Human Reproduction, Vol.26, No.2 pp.

323329, 2011
Advanced Access publication on December 15, 2010 doi:10.1093/humrep/deq348

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 Roosmalen 1, Catharina A.H. Janssen 6,
and Frans M. Helmerhorst 1,2,*
1

*Correspondence address. E-mail: f.m.helmerhorst@lumc.nl

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 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 mg misoprostol or placebo (administered 3 h prior to IUD insertion). The primary outcome measure was failed insertion. Secondary outcome measures were insertion-related complications, pain, difculty 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% condence interval (CI) 0.220.6]. 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 benet 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) 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 (Mirenaw) provides noncontraceptive benets,
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 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 signicantly
ante- or retroverted position of the uterus, has been described as
factors associated with a difcult 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: journals.permissions@oup.com

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Department 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

324

Materials and Methods

The study was conducted at the outpatient gynaecology department of the
Leiden University Medical Center (LUMC) and four afliated 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 inammatory 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. Stratication was applied according to parity. We dened 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 dened as (multi)parous. Patients with both a Cesarean
section and vaginal delivery were dened 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 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 (Oppegaard et 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 afliated 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 ve participating hospitals were previously instructed about how to ll 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, dened 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 difculty 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. Difculty of IUD insertion was measured by a 10-point scale, on
which 0 represented an extremely easy, and 10 an extremely difcult,
insertion. Both participant and clinician lled 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 38.08C) and diarrhea. The participant lled 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.

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The use of prophylactic nonsteroidal anti-inammatory drugs

(NSAIDs) prior to IUD insertion has been advocated to reduce pain
during insertion (Jensen et al., 1998; Saav 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 benet 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 mg misoprostol given vaginally 3 h 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 benets 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.

Dijkhuizen et al.

325

Misoprostol before intrauterine device 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

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.
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 ve
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 1 h, instead of 3 h, before IUD insertion. Three participants also used NSAIDs on their own initiative. One participant

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 ve). 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% condence 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.
Most IUDs were placed during the rst 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), difculty 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 0.72.2). 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 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). Difculty 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 signicantly more frequent in the misoprostol group: 56 participants (56.6%) who received misoprostol experienced any kind of sideeffect 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 38.08C) 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 signicant 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).
The check-up after 6 weeks revealed no substantial problems. Only
one partial IUD expulsion occurred in the placebo group; one

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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 signicant 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 x2 test or Fishers
exact and were given as percentages. Pain scores and difculty 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 signicant if
P-value was 0.05.

was given local anesthesia before insertion. All these participants

were analyzed according to the intention to treat principle.

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Dijkhuizen et al.

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-ve (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 signicant differences between medication groups in insertion-related
complications, VAS scores or difculty 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). Difculty 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 signicantly 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 inuenced 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 signicant (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 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

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

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Misoprostol before intrauterine device insertion

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 (n 5 102)

Placebo group
(n 5 97)

........................................................................................
Age (years)

31.6 + 8.6

30.7 + 8.4

Weight (kg)

66.9 + 12.3

70.6 + 13.2

Indication IUD
87 (85.3%)

82 (84.5%)

Therapeutical

15 (14.7%)

15 (15.5%)

LNG-IUD

91 (89.2%)

88 (90.7%)

Copper

11 (10.8%)

9 (9.3%)

Nulliparous

49 (48.0%)

46 (47.4%)

Parous

53 (52.0%)

51 (52.6%)

Caucasian

77 (75.5%)

71 (73.2%)

Other

10 (9.8%)

14 (14.4%)

Unknown

15 (14.7%)

12 (12.4%)

Type IUD

Parity

Ethnicity

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.

or lower pain scores as illustrated by several trials (Saav 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 ndings 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 nished (Schulz and Grimes, 2005) and that not even a trend
toward benet of misoprostol for the primary outcome was found,
it has to be acknowledged that the precision of the estimated misoprostol effect is inuenced 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 by Fiala et 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

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Contraception

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 benecial
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 dened 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 benet
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 ndings (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 gure
(1.5%). IUD insertion in nulliparous women who used sublingual
400 mg misoprostol and 100 mg diclofenac was signicantly 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 signicant) 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 benet to the patient.
The Heikinheimo study supports the latter statement (Heikinheimo et al., 2010): they recently published the results of a doubleblind RCT in which 43 women used sublingual 400 mg misoprostol
and 46 women used a placebo 3 h prior to an immediate replacement of a second LNG-IUD. No signicant effect on the ease of
insertion or on the patient-reported pain was seen. However, signicantly more side-effects were observed in the misoprostol than
the placebo group.

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Dijkhuizen et al.

Table II Outcomes related to insertion of an IUD.

Misoprostol group (n 5 102) Nulliparous
(n 5 49) Multiparous (n 5 53)

Outcome

Placebo group (n 5 97) Nulliparous (n 5 46)

Multiparous (n 5 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)

1/97 (1.0%)

0.59

1/46 (2.2%)

0.48

Multiparous(n 104)

2/53 (3.8%)

0.50

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)

Vasovagal-like reaction (total

n 186)

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

0
0

Perforation
Heavy bleeding

Expulsion

1 (1.0%)

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

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

Difculty of insertionc

0.45

Any complication; either failed insertion, vagal reaction, perforation, heavy bleeding or expulsion.
Pain estimation by the patient: Visual Analog score in mm.
Difculty of insertion; scored by the inserter, 0: very easy insertion 10: very difcult insertion.

b
c

Table III Side-effects following vaginal administration

of misoprostol or placebo 3 h before insertion of IUD.
Side-effect

Misoprostol
group (n 5 99)

Placebo
group
(n 5 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

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 rm 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 nal approval of the version to be published. O.M.D.: substantial contribution to statistical analysis, interpreting data, writing and revision of the manuscript and nal
approval of the version to be published. C.A.G.H.: substantial contribution to approval local medical ethical board, logistic arrangement in

Downloaded from http://humrep.oxfordjournals.org/ by guest on November 14, 2015

2/102 (2.0%)

Nulliparous (n 95)

Misoprostol before intrauterine device insertion

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

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afliating hospital, acquisition of data, revising the manuscript and nal

approval of the version to be published. C.J.M.G.: substantial contribution to approval local medical ethical board, logistic arrangement
in afliating hospital, acquisition of data, revising the manuscript and
nal approval of the version to be published. B.W.J.H.: substantial contribution to approval local medical ethical board, logistic arrangement
in afliating hospital, acquisition of data, revising the manuscript and
nal 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 nal approval of the version to be published.
C.A.H.J.: substantial contribution to approval local medical ethical
board, logistic arrangement in afliating hospital, acquisition of data,
revising the manuscript and nal 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 nal approval of the version to be
published.

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