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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
1

Kirsten Dijkhuizen , Olaf M. Dekkers , Cas A.G. Holleboom ,


4
5
Christianne J.M. de Groot , Bart W.J. Hellebrekers , Godelieve
1
6
J.J. van Roosmalen , Catharina A.H. Janssen ,
1,2,
and Frans M. Helmerhorst *
1

Department of Gynaecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Clinical
3
Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Gynaecology, Bronovo
4
Hospital, PO Box 96900, 2509 JH, The Hague, The Netherlands Department of Gynaecology, Medical Centre of the Haaglanden,
5
PO Box 432, 2501 CK, The Hague, The Netherlands Department of Gynaecology, HAGA Teaching Hospital, PO Box 40551, 2540 LN, The
6
Hague, The Netherlands Department of Gynaecology, Groene Hart Hospital, PO Box 1098, 2800 BB, Gouda, The Netherlands

*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 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) 0.2 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.
Key words: intrauterine device / misoprostol (vaginal) / cervical priming / intrauterine device insertion

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Netherlands, the use of IUDs among women aged 18 45 years has


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

Introduction

Reported complications related to IUD insertion are: 8.8% insertion failure,

Intrauterine devices (IUDs) are widely used as reversible contraceptives. Both

2.8 11.5% cervical problems, 0.2% cervical perforation, 0.2% syncope and

copper- and levonorgestrel (LNG)-releasing IUDs (LNG-IUDs) are safe, cost-

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

effective in the long term and equally effective compared with tubal sterilization

problems seem to occur more often among women who have never delivered

(Grimes et al., 2007; Grimes and Mishell, 2008). In addition, the LNG-IUD

vaginally (Farmer and Webb, 2003; Li et al., 2005). Cervical stenosis, an

(Mirenaw)

for

immature or small cervix and a significantly ante- or retroverted position of the

menorrhagia, dysmenorrhea and anemia (Luukkainen and Toivonen, 1995;

uterus, has been described as factors associated with a difficult sounding of the

Hurskainen et al., 2004; Milsom, 2007). The current use of IUDs among

cervical canal or even failure to insert the IUD (Preutthipan and Herabutya,

reproductive-aged women ranges from 8 to 15% worldwide (DArcangues,

2006).

provides

noncontraceptive

benefits,

such

as

treatment

2007). In the

& The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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324
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; 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 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 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 sideeffects (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 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
(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

Dijkhuizen et al.
par-ticipants were enrolled after giving written informed consent. The
study was solely funded by the LUMC. The trial was registered at the
P
European Clinical Trials Database; EudraCT 2006-006897-60.
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nerated 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/notscheduled 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
(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 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.

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325

Misoprostol before intrauterine device insertion

was given local anesthesia before insertion. All these participants


All patients were seen for a routine check-up 6 weeks after IUD insertion. During this visit, vaginal examination and/or vaginal ultrasound were were analyzed according to the intention to treat principle.
performed. IUD expulsions and infections were recorded.
dropped out of the study. Forty participants did not show up
I
on their scheduled appoint-ment for insertion. Twenty forms
U
Statistics
were untraceable in the medical record. Therefore, a total of
D
199 participants was included in the analysis for the primary
The sample size was calculated based on the primary outcome of
outcome.
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
2

analyzed using x 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 PAPsmears 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 pregnant before scheduled IUD insertion and therefore

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

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8

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 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 partici-pant, it was
impossible to sound the (pinpoint) ostium. One insertion could
not be completed owing to a technical problem with the LNGIUD 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 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 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 1.0 1.7). The most common sideeffect 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 sideeffects 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).

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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326

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


IUD.

Dijkhuizen et al.

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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 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 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).

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

Discussion

study, the degree of cervical dilatation was not measured.

The present multicenter RCT was conducted to assess


whether vaginal misoprostol prior to IUD insertion reduces
the amount of

this does not lead to easier insertions

Misoprostol might have an effect on cervical dilatation; however,

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327

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

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

a
n
d
H
er
a
b
ut
y
a,
1

Contraception

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%)

Type IUD

9)

Parity
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%)

Ethnicity

History
Cesarean section*

e
n
e
g
at
iv
e
re

8 (7.8%)

13/93 (14.0 %)

s
ul

Abortion
(spontaneous/induced)*

18/89 (20.2%)

15/83 (18.1%)

Menses during insertion*

41/91 (45.1%)

37/89 (41.6%)

of

Breastfeeding*

12/71 (16.9%)

7/71 (9.9%)

Remains of tablets
present in vagina*

62/85 (72.9%)

64/77 (83.1%)

ur

ts

st

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.

y
ar
e
u
nl
ik

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 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 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

el
y
to
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a
re
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t
of
a
n
in

adequate 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 to selection 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 of the 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 400 mg 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-heimo et 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.

Downloadedfromhttp://humrep.oxfordjournals.org/byguestonJune7,2015

328

Dijkhuizen et al.

Table II Outcomes related to insertion of an IUD.


Outcome

Misoprostol group (n 5 102) Nulliparous


(n 5 49) Multiparous (n 5 53)

Placebo group (n 5 97) Nulliparous (n 5 46) P-value


Multiparous (n 5 51)

.............................................................................................................................................................................................
a

Any complication (total

22/101 (21.8%)

n 195)
Nulliparous (n 93)

15/49 (30.6%)

Multiparous (n 101)

7/52 (13.5%)

Failed insertion (total n 199)

2/102 (2.0%)
0

Nulliparous (n 95)
Multiparous(n 104)
Vasovagal-like reaction (total

2/53 (3.8%)
20/96 (20.8%)

n 186)
Nulliparous (n 87)

15/46 (32.6%)

Multiparous (n 99)

5/50 (10.0%)

Syncope (total n 199)

3/102 (2.9%)

Nulliparous (n 95)

2/49 (4.1%)

Multiparous (n 104)
Perforation

1/53 (1.9%)
0

Heavy bleeding

Expulsion
Pain estimation by the patient
Total (n 190)
Nulliparous (n 92)
Multiparous (n 98)
c
Difficulty of insertion

0
b

mean, +SD
46, 28
59, 25
33, 26
mean, +SD

Total (n 191)

2.9, 2.8

Nulliparous (n 92)

3.4, 2.7

Multiparous (n 99)
18/94 (19.1%)

2.4, 2.8
0.65

15/44 (34.1%)

0.72

3/50 (6.0%)

0.21

1/97 (1.0%)

0.59

1/46 (2.2%)

0.48

0.50

15/90 (16.7%)

0.47

13/41 (31.7%)

0.93

2/49 (4.1%)

0.44

2/97 (2.1%)

0.70

1/46 (2.2%)

0.60

1/51 (2.0%)

1.00

0
0
1 (1.0%)

0.45

mean, +SD
40, 27

0.14

54, 23

0.34

26, 24

0.17

mean, +SD
2.8, 2.6

0.77

3.7, 3.0

0.63

1.9, 1.8

0.35

Downloadedfrom
a

Any complication; either failed insertion, vagal reaction, perforation, heavy


bleeding or expulsion. bPain estimation by the patient: Visual Analog score in
mm.
c

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

byguestonJune7,

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

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.

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

K.D.: substantial contribution to trial design, writing protocol,

Diarrhea

4 (4.0%)

2 (2.2%)

0.68

approval medical ethical board, statistical analysis, interpreting

Fever

0 (0%)

3 (3.3%)

0.11

data, writing and revising the manuscript and final approval of the

Other

14 (14.1%)

12 (13.0%)

0.48

version to be pub-lished. O.M.D.: substantial contribution to

Authors roles

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

2015

329

Misoprostol before intrauterine device insertion


of IUD trials: lessons learned. Contraception 2007;75:S55 S59.

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.

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