hum. reprod.-2011-dijkhuizen-323-9

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ORIGINAL ARTICLE Fertility control

Vaginal misoprostol prior to insertion

of an intrauterine device: an RCT

Kirsten Dijkhuizen 1, Olaf M. Dekkers 2, Cas A.G. Holleboom 3,

Christianne J.M. de Groot 4, Bart W.J. Hellebrekers 5,

Godelieve J.J. van Roosmalen1, Catharina A.H. Janssen 6,

and Frans M. Helmerhorst 1,2,*1Department of Gynaecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands 2Department of Clinical

Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands 3Department of Gynaecology, Bronovo

Hospital, PO Box 96900, 2509 JH, The Hague, The Netherlands 4Department of Gynaecology, Medical Centre of the Haaglanden,

PO Box 432, 2501 CK, The Hague, The Netherlands 5Department of Gynaecology, HAGA Teaching Hospital, PO Box 40551, 2540 LN,

The Hague, The Netherlands 6Department of Gynaecology, Groene Hart Hospital, PO Box 1098, 2800 BB, Gouda, The Netherlands

*Correspondence address. E-mail: [email protected]

Submitted on June 30, 2010; resubmitted on October 31, 2010; accepted on November 15, 2010

background: Misoprostol is an agent that may ripen the cervix in nonpregnant women. Here, we investigate whether vaginal miso-

prostol 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 mg misoprostol or placebo (administered 3 h prior to IUD insertion). The primary outcome measure was failed insertion. Sec-

ondary 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) 0.220.6]. The overall incidence of insertion-related com-plications 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 0.72.0). 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 1.01.7).

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.

Key words: intrauterine device / misoprostol (vaginal) / cervical priming / intrauterine device insertion

Introduction

Intrauterine devices (IUDs) arewidely usedas reversiblecontraceptives.Both copper- and levonorgestrel (LNG)-releasing IUDs (LNG-IUDs)

are safe, cost-effective in the long term and equally effective compared

withtubal sterilization (Grimes etal., 2007; Grimes and Mishell, 2008).In

addition, the LNG-IUD (Mirenaw) 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 (DArcangues, 2007). In the

Netherlands, the use of IUDs among women aged 1845 years has

increased from 3 to 8% over the last 10 years ( CBS, 2008).

Reported complications related to IUD insertion are: 8.8% insertionfailure, 2.811.5% cervical problems, 0.2% cervical perforation, 0.2%

syncope and 5.8% expulsion (Farmer and Webb, 2003). Insertion fail-

ures 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 Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

For Permissions, please email: [email protected]

Human Reproduction, Vol.26, No.2 pp. 323 329, 2011

Advanced Access publication on December 15, 2010 doi:10.1093/humrep/deq348


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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;Saavet 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 (Hubacheret 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;Oppegaardet 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 lacera-

tion (Crane and Healey, 2006; Preutthipan and Herabutya, 2006). A

single dose of 400 mg misoprostol given vaginally 3 h before the inter-vention 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 pre-treatment with misoprostol facilitates the insertion of an IUD in

nulli- and (multi)parous women.

Materials and MethodsThe 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 (preg-

nancy, prostaglandin allergy) or contraindications for IUD use (,6 weeks

postpartum, gynecologic malignancy, pelvic inflammatory disease, unex-

plained 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 par-

ticipants 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 con-

secutively. Stratification was applied according to parity. We defined par-

ticipants 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 dila-

tation, 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 clini-

cian. After enrollment and written informed consent, participants received

a numbered, blinded packet with either two tablets of 200 mg misoprostol

(total dose of 400 mg 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 3 h

before IUD insertion, as deep as possible, and to remain in supine position

for half an hour. We chose this accepted concept (Oppegaardet al., 2006)

for logistic reasons: patients were able to continue their daily routine

without waiting in the hospital for 3 h. 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 pro-

vided or suggested analgesics for treating postinsertion discomfort.Insertions were performed by interns, residents, midwives or gynecolo-

gists. 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 parti-

cipating 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 rep-

resent 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 milli-

meters. 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 partici-

pant. Hereby, a box was ticked per side-effect; ranging from mild, moder-

ate to severe. The side-effects queried were headache, nausea/vomiting,

abdominal cramping, shivering, fever (temperature 38.08C) and diar-

rhea. 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.

324 Dijkhuizen et al.


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All patients were seen for a routine check-up 6 weeks after IUD inser-

tion. 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 ofFarmer 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 x2 test or Fishers

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 hys-

terectomy instead of an LNG-IUD and one participant got pregnantbefore scheduled IUD insertion and therefore dropped out of the

study. Forty participants did not show up on their scheduled appoint-

ment 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.

The participants in the two groups had comparable baseline charac-

teristics (Table I). Most of them had LNG-IUDs inserted (89.9%),

whereas 20 participants (10.1%) had copper-IUDs inserted (four Mul-

tiload 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 adminis-

tered the tablets 1 h, instead of 3 h, before IUD insertion. Three par-

ticipants 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.

IUD insertion

Insertions were performed by 38 different health care workers (resi-

dents, 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 inser-

tions failed, two in the misoprostol group and one in the placebo

group [P 0.59, relative risk (RR) 1.9, 95% confidence interval (CI)

0.220.6] (Table II). In one nulliparous and one multiparous partici-

pant, it was impossible to sound the (pinpoint) ostium. One insertion

could not be completed owing to a technical problem with the

LNG-IUD device.

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 sub-

sequent attempt to insert the IUD were technical problems with

the device (n 4), difficulty sounding the uterus (n 6) or unre-

ported reasons (n

6). However, if subsequent attempts wereneeded, 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 0.72.2). 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 postinser-

tion 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 partici-

pants (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 1.01.7). The most common side-effect was cramping in

the abdomen (38.2%). Fever (temperature 38.08C) 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 (TableIII).

The check-up after 6 weeks revealed no substantial problems. Only

one partial IUD expulsion occurred in the placebo group; one

Misoprostol before intrauterine device insertion 325


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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%) partici-

pants were lost to follow-up; 17 in the misoprostol and 18 in the

placebo group. Subgroup analysis according to parity revealed no sig-

nificant 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, irrespec-

tive of medication group: 57 versus 30, respectively (P, 0.001).

Vasovagal-like reactions were more common among nulliparous par-

ticipants; 28 versus 7 times among multiparous participants (P,

0.001, RR 4.6, 95% CI 2.19.9). Difficulty of insertion was also differ-

ent between the two groups: 2.2 among multiparous versus 3.5

among nulliparous participants (P, 0.001). Side-effects were not sig-

nificantly 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 mis-

oprostol 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;

Saav et al., 2007). Remarkable, however, is that fever, a frequently

reported side-effect in other trials, was not reported among partici-

pants using misoprostol in our trial.

Our study did not show a positive effect of administration of miso-

prostol, 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

Figure 1 Flow chart of RCT of vaginal misoprostol prior to insertion of an IUD.



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or lower pain scores as illustrated by several trials (Saavet al., 2007;

Heikinheimoet 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 ofFarmer

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 miso-

prostol effect is influenced by the low number of failures. Third, we

only investigated one dose (400 mg) of misoprostol, one route of

administration (vaginal) and one time interval between administration

and IUD insertion (3 h) as investigated byFialaet al. (2007). However,

vaginal misoprostol administered with an interval of 624 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 general-

izable 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 toselection bias. Therefore, this is a rare exception where not all ran-

domized 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, gyne-

cologists and residents. These factors enhance the generalizability ofthe findings (Dekkers et al., 2010).

In the period that our trial was running, the results of an RCT with

sublingual misoprostol 1 h prior to insertion of a copper-IUD among

nulliparous women were published (Saav 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

400mg 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 inser-

tions 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 (Heikin-

heimoet al., 2010): they recently published the results of a double-

blind RCT in which 43 women used sublingual 400 mg misoprostol

and 46 women used a placebo 3 h prior to an immediate replace-

ment of a second LNG-IUD. No significant effect on the ease of

insertion or on the patient-reported pain was seen. However, sig-

nificantly more side-effects were observed in the misoprostol than

the placebo group.

........................................................................................

Table I Characteristics of participants in the RCT who

had vaginal administration of misoprostol or placebo 3 h

before insertion of an IUD.

Characteristics Misoprostol

group (n5 102)

Placebo group

(n5 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.



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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 pub-

lished. O.M.D.: substantial contribution to statistical analysis, inter-

preting data, writing and revision of the manuscript and final

approval of the version to be published. C.A.G.H.: substantial contri-

bution to approval local medical ethical board, logistic arrangement in

.............................................................................................................................................................................................

Table II Outcomes related to insertion of an IUD.

Outcome Misoprostol group (n5 102) Nulliparous

(n5 49) Multiparous (n5 53)

Placebo group (n5 97) Nulliparous (n5 46)

Multiparous (n5 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) 0 1/46 (2.2%) 0.48

Multiparous(n 104) 2/53 (3.8%) 0 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 0 0

Heavy bleeding 0 0

Expulsion 0 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.b

Pain estimation by the patient: Visual Analog score in mm.cDifficulty of insertion; scored by the inserter, 0: very easy insertion 10: very difficult insertion.

........................................................................................

Table III Side-effects following vaginal administration

of misoprostol or placebo 3 h before insertion of IUD.

Side-effect Misoprostol

group (n5 99)

Placebo

group

(n5 92)

P-value

Any side-effect 56 (56.6%) 39 (42.4%) 0.05

Nulliparous 29/48 (60.4%) 20/44 (45.5%) 0.15Multiparous 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



7/7

affiliating hospital, acquisition of data, revising the manuscript and final

approval of the version to be published. C.J.M.G.: substantial contri-

bution 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 con-

tribution 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 con-

tribution 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 pub-

lished. 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.

ReferencesAronsson A, Bygdeman M, Gemzell-Danielsson K. Effects of misoprostol

on uterine contractility following different routes of administration.

Hum Reprod2004;19:8184.

Barcaite E, Bartusevicius A, Railaite DR, Nadisauskiene R. Vaginal

misoprostol for cervical priming before hysteroscopy in perimenopausal

and postmenopausal women.Int J Gynaecol Obstet2005;91:141145.

Centraal Bureau voor de Statistiek (CBS). Geboorteregeling in 2008.www

.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/

0/2009k1b15p54art.pdf(22 April 2010, date last accessed).

Crane JM, Healey S. Use of misoprostol before hysteroscopy: a systematic

review. J Obstet Gynecol Can 2006;28:373379.DArcangues C. Worldwide use of intrauterine devices for contraception.

Contraception2007;75:27.

Dekkers OM, Elm EV, Algra A, Romijn JA, Vandenbroucke JP. How to

assess the external validity of therapeutic trials: a conceptual

approach. Int J Epidemiol2010;39:8994.

Farmer M, Webb A. Intrauterine device insertion-related complications:

can they be predicted? J Fam Plann Reprod Health Care 2003;

29:227231.

Fiala C, Gemzell-Dabielsson K, Tang OS, von Hertzen H. Cervical priming

with misoprostol prior to transcervical procedures. Int J Gynecol Obstet

2007;99:168171.

Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy.

N Engl J Med2001;344:3847.

Grimes DA, Mishell DR. Intrauterine contraception as an alternative to

interval tubal sterilization. Contraception 2008;77:69.

Grimes DA, Lopez LM, Manion C, Schulz KF. Cochrane systematic reviews

of IUD trials: lessons learned. Contraception 2007;75:S55S59.

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;81:481486.

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 Gynaecol2006;195:12721277.

Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela 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;291:14561463.

Jensen HH, Blaabjerg S, Lyndrup J. Profylaktisk brug af

prostaglandinesynthetasehaemmere ved oplaegning af spiral. Ungeskr

Laeger1998;160:69586961.

Li YT, Kuo TC, Kuan LC, Chu YC. Cervical softening with vaginal

misoprostol before intrauterine device insertion. Int J Gynecol Obstet

2005;89:6768.

Luukkainen T, Toivonen J. Levonorgestrel-releasing IUD as a method

of contraception with therapeutic properties. Contraception 1995;

52:269276.

Milsom I. The levonorgestrel-releasing intrauterine system as an alternativeto hysterectomy in perimenopausal women. Contraception 2007;

75:S152S154.

Ngai SW, Chan YM, Liu KL, Ho PC. Oral misoprostol for cervical priming

in non-pregnant women. Hum Reprod1997;12:23732375.

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 Reprod1999;14:21392142.

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;113:5864.

Preutthipan S, Herabutya Y. A randomized controlled trial of vaginal

misoprostol for cervical priming before hysteroscopy. Obstet Gynecol

1999;94:427430.

Preutthipan S, Herabutya Y. A randomized comparison of vaginalmisoprostol and dinoprostone for cervical priming in nulliparous

women before operative hysteroscopy. Fertil Steril2006;86:990994.

Saav 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

Reprod2007;22:26472652.

Schulz KF, Grimes DA. Sample size calculations in randomised trials:

mandatory and mystical. Lancet 2005;365:13481353.

Singh K, Fong YF. Preparation of the cervix for surgical termination

of pregnancy in the first trimester. Hum Reprod Update 2000;

6:442448.

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 Ther1983;34:234239.

Wing DA, Gaffaney CA. Vaginal misoprostol administration for cervical

ripening and labor induction. Clin Obstet Gynecol 2006;49:

627641.

http://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://localhost/var/www/apps/conversion/tmp/scratch_3/)http://localhost/var/www/apps/conversion/tmp/scratch_3/)http://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdfhttp://www.cbs.nl/NR/rdonlyres/8B92B0BC-2485-40F2-BEA4-ED360A60C2A9/0/2009k1b15p54art.pdf

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