J
Misoprostol to treat postpartum haemorrhage: a systematic review
BJOG
 , 
2005
, vol. 
112
 (pg. 
547
-
553
)
Hubacher
D
Lara-Ricalde
R
Taylor
DJ
Guerra-Infante
F
Guzman-Rodriguez
R
Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women
N Engl J Med
 , 
2001
, vol. 
23
 (pg. 
561
-
567
)
Lauersen
NH
Kurkulos
M
Graves
ZR
Leeds
L
A new iud insertion technique utilizing cervical priming with prostaglandin
Contraception
 , 
1982
, vol. 
26
 (pg. 
59
-
63
)
Lawrie
A
Penney
G
Templeton
AA
A randomised comparison of oral and vaginal misoprostol for cervical priming before suction termination of pregnancy
Br J Obstet Gynecol
 , 
1996
, vol. 
103
 (pg. 
1117
-
1119
)
Luukkainen
T
Nielsen
NC
Nygren
KG
Pyorala
T
Nulliparous women, IUD and pelvic infection
Ann Clin Res
 , 
1979
, vol. 
11
 (pg. 
121
-
124
)
McKinley
C
Joo Thing
K
Baird
DT
The effect of dose of mifepristone and gestation on the efficacy of medical abortion with mifepristone and misoprostol
Hum Reprod
 , 
1993
, vol. 
8
 (pg. 
1502
-
1505
)
Meirik
O
Farley
TM
Sivin
I
Safety and efficacy of levonorgestrel implant, intrauterine device, and sterilization
Obstet Gynecol
 , 
2001
, vol. 
97
 (pg. 
539
-
547
)
Ngai
SW
Tang
OS
Lao
T
Ho
PC
Ma
HK
Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy
Hum Reprod
 , 
1995
, vol. 
10
 (pg. 
1220
-
1222
)
Ngai
SW
Chan
YM
Liu
KL
Ho
PC
Oral misoprostol for cervical priming in non-pregnant women
Hum Reprod
 , 
1997
, vol. 
12
 (pg. 
2373
-
2375
)
Ngai
SW
Chan
YM
Tang
OS
Ho
PC
The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial
Hum Reprod
 , 
1999
, vol. 
14
 (pg. 
2139
-
2142
)
Ngai
SW
Tang
OS
Ho
PC
Randomized comparison of vaginal (200 microg every 3 h) and oral (400 microg every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy
Hum Reprod
 , 
2000
, vol. 
15
 (pg. 
2205
-
2208
)
Penney
G
Brechin
S
de Souza
A
Bankowska
U
Belfield
T
Gormley
M
Olliver
M
Hampton
N
Howlett-Shipley
R
Hughes
S
, et al.  . 
The copper intrauterine device as long-term contraception
J Fam Plann Reprod Health Care
 , 
2004
, vol. 
30
 (pg. 
29
-
41
)
Suhonen
S
Haukkamaa
M
Jakobsson
T
Rauramo
I
Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study
Contraception
 , 
2004
, vol. 
69
 (pg. 
407
-
412
)
Tang
OS
Ho
PC
Pilot study on the use of sublingual misoprostol for medical abortion
Contraception
 , 
2001
, vol. 
64
 (pg. 
315
-
317
)
Tang
OS
Schweer
H
Seyberth
HW
Lee
SW
Ho
PC
Pharmacokinetics of different routes of administration of misoprostol
Hum Reprod
 , 
2002
, vol. 
17
 (pg. 
332
-
336
)
Tang
OS
Mok
KH
Ho
PC
A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester
Hum Reprod
 , 
2004
, vol. 
19
 (pg. 
1101
-
1114
)
Thomas
JA
Leyland
N
Durand
N
Windrim
RC
The use of oral misoprostol as a cervical ripening agent in operative hysteroscopy: a double-blind, placebo-controlled trial
Am J Obstet Gynecol
 , 
2002
, vol. 
186
 (pg. 
876
-
879
)
Villar
J
Gulmezoglu
AM
Hofmeyer
GJ
Forna
F
Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage
Obstet Gynecol
 , 
2002
, vol. 
100
 (pg. 
1301
-
1312
)
Wildemeerch
D
Batár
I
Affandi
B
Andrade
A
Shangchun
W
Jing
H
Xiaoming
C
The frameless intrauterine system for long-term reversible contraception: a review of 15 years of clinical experience
Obstet Gynaecol
 , 
2003
, vol. 
3
 (pg. 
164
-
173
)
Wildemeersch
D
Janssens
D
Vrijens
M
Weyers
S
Ease of insertion, contraceptive efficacy and safety of new T-shaped levonorgestrel-releasing intrauterine systems
Contraception
 , 
2005
, vol. 
71
 (pg. 
465
-
469
)
WHO
Mechanism of action, safety and efficacy of intrauterine devices: report of a WHO Scientific Group
World Health Organ Tech Rep Ser
 , 
1987
, vol. 
753
 (pg. 
1
-
91
)
Zieman
M
Fong
SK
Benowitz
NL
Banskter
D
Darney
PD
Absorption kinetics of misoprostol with oral or vagina administration
Obstet Gynecol
 , 
1997
, vol. 
90
 (pg. 
88
-
92
)