Abstract

BACKGROUND

Misoprostol is an agent that may ripen the cervix in nonpregnant women. Here, we investigate whether vaginal misoprostol administered prior to intrauterine device (IUD) insertion reduces the number of failed insertions, insertion-related complications and pain during insertion.

METHODS

We conducted a double-blinded, multicenter randomized controlled trial among patients requesting an IUD. Nulli- and multi-parous women were included, and both copper-containing and levonorgestrel-releasing IUDs were used. Participants were allocated to either 400 μg misoprostol or placebo (administered 3h prior to IUD insertion). The primary outcome measure was failed insertion. Secondary outcome measures were insertion-related complications, pain, difficulty of insertion and side-effects.

RESULTS

Two hundred and seventy participants were randomized. After drop out for various reasons (mainly no show), 199 participants had an IUD inserted; 102 received misoprostol and 97 received placebo. Only three insertions failed; two in the misoprostol group and one in the placebo group [P = 0.59, relative risk (RR) 1.9, 95% confidence interval (CI) 0.2–20.6]. The overall incidence of insertion-related complications was 21.8% in the misoprostol versus 19.1% in the placebo group (mainly vasovagal-like reactions) and did not differ between groups (P = 0.65, RR 1.1, 95% CI 0.7–2.0). No difference in pain scores between groups was found. Side-effects were more common in the misoprostol group (P = 0.05, RR 1.3, 95% CI 1.0–1.7).

CONCLUSION

The study showed no benefit for use of misoprostol prior to IUD insertion. However, there is a tendency of possible harm regarding side-effects. Therefore, we would not recommend standard pretreatment with misoprostol.

The trial was registered in the European Clinical Trials Database EudraCT 2006-006897-60.

Introduction

Intrauterine devices (IUDs) are widely used as reversible contraceptives. Both copper- and levonorgestrel (LNG)-releasing IUDs (LNG-IUDs) are safe, cost-effective in the long term and equally effective compared with tubal sterilization (Grimes et al., 2007; Grimes and Mishell, 2008). In addition, the LNG-IUD (Mirena®) provides noncontraceptive benefits, such as treatment for menorrhagia, dysmenorrhea and anemia (Luukkainen and Toivonen, 1995; Hurskainen et al., 2004; Milsom, 2007). The current use of IUDs among reproductive-aged women ranges from 8 to 15% worldwide (D'Arcangues, 2007). In the Netherlands, the use of IUDs among women aged 18–45 years has increased from 3 to 8% over the last 10 years (CBS, 2008).

Reported complications related to IUD insertion are: 8.8% insertion failure, 2.8–11.5% cervical problems, 0.2% cervical perforation, 0.2% syncope and 5.8% expulsion (Farmer and Webb, 2003). Insertion failures and cervical problems seem to occur more often among women who have never delivered vaginally (Farmer and Webb, 2003; Li et al., 2005). Cervical stenosis, an immature or small cervix and a significantly ante- or retroverted position of the uterus, has been described as factors associated with a difficult sounding of the cervical canal or even failure to insert the IUD (Preutthipan and Herabutya, 2006). The use of prophylactic nonsteroidal anti-inflammatory drugs (NSAIDs) prior to IUD insertion has been advocated to reduce pain during insertion (Jensen et al., 1998; Sääv et al., 2007) and has been common practice in the Netherlands for years. However, in a large randomized controlled trial (RCT) comparing prophylactic 400 mg ibuprofen with placebo prior to IUD insertion, no pain reduction was shown (Hubacher et al., 2006).

Misoprostol is an inexpensive prostaglandin E1-analogue, which is associated with few side-effects (Goldberg et al., 2001; Wing and Gaffaney, 2006) and an effective method for treatment of missed and incomplete abortion, induction of provocative abortion as well as for labor induction and prevention and treatment of postpartum hemorrhage (Ngai et al., 1999; Goldberg et al., 2001). Moreover, several studies have shown the benefit of misoprostol as a cervical ripening agent in nonpregnant women (Ngai et al., 1997; Singh and Fong, 2000; Barcaite et al., 2005; Oppegaard et al., 2006; Preutthipan and Herabutya, 2006). Priming with misoprostol prior to hysteroscopy and dilatation and curettage (D&C) in premenopausal women resulted in an increased cervical dilatation and a lower rate of cervical laceration (Crane and Healey, 2006; Preutthipan and Herabutya, 2006). A single dose of 400 μg misoprostol given vaginally 3h before the intervention has given the best effectiveness with the least side-effects. Higher doses or longer intervals do not improve the effect on the cervix, whereas higher doses actually increase side-effects (Singh and Fong, 2000; Fiala et al., 2007).

Given the benefits of misoprostol prior to hysteroscopy, we hypothesized that administering a cervical ripening agent prior to IUD insertion would reduce failure rates, complications and pain during insertion.

A study among eight women with an initially failed IUD insertion showed that a second attempt, after pretreatment with misoprostol, was successful in all eight cases (Li et al., 2005). However, larger studies on the effect of misoprostol for IUD insertion are lacking. We therefore conducted a RCT aiming to investigate whether pretreatment with misoprostol facilitates the insertion of an IUD in nulli- and (multi)parous women.

Materials and Methods

The study was conducted at the outpatient gynaecology department of the Leiden University Medical Center (LUMC) and four affiliated hospitals (HAGA Teaching Hospital, Medical Centre of the Haaglanden, Groene Hart Hospital and Bronovo Hospital) between May 2007 and December 2008.

Both nulli- and (multi)parous women ≥ 18 years were eligible for inclusion if they had an IUD to be inserted, regardless of the indication and the type of IUD. Women who had an IUD to be replaced were also eligible. Insertion could take place any time during the menstrual cycle. Exclusion criteria were contraindications for misoprostol use (pregnancy, prostaglandin allergy) or contraindications for IUD use (<6 weeks postpartum, gynecologic malignancy, pelvic inflammatory disease, unexplained vaginal bleeding and pregnancy). Participants were allowed to breastfeed provided that they would leave an interval of 4 h between time of administration of misoprostol and breastfeeding. The Institutional Committee for Medical Ethics approved the protocol (P 07-017). All participants were enrolled after giving written informed consent. The study was solely funded by the LUMC. The trial was registered at the European Clinical Trials Database; EudraCT 2006-006897-60.

Participants were randomly allocated to either the misoprostol or placebo group by means of a computer-generated randomization list, and by using sealed opaque medication packets, numbered and used consecutively. Stratification was applied according to parity. We defined participants who never had a vaginal delivery and had undergone (a) primary/scheduled Cesarean section as nulliparous. Participants with a history of secondary/not-scheduled Cesarean section, i.e. who had had cervical dilatation, were defined as (multi)parous. Patients with both a Cesarean section and vaginal delivery were defined as multiparous.

At enrollment, basic patient characteristics were recorded by the clinician. After enrollment and written informed consent, participants received a numbered, blinded packet with either two tablets of 200 μg misoprostol (total dose of 400 μg misoprostol) or two tablets of placebo. The placebo was an adequate blind. Medication packets were prepared by the LUMC department of Pharmacy.

Participants were instructed to administer the two tablets vaginally 3h before IUD insertion, as deep as possible, and to remain in supine position for half an hour. We chose this accepted concept (Oppegaard et al., 2006) for logistic reasons: patients were able to continue their daily routine without waiting in the hospital for 3h. According to the study protocol, no NSAIDs were administered prior to insertion. However, clinicians of the affiliated hospitals were to decide for themselves whether they provided or suggested analgesics for treating postinsertion discomfort.

Insertions were performed by interns, residents, midwives or gynecologists. The experience of the inserter was scored. Interns were considered to have little experience, whereas residents/midwives and gynecologists were considered to have at least average experience based on the number of insertions per year. All healthcare workers from the five participating hospitals were previously instructed about how to fill out the evaluation forms.

The study was conducted in a double-blind fashion: neither clinician nor participant knew whether placebo or misoprostol was administered, and this ensured blinded end-point adjudication. The randomization list was kept concealed from the investigators until the study was completed, thereby ensuring a concealed allocation.

Study outcome measures

The primary outcome measure of this study was the proportion of failed IUD insertions, defined as an unsuccessful insertion, regardless of the reason (e.g. immediate expulsion or impossibility to sound the uterus). It was recorded whether the initial attempt of insertion was successful or whether more attempts were needed within the same outpatient visit.

Secondary outcome measures were uterine or cervical perforation, heavy bleeding, vasovagal-like reactions (dizziness, nausea and vomiting), syncope, partial- or total expulsion, pain during insertion and difficulty of IUD insertion, as estimated by the inserter. Pain was measured using a visual analog scale (VAS). This validated pain scale uses a 10 cm line to represent the continuum of ‘no pain' to ‘worst imaginable pain' (Sriwatanakul et al., 1983). Participants were taught by the clinician how to use the VAS scale. Pain scores were measured by the investigator and recorded in millimeters. Difficulty of IUD insertion was measured by a 10-point scale, on which 0 represented an extremely easy, and 10 an extremely difficult, insertion. Both participant and clinician filled out the scale directly after the insertion procedure.

Side-effects of misoprostol or placebo were also scored by the participant. Hereby, a box was ticked per side-effect; ranging from mild, moderate to severe. The side-effects queried were headache, nausea/vomiting, abdominal cramping, shivering, fever (temperature ≥38.0°C) and diarrhea. The participant filled out this side-effect form before IUD insertion took place to ensure that side-effects from medication/placebo were not mistaken for side-effects related to insertion.

All patients were seen for a routine check-up 6 weeks after IUD insertion. During this visit, vaginal examination and/or vaginal ultrasound were performed. IUD expulsions and infections were recorded.

Statistics

The sample size was calculated based on the primary outcome of failed insertion setting a type 1 error of 0.05 and a power of 0.80. We aimed at detecting a significant difference of expected failed insertions of 1.3% (misoprostol group) versus 8.8% (placebo group). This was based on the 8.8% failed insertions found in the retrospective study of Farmer and Webb (2003). The calculated sample size was, therefore, 266 patients. The power of the study to detect a 30% increase in side-effects was 0.44.

Data were analyzed using the Statistical Package for the Social Sciences, version 14. Continuous variables were presented as mean ± SD and compared using unpaired t-tests. Independent nominal data, such as complications and side-effects, were analyzed using χ2 test or Fisher's exact and were given as percentages. Pain scores and difficulty of insertion were given as mean ± SD and compared using unpaired t-tests. Analyses were performed according to the intention-to-treat principle. Differences between groups were considered statistically significant if P-value was ≤ 0.05.

Results

Patient characteristics

From May 2007 until December 2008, a total of 270 participants were randomized: 136 were assigned to the misoprostol group and 134 to the placebo group. Seventy-one participants (34 in the misoprostol and 37 in the placebo group) dropped out of the study after group allocation for various reasons (see Fig. 1). Three participants had PAP-smears that required further investigation, six withdrew their consent after being allocated, one participant decided to have a hysterectomy instead of an LNG-IUD and one participant got pregnant before scheduled IUD insertion and therefore dropped out of the study. Forty participants did not show up on their scheduled appointment for insertion. Twenty forms were untraceable in the medical record. Therefore, a total of 199 participants was included in the analysis for the primary outcome.

Figure 1

Flow chart of RCT of vaginal misoprostol prior to insertion of an IUD.

Figure 1

Flow chart of RCT of vaginal misoprostol prior to insertion of an IUD.

The participants in the two groups had comparable baseline characteristics (Table I). Most of them had LNG-IUDs inserted (89.9%), whereas 20 participants (10.1%) had copper-IUDs inserted (four Multiload 375, six T-safe CU 380, four Flexi-T, one Frameless and five other copper-IUD). Most IUDs were inserted for contraceptive reasons [169 (85%)]. The minority of participants (30, 15%) had an IUD inserted for therapeutic reasons e.g. menorrhagia, dysmenorrhea and anemia. One participant had an IUD replaced. There were 21 (10.6%) participants with previous Cesarean sections, 33 (16.6%) had a history of spontaneous or induced abortion, 19 (9.5%) were breastfeeding and 78 (39.2%) were having their menstrual period at the time of insertion. There were four participants with a history of loop electrical excision procedure. In most of the participants (126, 78%), remains of the tablets were present in the vagina (Table I). Two participants used only one tablet of misoprostol or placebo, two participants took the tablets orally and one participant administered the tablets 1h, instead of 3h, before IUD insertion. Three participants also used NSAIDs on their own initiative. One participant was given local anesthesia before insertion. All these participants were analyzed according to the intention to treat principle.

Table I

Characteristics of participants in the RCT who had vaginal administration of misoprostol or placebo 3h before insertion of an IUD.

Characteristics Misoprostol group (n = 102) Placebo group (n = 97) 
Age (years) 31.6 ± 8.6 30.7 ± 8.4 
Weight (kg) 66.9 ± 12.3 70.6 ± 13.2 
Indication IUD 
 Contraception 87 (85.3%) 82 (84.5%) 
 Therapeutical 15 (14.7%) 15 (15.5%) 
Type IUD 
 LNG-IUD 91 (89.2%) 88 (90.7%) 
 Copper 11 (10.8%) 9 (9.3%) 
Parity 
 Nulliparous 49 (48.0%) 46 (47.4%) 
 Parous 53 (52.0%) 51 (52.6%) 
Ethnicity 
 Caucasian 77 (75.5%) 71 (73.2%) 
 Other 10 (9.8%) 14 (14.4%) 
 Unknown 15 (14.7%) 12 (12.4%) 
History 
 Cesarean section* 8 (7.8%) 13/93 (14.0 %) 
 Abortion (spontaneous/induced)* 18/89 (20.2%) 15/83 (18.1%) 
Menses during insertion* 41/91 (45.1%) 37/89 (41.6%) 
Breastfeeding* 12/71 (16.9%) 7/71 (9.9%) 
Remains of tablets present in vagina* 62/85 (72.9%) 64/77 (83.1%) 
Characteristics Misoprostol group (n = 102) Placebo group (n = 97) 
Age (years) 31.6 ± 8.6 30.7 ± 8.4 
Weight (kg) 66.9 ± 12.3 70.6 ± 13.2 
Indication IUD 
 Contraception 87 (85.3%) 82 (84.5%) 
 Therapeutical 15 (14.7%) 15 (15.5%) 
Type IUD 
 LNG-IUD 91 (89.2%) 88 (90.7%) 
 Copper 11 (10.8%) 9 (9.3%) 
Parity 
 Nulliparous 49 (48.0%) 46 (47.4%) 
 Parous 53 (52.0%) 51 (52.6%) 
Ethnicity 
 Caucasian 77 (75.5%) 71 (73.2%) 
 Other 10 (9.8%) 14 (14.4%) 
 Unknown 15 (14.7%) 12 (12.4%) 
History 
 Cesarean section* 8 (7.8%) 13/93 (14.0 %) 
 Abortion (spontaneous/induced)* 18/89 (20.2%) 15/83 (18.1%) 
Menses during insertion* 41/91 (45.1%) 37/89 (41.6%) 
Breastfeeding* 12/71 (16.9%) 7/71 (9.9%) 
Remains of tablets present in vagina* 62/85 (72.9%) 64/77 (83.1%) 

Age and weight are mean ± SD. All other data are n (%) but some (*) had missing data for some characteristics and these are given as n/patients with available data (%). No unexpected differences in baseline variables were produced by the randomization process.

LNG-IUD, levonorgestrel-releasing IUD.

IUD insertion

Insertions were performed by 38 different health care workers (residents, interns, midwives and gynecologists) from participating hospitals (mean number of insertions per healthcare worker was five). In none of the participants was it necessary to dilate the cervix. Three insertions failed, two in the misoprostol group and one in the placebo group [P = 0.59, relative risk (RR) 1.9, 95% confidence interval (CI) 0.2–20.6] (Table II). In one nulliparous and one multiparous participant, it was impossible to sound the (pinpoint) ostium. One insertion could not be completed owing to a technical problem with the LNG-IUD device.

Table II

Outcomes related to insertion of an IUD.

Outcome Misoprostol group (n = 102) Nulliparous (n = 49) Multiparous (n = 53) Placebo group (n = 97) Nulliparous (n = 46) Multiparous (n = 51) P-value 
Any complicationa (total n = 195) 22/101 (21.8%) 18/94 (19.1%) 0.65 
 Nulliparous (n = 93) 15/49 (30.6%) 15/44 (34.1%) 0.72 
 Multiparous (n = 101) 7/52 (13.5%) 3/50 (6.0%) 0.21 
Failed insertion (total n = 199) 2/102 (2.0%) 1/97 (1.0%) 0.59 
 Nulliparous (n = 95) 1/46 (2.2%) 0.48 
 Multiparous(n = 104) 2/53 (3.8%) 0.50 
Vasovagal-like reaction (total n = 186) 20/96 (20.8%) 15/90 (16.7%) 0.47 
 Nulliparous (n = 87) 15/46 (32.6%) 13/41 (31.7%) 0.93 
 Multiparous (n = 99) 5/50 (10.0%) 2/49 (4.1%) 0.44 
Syncope (total n = 199) 3/102 (2.9%) 2/97 (2.1%) 0.70 
 Nulliparous (n = 95) 2/49 (4.1%) 1/46 (2.2%) 0.60 
 Multiparous (n = 104) 1/53 (1.9%) 1/51 (2.0%) 1.00 
Perforation  
Heavy bleeding  
Expulsion 1 (1.0%) 0.45 
Pain estimation by the patientb mean, ±SD mean, ±SD  
 Total (n = 190) 46, 28 40, 27 0.14 
 Nulliparous (n = 92) 59, 25 54, 23 0.34 
 Multiparous (n = 98) 33, 26 26, 24 0.17 
Difficulty of insertionc mean, ±SD mean, ±SD  
 Total (n = 191) 2.9, 2.8 2.8, 2.6 0.77 
 Nulliparous (n = 92) 3.4, 2.7 3.7, 3.0 0.63 
 Multiparous (n = 99) 2.4, 2.8 1.9, 1.8 0.35 
Outcome Misoprostol group (n = 102) Nulliparous (n = 49) Multiparous (n = 53) Placebo group (n = 97) Nulliparous (n = 46) Multiparous (n = 51) P-value 
Any complicationa (total n = 195) 22/101 (21.8%) 18/94 (19.1%) 0.65 
 Nulliparous (n = 93) 15/49 (30.6%) 15/44 (34.1%) 0.72 
 Multiparous (n = 101) 7/52 (13.5%) 3/50 (6.0%) 0.21 
Failed insertion (total n = 199) 2/102 (2.0%) 1/97 (1.0%) 0.59 
 Nulliparous (n = 95) 1/46 (2.2%) 0.48 
 Multiparous(n = 104) 2/53 (3.8%) 0.50 
Vasovagal-like reaction (total n = 186) 20/96 (20.8%) 15/90 (16.7%) 0.47 
 Nulliparous (n = 87) 15/46 (32.6%) 13/41 (31.7%) 0.93 
 Multiparous (n = 99) 5/50 (10.0%) 2/49 (4.1%) 0.44 
Syncope (total n = 199) 3/102 (2.9%) 2/97 (2.1%) 0.70 
 Nulliparous (n = 95) 2/49 (4.1%) 1/46 (2.2%) 0.60 
 Multiparous (n = 104) 1/53 (1.9%) 1/51 (2.0%) 1.00 
Perforation  
Heavy bleeding  
Expulsion 1 (1.0%) 0.45 
Pain estimation by the patientb mean, ±SD mean, ±SD  
 Total (n = 190) 46, 28 40, 27 0.14 
 Nulliparous (n = 92) 59, 25 54, 23 0.34 
 Multiparous (n = 98) 33, 26 26, 24 0.17 
Difficulty of insertionc mean, ±SD mean, ±SD  
 Total (n = 191) 2.9, 2.8 2.8, 2.6 0.77 
 Nulliparous (n = 92) 3.4, 2.7 3.7, 3.0 0.63 
 Multiparous (n = 99) 2.4, 2.8 1.9, 1.8 0.35 

aAny complication; either failed insertion, vagal reaction, perforation, heavy bleeding or expulsion.

bPain estimation by the patient: Visual Analog score in mm.

cDifficulty of insertion; scored by the inserter, 0: very easy insertion 10: very difficult insertion.

Most IUDs were placed during the first attempt: 88 (88%) in the misoprostol group (data for 100 patients) versus 89 (94.7%) in the placebo group (data for 94 patients; P = 0.13). Reasons for a subsequent attempt to insert the IUD were technical problems with the device (n = 4), difficulty sounding the uterus (n = 6) or unreported reasons (n = 6). However, if subsequent attempts were needed, they took place within the same outpatient visit.

Complications and reported pain scores

Major complications such as perforation or major bleeding did not occur. Vasovagal-like responses such as dizziness, nausea and vomiting occurred in 20 participants in the misoprostol- and 15 participants in the placebo group (P = 0.47, RR 1.2, 95% CI 0.7–2.2). Syncope was reported in three participants in the misoprostol group compared with two participants in the placebo group (P = 0.70, RR 1.4, 95% CI 0.3–8.2). Three participants with syncope were nulliparous. No postinsertion infections were reported. The total number of complications did not differ between groups (P = 0.65, RR 1.1, 95% CI 0.7.–2.0).

Reported pain scores were generally low. The mean pain scores were similar in both groups; 46 mm in the misoprostol group versus 40 mm in the placebo group (P = 0.14). Difficulty of insertion, as stated by the inserter, did not differ between the groups: 2.9 versus 2.8 in the misoprostol and placebo group (P = 0.77). No correlation between experience of the inserter and number of complications, VAS-scores or ease of insertion was found (data not shown).

Side-effects were quite common in both groups; however, they were significantly more frequent in the misoprostol group: 56 participants (56.6%) who received misoprostol experienced any kind of side-effect compared with 39 (42.4%) in the placebo group (P = 0.05, RR 1.3, 95% CI 1.0–1.7). The most common side-effect was cramping in the abdomen (38.2%). Fever (temperature ≥38.0°C) did not occur in the misoprostol group, whereas 3.3% of patients in the placebo group experienced fever. Other side-effects included itching, exanthema, sweating, dysuria and paraesthesia and, did not differ between groups (P = 0.48). In general, all of the side-effects were mild (Table III). The significant difference between treatment groups for any side-effect does not persist when subgroup analysis according to parity is carried out; however, a trend towards more side-effects in the misoprostol group is recognizable (Table III).

Table III

Side-effects following vaginal administration of misoprostol or placebo 3h before insertion of IUD.

Side-effect Misoprostol group (n = 99) Placebo group (n = 92) P-value 
Any side-effect 56 (56.6%) 39 (42.4%) 0.05 
 Nulliparous 29/48 (60.4%) 20/44 (45.5%) 0.15 
 Multiparous 27/51 (52.9%) 19/48 (39.6%) 0.18 
Abdominal cramping 44 (44.4%) 29 (31.5%) 0.07 
Headache 13 (13.3%) 6 (6.5%) 0.12 
Nausea 8 (8.1%) 2 (2.2%) 0.10 
Diarrhea 4 (4.0%) 2 (2.2%) 0.68 
Fever 0 (0%) 3 (3.3%) 0.11 
Other 14 (14.1%) 12 (13.0%) 0.48 
Side-effect Misoprostol group (n = 99) Placebo group (n = 92) P-value 
Any side-effect 56 (56.6%) 39 (42.4%) 0.05 
 Nulliparous 29/48 (60.4%) 20/44 (45.5%) 0.15 
 Multiparous 27/51 (52.9%) 19/48 (39.6%) 0.18 
Abdominal cramping 44 (44.4%) 29 (31.5%) 0.07 
Headache 13 (13.3%) 6 (6.5%) 0.12 
Nausea 8 (8.1%) 2 (2.2%) 0.10 
Diarrhea 4 (4.0%) 2 (2.2%) 0.68 
Fever 0 (0%) 3 (3.3%) 0.11 
Other 14 (14.1%) 12 (13.0%) 0.48 

The check-up after 6 weeks revealed no substantial problems. Only one partial IUD expulsion occurred in the placebo group; one multiparous participant had a LNG-IUD that was located in the cervix. No postinsertion infections were recorded.

Incomplete information about insertion-related complications and pain scores occurred in 13 participants. Thirty-five (17.6%) participants were lost to follow-up; 17 in the misoprostol and 18 in the placebo group. Subgroup analysis according to parity revealed no significant differences between medication groups in insertion-related complications, VAS scores or difficulty of insertion (Table II).

However, pain scores experienced by nulliparous participants were higher than those experienced by multiparous participants, irrespective of medication group: 57 versus 30, respectively (P < 0.001). Vasovagal-like reactions were more common among nulliparous participants; 28 versus 7 times among multiparous participants (P < 0.001, RR 4.6, 95% CI 2.1–9.9). Difficulty of insertion was also different between the two groups: 2.2 among multiparous versus 3.5 among nulliparous participants (P < 0.001). Side-effects were not significantly different between nulliparous and multiparous participants; 53.3 versus 46.5% (P = 0.34).

Discussion

The present multicenter RCT was conducted to assess whether vaginal misoprostol prior to IUD insertion reduces the amount of failed insertions and insertion-related complications. The study showed that pretreatment with misoprostol reduced neither the number of failed insertions nor complications during IUD insertion. Moreover, pain during insertion was not influenced by misoprostol. The overall number of major complications was low. Vasovagal-like reactions, however, were quite common (20 vasovagal-like reactions in the misoprostol group and 15 in the placebo group: 35/186= 18.8%), but did not differ between groups. No correlation between experience of the inserter and complications, VAS scores and ease of insertion was found. Side-effects (of which abdominal cramping was the most predominant) occurred in 57% of participants using misoprostol and in 42% using placebo. This difference was significant (P = 0.05). The overall number of side-effects of misoprostol gathered in our trial was in line with those from other studies (Aronsson et al., 2004; Oppegaard et al., 2006; Preutthipan and Herabutya, 2006; Sääv et al., 2007). Remarkable, however, is that fever, a frequently reported side-effect in other trials, was not reported among participants using misoprostol in our trial.

Our study did not show a positive effect of administration of misoprostol, in contrast to our hypothesis. Several aspects have to be kept in mind when interpreting the results. First, in our study, the degree of cervical dilatation was not measured. Misoprostol might have an effect on cervical dilatation; however, this does not lead to easier insertions or lower pain scores as illustrated by several trials (Sääv et al., 2007; Heikinheimo et al., 2010). We therefore chose to assess only clinically relevant end-points (e.g. failed insertions, syncope, perforation, heavy bleeding and expulsion). Second, our study was powered based on a higher failed insertion rate (i.e. 8.8%, based on the findings of Farmer and Webb, 2003) than was actually found in the placebo group. Despite the fact that power is of no major concern once the trial has finished (Schulz and Grimes, 2005) and that not even a trend toward benefit of misoprostol for the primary outcome was found, it has to be acknowledged that the precision of the estimated misoprostol effect is influenced by the low number of failures. Third, we only investigated one dose (400 μg) of misoprostol, one route of administration (vaginal) and one time interval between administration and IUD insertion (3 h) as investigated by Fiala et al. (2007). However, vaginal misoprostol administered with an interval of 6–24 h prior to hysteroscopy resulted in a lower cervical resistance compared with placebo, although the rationale for using this longer interval has never been explained or compared with shorter intervals (Preutthipan and Herabutya, 1999). The negative results of our study are unlikely to be a result of an inadequate dose, or route of administration, as misoprostol-treated subjects experienced more side-effects, which is consistent with treatment and in the expected proportion based on previous studies. Also, it is not known whether there is a beneficial effect of misoprostol pretreatment when used 12 h prior to insertion. It cannot be inferred that the negative results of our study are generalizable to different time intervals of misoprostol. Fourth, drop-out rates in both groups were substantial (26.3%). In our study, a time window of several weeks between randomization and scheduled IUD insertion existed and the majority of drop outs were because of no show at the scheduled appointment for IUD insertion. Importantly, up to the day of the scheduled appointment both patients and controls were not treated with study medication. It is very likely that the drop out is unrelated to both the allocated treatment and the outcome, because drop out was defined as a participant in which there was no attempt to insert an IUD. As was shown, drop-out rates were similar in the two groups (34 versus 37). The fact that the drop-out rates were similar and were independent of treatment allocation means the potential differences in clinical characteristics between the two groups should be attributed to random error and not to selection bias. Therefore, this is a rare exception where not all randomized participants were included in an intention-to-treat analysis without introducing a structural bias in the study results. A sensitivity analysis including all randomized participants in which for all drop outs, the IUD insertion was assumed to have failed, showed also no benefit of misoprostol (misoprostol: 36/136 = 26.5% versus placebo: 38/134 = 28.4%; P = 0.73).

The strength of this study is its design (multicenter, randomized, double-blind and placebo-controlled), and representation of daily practice in both referral and nonreferral hospitals. All types of IUDs were used during the study and both nulli- and (multi)parous women were included. Insertions were performed by midwives, gynecologists and residents. These factors enhance the generalizability of the findings (Dekkers et al., 2010).

In the period that our trial was running, the results of an RCT with sublingual misoprostol 1h prior to insertion of a copper-IUD among nulliparous women were published (Sääv et al., 2007). Their low number of failed insertions (2.5%) corresponded with our figure (1.5%). IUD insertion in nulliparous women who used sublingual 400 μg misoprostol and 100 mg diclofenac was significantly easier than in women who used 100 mg diclofenac alone (1 h prior to IUD insertion). However, no difference in dilatation of the cervix, as well as patient-scored pain estimation and the number of failed insertions was observed between the two groups. More side-effects (of which shivering was significant) were recorded in the misoprostol group. This highlights the possible harm that can be caused (owing to side-effects) by routinely pretreating patients with misoprostol without evidence of a benefit to the patient.

The Heikinheimo study supports the latter statement (Heikinheimo et al., 2010): they recently published the results of a double-blind RCT in which 43 women used sublingual 400 μg misoprostol and 46 women used a placebo 3 h prior to an immediate replacement of a second LNG-IUD. No significant effect on the ease of insertion or on the patient-reported pain was seen. However, significantly more side-effects were observed in the misoprostol than the placebo group.

Whether misoprostol might be useful in those patients having a prior failed IUD insertion warrants further investigation. The only trial to date (Li et al., 2005) addressing this question showed a 100% successful insertion after pretreatment with misoprostol. However, the trial was not randomized and included only eight patients and, therefore, no firm conclusions can be reached.

In conclusion, our study, in agreement with other studies, showed that routine administration of misoprostol prior to IUD insertion is ineffective and might even cause side-effects.

Authors' roles

K.D.: substantial contribution to trial design, writing protocol, approval medical ethical board, statistical analysis, interpreting data, writing and revising the manuscript and final approval of the version to be published. O.M.D.: substantial contribution to statistical analysis, interpreting data, writing and revision of the manuscript and final approval of the version to be published. C.A.G.H.: substantial contribution to approval local medical ethical board, logistic arrangement in affiliating hospital, acquisition of data, revising the manuscript and final approval of the version to be published. C.J.M.G.: substantial contribution to approval local medical ethical board, logistic arrangement in affiliating hospital, acquisition of data, revising the manuscript and final approval of the version to be published. B.W.J.H.: substantial contribution to approval local medical ethical board, logistic arrangement in affiliating hospital, acquisition of data, revising the manuscript and final approval of the version to be published. G.J.J.R.: substantial contribution to trial design, writing protocol, acquisition of data, revising the manuscript and final approval of the version to be published. C.A.H.J.: substantial contribution to approval local medical ethical board, logistic arrangement in affiliating hospital, acquisition of data, revising the manuscript and final approval of the version to be published. F.M.H.: substantial contribution to trial design, writing protocol, approval medical ethical board, interpreting data, writing manuscript, revising the manuscript and final approval of the version to be published.

Funding

The trial was solely funded by the Leiden University Medical Center.

References

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
)
Barcaite
E
Bartusevicius
A
Railaite
DR
Nadisauskiene
R
Vaginal misoprostol for cervical priming before hysteroscopy in perimenopausal and postmenopausal women
Int J Gynaecol Obstet
 , 
2005
, vol. 
91
 (pg. 
141
-
145
)
Centraal Bureau voor de Statistiek (CBS)
Geboorteregeling in 2008
 
Crane
JM
Healey
S
Use of misoprostol before hysteroscopy: a systematic review
J Obstet Gynecol Can
 , 
2006
, vol. 
28
 (pg. 
373
-
379
)
D'Arcangues
C
Worldwide use of intrauterine devices for contraception
Contraception
 , 
2007
, vol. 
75
 (pg. 
2
-
7
)
Dekkers
OM
Elm
EV
Algra
A
Romijn
JA
Vandenbroucke
JP
How to assess the external validity of therapeutic trials: a conceptual approach
Int J Epidemiol
 , 
2010
, vol. 
39
 (pg. 
89
-
94
)
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
)
Fiala
C
Gemzell-Dabielsson
K
Tang
OS
von Hertzen
H
Cervical priming with misoprostol prior to transcervical procedures
Int J Gynecol Obstet
 , 
2007
, vol. 
99
 (pg. 
168
-
171
)
Goldberg
AB
Greenberg
MB
Darney
PD
Misoprostol and pregnancy
N Engl J Med
 , 
2001
, vol. 
344
 (pg. 
38
-
47
)
Grimes
DA
Mishell
DR
Intrauterine contraception as an alternative to interval tubal sterilization
Contraception
 , 
2008
, vol. 
77
 (pg. 
6
-
9
)
Grimes
DA
Lopez
LM
Manion
C
Schulz
KF
Cochrane systematic reviews of IUD trials: lessons learned
Contraception
 , 
2007
, vol. 
75
 (pg. 
S55
-
S59
)
Heikinheimo
O
Inki
P
Kunz
M
Parmhed
S
Anttila
AM
Olsson
SE
Hurskainen
R
Gemzell-Danielsson
K
Double-blind, randomized, placebo-controlled study on the effect of misoprostol on ease of consecutive insertion of the levonorgestrel-releasing intrauterine system
Contraception
 , 
2010
, vol. 
81
 (pg. 
481
-
486
)
Hubacher
D
Reyes
V
Lillo
RN
Zepeda
A
Chen
PL
Croxatto
H
Pain from copper intrauterine device insertion: Randomized trial of prophylactic ibuprofen
Am J Obstet Gynaecol
 , 
2006
, vol. 
195
 (pg. 
1272
-
1277
)
Hurskainen
R
Teperi
J
Rissanen
P
Aalto
AM
Grenman
S
Kivelä
A
Kujansuu
E
Vuorma
S
Yliskoski
M
Paavonen
J
Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up
JAMA
 , 
2004
, vol. 
291
 (pg. 
1456
-
1463
)
Jensen
HH
Blaabjerg
S
Lyndrup
J
Profylaktisk brug af prostaglandinesynthetasehaemmere ved oplaegning af spiral
Ungeskr Laeger
 , 
1998
, vol. 
160
 (pg. 
6958
-
6961
)
Li
YT
Kuo
TC
Kuan
LC
Chu
YC
Cervical softening with vaginal misoprostol before intrauterine device insertion
Int J Gynecol Obstet
 , 
2005
, vol. 
89
 (pg. 
67
-
68
)
Luukkainen
T
Toivonen
J
Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties
Contraception
 , 
1995
, vol. 
52
 (pg. 
269
-
276
)
Milsom
I
The levonorgestrel-releasing intrauterine system as an alternative to hysterectomy in peri- menopausal women
Contraception
 , 
2007
, vol. 
75
 (pg. 
S152
-
S154
)
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
)
Oppegaard
KS
Qvigstad
E
Nesheim
BI
Oral versus self-administered vaginal misoprostol at home before surgical termination of pregnancy: a randomised controlled trial
BJOG
 , 
2006
, vol. 
113
 (pg. 
58
-
64
)
Preutthipan
S
Herabutya
Y
A randomized controlled trial of vaginal misoprostol for cervical priming before hysteroscopy
Obstet Gynecol
 , 
1999
, vol. 
94
 (pg. 
427
-
430
)
Preutthipan
S
Herabutya
Y
A randomized comparison of vaginal misoprostol and dinoprostone for cervical priming in nulliparous women before operative hysteroscopy
Fertil Steril
 , 
2006
, vol. 
86
 (pg. 
990
-
994
)
Sääv
A
Aronsson
A
Marions
L
Stephansson
O
Gemzell-Danielsson
K
Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: a randomized trial
Hum Reprod
 , 
2007
, vol. 
22
 (pg. 
2647
-
2652
)
Schulz
KF
Grimes
DA
Sample size calculations in randomised trials: mandatory and mystical
Lancet
 , 
2005
, vol. 
365
 (pg. 
1348
-
1353
)
Singh
K
Fong
YF
Preparation of the cervix for surgical termination of pregnancy in the first trimester
Hum Reprod Update
 , 
2000
, vol. 
6
 (pg. 
442
-
448
)
Sriwatanakul
K
Kelvie
W
Lasagna
L
Calimlim
JF
Weis
OF
Mehta
G
Studies with different types of visual analog scales for measurement of pain
Clin Pharmacol Ther
 , 
1983
, vol. 
34
 (pg. 
234
-
239
)
Wing
DA
Gaffaney
CA
Vaginal misoprostol administration for cervical ripening and labor induction
Clin Obstet Gynecol
 , 
2006
, vol. 
49
 (pg. 
627
-
641
)