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Cervical priming with sublingual misoprostol priorto insertion of an intrauterine device in nulliparous womena randomized controlled trial

I. Saav, A. Aronsson, L. Marions, O. Stephansson and K. Gemzell-Danielsson1

Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Institutet, S-171 76 Stockholm, Swed

1Correspondence address. Tel: 46 851772128; Fax: 46 851774314; E-mail: kristina.gemzell@ki.se

BACKGROUND: The copper intrauterine device (IUD) is a highly effective and safe contraceptive method, also

nulliparous women. However, insertion of an IUD through a narrow cervix may be technically difficult. Misoprost

has been shown to be effective for cervical priming in non-pregnant women prior to hysteroscopy. METHODS: Eigh

nulliparous women requesting an IUD were randomly allocated to receive sublingually 400mg misoprostol an

100 mg diclofenac (misoprostol group) or 100 mg diclofenac alone (control group) 1 h prior to IUD insertion. Cervic

dilatation was measured prior to insertion using Hegar pins. Ease of insertion was judged by the investigator. Pai

bleeding and side effects were recorded at insertion and until follow-up performed one month later. RESULTS: Fo

lowing treatment with misoprostol, insertion was significantly easier than in the control group [P5 0.039, differen

19.36%, confidence interval (CI) 20.013, 39.99]. Pain estimated on a visual analogue scale (110) showed no eviden

of a difference between the groups. The overall distribution of side effects did not differ. However, shivering was mo

common in the misoprostol group (P5 0.0084, difference 23.27%, CI 6.64, 39.90). CONCLUSIONS: Misoprost

facilitates insertion of an IUD, and reduces the number of difficult and failed attempts of insertions in women wi

a narrow cervical canal. The optimal regimen of misoprostol remains to be defined.

Keywords:cervical priming; copper intrauterine device; misoprostol; nullipara; sublingual

Introduction

The copper intrauterine device (IUD) is a highly effective

contraceptive method, also in young or nulliparous women

(WHO, 1987; Penney et al., 2004). Furthermore, the copper

IUD is the most effective emergency contraceptive method

available (Contraception Technology Update, 1995). Compli-

cations are not more common at insertion post-coitally at any

time during the menstrual cycle than at routine insertion

during or after the menstrual period. However, a disadvantage

in nulliparous women is that the insertion of an IUD through a

narrow cervix may be technically difficult and painful (Farmer

and Webb, 2003). Failed insertion, complications and side

effects are significantly more common among women who

have no previous vaginal delivery. Nulliparous women havean increased risk of cervical problems and bradycardia.

Complications include partial or total expulsion and following

unintended pregnancy, pain, abnormal and heavy bleeding.

Sometimes insertion has to be performed under general anaes-

thesia. The fear of painful insertion may make women hesitate

to use an IUD. In lieu of using an IUD, women may prema-

turely request sterilization (and may regret it later), choose

less effective or less convenient methods, or risk an unwanted

pregnancy.

Misoprostol (Cytotec) is a prostaglandin (PG) E1 analog

commercially widely available and used to decrease the ulcer

genic effects of non-steroidal anti-inflammatory drugs (NSAID

Misoprostol is available in oral tablets and the dose used ther

peutically is 400 800 mg daily. PG analogues are used f

cervical dilatation prior to surgical abortion in order to avo

damage to the cervix and uterus due to a rigid cervix and

decrease the bleeding (Ngai et al., 1995,1999; Lawrie et a

1996). Today, the PG analogue of choice is misoprostol. Mis

prostol has also been shown to be a highly effective method f

termination of first and second trimester pregnancy (WH

1987; Ngaiet al. 2000) as well as for labour induction and po

partum haemorrhage (Bugalho et al., 2001; Alfirevic et a

2002; Villar et al., 2002; Hofmeyret al., 2005).The effect of misoprostol is dependent of the route of admin

stration. Oral administration of misoprostol is highly effective

terminating early pregnancy if the duration of amenorrhoea

,50 days. Thereafter, clinical data indicate that oral misopro

tol is less effective (McKinley et al., 1993). However, if mis

prostol (tablets for oral use) is administered vaginally t

efficacy is increased and side effects decreased (El-Refa

et al., 1995). A possible reason for the more pronounc

effect of vaginal misoprostol could be a slower uptake a

# The Author 2007. 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@oxfordjournals.org

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Human Reproduction Vol.22, No.10 pp. 26472652, 2007 doi:10.1093/humrep/dem2

Advance Access publication on July 25, 2007

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metabolism and a more prolonged elevated plasma

concentration compared with the oral route that allows develop-

ment of uterine contractions (Gemzell-Danielsson et al., 1999).

Although vaginal misoprostol has been shown to be more effec-

tive and with less side effects, oral administration is preferred by

many women (Ngai et al., 2000).

A possible alternative is to administer misoprostol

sublingually (Tang and Ho, 2001; Aronsson et al., 2004a).

At sublingual administration the tablet is allowed to melt

under the tongue and has usually melted and disappeared

after 1020 min. (Tang et al., 2002; Aronsson et al., 2004a).

In case the tablet by mistake is swallowed too early the

effect will be at least that following oral administration.

Pharmacokinetic studies as well as studies on uterine con-

tractility in pregnant women indicate that sublingual adminis-

tration of misoprostol results in a more rapid elevation of

plasma levels compared with vaginal administration, a longer

duration of elevated plasma concentration of the active miso-

prostol free acid compared with oral administration and devel-

opment of uterine contractility similar to vaginal treatment

(Tanget al., 2002; Aronssonet al., 2004b). Sublingual admini-

stration of misoprostol has been shown to be more effectivealso for cervical priming compared with oral administration

(Aronsson et al., 2004a) and equally effective as vaginal

administration (Hamoda et al., 2004; Tang et al., 2004).

Another possible indication for use of misoprostol is cervical

priming prior to insertion of an IUD, which would be of benefit

especially in nulliparous women with a narrow cervical canal.

Misoprostol has been shown to be effective for cervical

priming in non-pregnant women of fertile age. Previous

studies have shown the benefit of misoprostol for cervical dila-

tation prior to hysteroscopy (Ngai et al., 1997; Thomas et al.,

2002). Regimens of 400 micro;g misoprostol orally 3 12 h

prior to surgery have been used with a significant effect on cer-

vical resistance and diameter. In an earlier study, a PG F2aanalogue given as a vaginal suppository 1 h prior to IUD inser-

tion was shown to be well tolerated and to reduce nausea and

syncope (Lauersen et al., 1982). A mean increase in cervical

diameter of 2.14 mm was achieved.

The aim of the present study is to compare, in a randomized

fashion, treatment with sublingual misoprostol plus diclofenac

to diclofenac-alone given 1 h prior to insertion of an IUD and

to evaluate the effect on cervical dilatation, side effects

(i.e. nausea, diarrhoea, skin rash, fever/shivering, bradycardia,syncope), pain, bleeding and acceptability.

Materials and Methods

The study was conducted in the Department of Obstetrics and

Gynaecology at the Karolinska University Hospital between Septem-

ber 2004 and July 2006.

Participants were recruited among women requesting a copper IUD

insertion. The study included nulliparous women or women with no

previous vaginal delivery admitted to the clinic for insertion of a

copper IUD. All women were considered to be of good general

health, over 18 years of age and willing and able to participate and

to sign an informed consent. Exclusion criteria were any signs of

genital infection, contraindications to misoprostol or a positive

pregnancy test. The study was approved by the ethics committee at

Karolinska Institutet.

Patients were randomly allocated to either treatment with misopros-

tol with diclofenac (a pain medication) (misoprostol group), or to only

diclofenac (control group), by means of a computer-generated number

table, and by using sealed opaque envelopes, numbered and used con-

secutively. A study nurse, not directly involved in the study, generated

the computerized randomization list. Prior to enrolment, a written

informed consent was obtained from the patient by the investigators.

Women who met the inclusion criteria and not the exclusion criteria

were assigned to trial group according to the randomization number

by a study nurse. The randomization list was kept concealed from

the investigators until the study was completed. The women received,

after randomization, 400 mg (two tablets) of misoprostol sublingually

and 100 mg diclofenac or 100 mg diclofenac-alone 1 h prior to

the IUD insertion. In case of contraindications to NSAID two

T. Citodon (paracetamol and codein) was given instead of diclofenac.

A nurse administered the allocated study medication 1 h prior to

insertion of the IUD (Nova-T, Schering AG, Berlin). The study was

conducted in a single-blinded fashion, the drug administered was

unknown (blinded) to the investigating doctors (n 4) and staff

performing the insertion of the IUD, but not to the patients.

Cervical dilatation was recorded at the insertion of the IUD. The

degree of dilatation was determined by whether or not Hegar dilatorswith a diameter of 4 mm or smaller could pass through the internal cer-

vical os without resistance. Any resistance or need for dilatation was

recorded, as well as the degree of difficulty of the IUD insertion

judged as the resistance of the internal cervical os experienced by

the investigator and classified as easy, moderate or difficult. In

addition, the investigators were asked to judge based on the ease

or difficulty of insertion in each woman whether they believed that

pretreatment with misoprostol had been given or not.

Pain was indicated by the woman on a visual analogue scale (VAS)

graded from 0 to 10, 0 representing no pain at all and 10 worst possible

pain imaginable. It was also noted how difficult the insertion had been,

from the patients point of view. The general experience of the inser-

tion was estimated by the patient as very unpleasant, unpleasant

or very little unpleasant. Side effects such as nausea, diarrhoea,skin rash, fever/shivering, bradycardia or syncope were recorded. Inaddition, women were asked to keep daily records of pain, bleeding

and any side effects experienced until follow-up.

The patients returned for a follow-up visit one month after insertion

of the IUD. At the follow-up visit a vaginal examination was per-

formed, and the pain, side effects and bleeding diary was collected.

The main outcome of the study was the cervical resistance judged by

the investigator. No previous study using misoprostol prior to IUD inser-

tion has been published. We postulated that cervical dilatation would

clinically correspond to level of difficulty of IUD insertion. Therefore,

for calculation of the sample size, previous data on the effect of miso-

prostol for cervical priming was used. When the effect of misoprostol

was studied in non-pregnant women the effect on cervical dilatation

was found to be similar to the effect seen in pregnant women. In a pre-vious study, the baseline cervical diameter in pregnant nulliparous

women was 4.1 mm (SD 1.4) and increased to 7.4 mm (SD 2.0) after

oral misoprostol administration (Ngai et al., 1995). In non-pregnant

women baseline cervical diameter was 3.2 mm (SD 1.3) (Ngai et al.,

1997). Based on these previous studies with samples sizes of 75 and

44 women, respectively, a sample size of 80 women was estimated to

be enough to show a difference in ease of insertion between the groups.

Statistics

To evaluate the differences between the two groups with regard to

cervical resistance indicated by difficulty or ease of insertion,

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judged by the investigator, the Fishers Exact test was used (one-sided

mid-P-value). The Fishers Exact test (two-sided) or the chi-squared

test was used for independent nominal data such as side effects and

overall experience of the insertion. Continuous variables with a

normal distribution such as age and BMI were presented as

mean+SD. Comparison was made using the unpairedt-test. Discrete

numerical variables such as number of previous pregnancies, dilata-

tion of the cervical internal os, bleeding and pain were presented as

medians and ranges and assessed for normality and comparison

using the Mann WhitneyU-test. Results were considered statistically

significant ifP-value was ,0.05.

Results

A total of 80 women were recruited to the study. All 80 women

fulfilled the inclusion criteria and none of the exclusion criteria.

The subjects in the two groups were comparable in age and

BMI (Table 1). There were nine previous pregnancies in the

misoprostol group and eight in the control group, all terminated

during first trimester through spontaneous or induced abortion.

Five women were given Citodon, all due to a previous medical

history of asthma. Two of the women were in the misoprostol

group and three in the control group.There were no failed insertions in the misoprostol group.

One patient in the misoprostol group interrupted the insertion

procedure before the IUD had been inserted. The insertions

were performed in a standardized manner, to avoid differences

between the inserters, and also to prevent differences depend-

ing on the anatomy of the uterus. A Schroder forceps was

applied on the portio. Thereafter, dilatation was measured

using Hegar pins. If necessary, dilatation was performed up

to Hegar 4 mm. A uterine sound measurement was performed

followed by the IUD insertion. The forceps can cause some

pain, but decreases the risk of uterine perforation, particularly

in an ante- or retroverted uterus. The patient who interrupted

the procedure did so after the forceps had been applied, andthere was no attempt made to introduce the Hegar pins,

uterine sound or to insert the IUD. Two insertions failed in

the controlled group, both due to a narrow cervix and failure

to dilate (Fig. 1).

When dilatation was measured as Hegar 4 mm or less that

could pass through the internal cervical os without resistance

there was no evidence of a difference between the groups

(median 4 mm following misoprostol and 4 mm in the

control group (P 0.44). However, when resistance was

measured as difficulty or ease of insertion there was a signifi-

cant difference between the groups (P 0.039, difference

19.36%, confidence interval (CI) 20.013, 39.99) (Table 2).

The number of patients with a strong resistance of the internal

cervical os judged as difficult insertions was three in the

treatment group, compared with six in the control group. T

insertion was estimated to be easy in 29 women in the mis

prostol group compared with 22 in the control group, and inte

mediate or difficult in 10 patients compared with 18 in th

control group. The investigators assumption was that 27 o

of the 40 women in the misoprostol group and 20 out of t

40 women in the control group had received treatment wimisoprostol.

Insertion was performed on cycle Day 17 for women wi

regular menses or withdrawal bleeding. There were no diffe

ences in the number of women with or without bleeding

insertion (28 and 29 women in the control and misoprost

group, respectively (P 0.65). The median number of blee

ing days after insertion was 4 in both groups (Table 3).

Side effects such as nausea, vomiting, diarrhoea, shiverin

and fever were recorded. Over all, there was no evidence

a difference between the groups in the distribution of si

Figure 1: Flow chart of the study

Table 2: Difficulty of IUD insertion, as estimated by the inserter

Estimation of difficultyof insertion

Misoprostolgroup, n 39 (%)

Control groun 40 (%)

Easy 29 (74.4) 22 (55.0)Intermediate or difficult 10 (25.6) 18 (45.0)

P 0.039; Fishers Exact test, mid-P-value. Degrees of freedom 1.

Table 1: Characteristics of study subjects

Characteristics Misoprostol group Control group

Age (years) 22.7 (3.1) (1836) 23.1 (2.9) (1931) aP 0.52BMI 21.4 (2.4) (17.925.7) 21.8 (2.8) (16.829.4) aP 0.58

Results are presented as mean+SD and range.aUnpaired t-test.

Table 3: Comparisons between the study groups

Misoprostol,n 39

Control,n 40

Significan

Median dilatation of cervix 4 mm(04 mm)

4 mm(04 mm)

P 0.44CI 0, 0

Median VAS pain estimation 7 (2.510) 6.5 (010) P 0.20CI 0, 1.5

Median no. of days with painuntil follow-up

5 (1 20) 7 (0 28) P 0.18CI 24, 1

Median no days with bleeding

after insertion

4 (0 29) 4 (0 31) P 0.96

CI 22, 1Median no. of days with

bleeding until follow-up10 (3 29) 15 (1 31) P 0.11

CI 26, 1

MannWhitney U-test, median (range).CI, confidence interval for difference between medians; VAS, visualanalogue scale.

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effects reported (P 0.21) (Table 4). Twelve women reported

shivering, 1 fever, 14 nausea and 12 diarrhoea in the misopros-

tol group whereas 3 women in the control group reported shi-

vering, 0 fever, 17 nausea and 6 diarrhoea. There was a

significant difference for shivering (P 0.0084, difference

23.27%, CI 6.64, 39.90).

The pain experienced by the woman was recorded on a VAS

scale (010). There was no evidence of a difference between

the groups. The median VAS scores were 7.0 (range 2.510)

in the misoprostol group compared with 6.5 (range 010) inthe control group (P 0.20, CI 0, 1.5). The general experience

of the insertion was estimated by the patient as very unplea-

sant, unpleasant or very little unpleasant, and showed strik-

ing similarities between the groups with no evidence of a

difference. In the misoprostol group, 17 patients found the

procedure very unpleasant, 18 unpleasant and 4 very little

unpleasant, compared with 13, 19 and 8 patients, respectively,

in the control group (P 0.39, degrees of freedom 2, test).

Pain and bleeding during the first month after insertion were

also comparable between the groups and showed no evidence

of a difference. The median number of days with any pain

reported was 5 (range 120) in the group treated with miso-

prostol and 7 (range 028) in the control group (P 0.18,

CI 24, 1, Mann WhitneyU-test).

The IUD was well tolerated in both groups. Five women

declared they would not go through the insertion again, but

63 stated they would if necessary. Twelve women did not

answer the question; the women with failed or interrupted

insertion are also in this latter group. Of the five women who

would not go though the insertion again, three were in the

misoprostol group and two in the control group. Of the 63

women who were willing to go though the procedure again,

31 were in the misoprostol group and 32 in the control

group. No post-insertion infection or expulsion occurred in

the month of follow-up. Of the 77 successful IUD insertions,75 patients returned for the follow-up visit one month after

insertion, and 1 woman was contacted on the telephone while

1 woman was lost to follow-up.

Discussion

In the present study, priming of the cervix with misoprostol in

addition to pain medication was compared with only pain

medication prior to IUD insertion in nulliparous women. The

difficulty of insertion was estimated in regard to the resistance

of the cervix.

A facilitating effect of misoprostol on IUD insertion was

found, with significantly less resistance of the internal cervical

os and following technically less difficult insertions compared

with the untreated controls. However, on the whole, the inser-

tion of an IUD in nulliparous women was generally less com-

plicated than expected. In fact, the inserters guessed that a total

of 47 women had received treatment; 27 in the misoprostol

group and 20 in the control group. This should indicate that

the insertions were overall easier and more uncomplicated

than had been anticipated.

There were very few failures to insert the IUD, only two

insertions failed due to very narrow cervix in the control

group. None of the insertions failed in the misoprostol group.

An IUD can be a safe and effective contraceptive alternative

also for nulliparous women. Importantly, a smaller uterus

does not reduce efficacy of an IUD, which does not differ

between nulliparous and parous women (Duenas et al., 1996;

Wildemeersch et al., 2005) and continuation rates with IUD

in nulliparous women do not seem to be lower than continu-

ation rates in parous women (Meiriket al., 2001).Although failed insertion, complications and side effects are

significantly more common among women who have no pre-

vious vaginal delivery there is no increased risk for infections

or infertility following IUD use in nulliparous women

(Luukkainenet al., 1979; Hubacheret al., 2001; Wildermeesch

et al., 2003). Importantly, copper IUD use was not associated

with tubal infertility in nulliparous women, but with a past

Chlamydia infection (Hubacher et al., 2001). An increased

risk of infections during the first month post-IUD insertion

has been shown while infection rates thereafter remain low

and constant for up to 12 years (Farley et al., 1992). In the

present study there was no post-insertion infection recorded.

A possible advantage with the levonorgestrel releasingintrauterine system (LNG-IUS) with regard to infections is

the effect on the cervical mucus which render it less permeable

for sperms as well as for pathogens. The LNG-IUS has a lower

reported rate of infections in nulliparous as well as fewer

removals due to pelvic inflammatory disease (Andersson

et al., 1994). Another important advantage with the IUS com-

pared with combined oral contraceptive in nulliparous women

is a higher continuation rate (Suhonen et al., 2004). A disad-

vantage with the LNG-IUS is the larger diameter of the IUS

compared with the copper IUD. Therefore, the priming effect

of misoprostol might be even more advantageous for

LNG-IUS insertion. In the present study, a smaller copper

IUD (Nova-T, Schering AG) was used which may haveaffected the results.

For estimation of cervical dilatation Hegar dilators were

used. There was no significant difference in the number of

women without resistance to the Hegar dilator with a diameter

of 4 mm (cervical diameter 4 mm or more). However, when

resistance was judged as ease or difficulty of insertion there

were a larger proportion of easy insertions in the misoprostol

group. The difference in cervical dilatation might have been

better estimated if the diameter had been measured as the

largest Hegar pin that could pass through the cervical

Table 4: Number of patients with side effects

Side effects Misoprostolgroup, n 39 (%)

Control group,n 40 (%)

P-value

Any side effect 23 (60.0) 18 (45.0) aP 0.21Shivering 12 (30.8) 3 (7.5) aP 0.0084Diarrhoea 12 (30.8) 6 (15.0) aP 0.075Nausea 14 (35.9) 17 (42.5) aP 0.55Vomiting 2 (5.1) 1 (2.5) bP 0.62

Degrees of freedom 1.achi-squared test.bFishers exact test.

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internal os. However, this measurement was not performed due

to the possible risk of increased expulsion or infection rate with

an unnecessary dilatation.

Our results are consistent with a report on IUD insertion in a

small group of 11 nulliparous women following vaginal

administration of 0.5 mg 15-ME-PGF2a. One hour following

treatment cervical diameter was increased by 2 4 mm

measured by Hegar pins. A majority of the patients experienced

uterine contractions following administration of PG while few

other side effects were recorded.

Due to its higher uterine specificity, low side effects and low

cost misoprostol has come to replace other PGs for several indi-

cations in obstetrics and gynaecology. Misoprostol is highly

effective for cervical dilatation in pregnant women and

widely used off-label for this indication. The route of adminis-

tration seems to be more important than the dose given. Fol-

lowing oral intake there is a rapid increase in plasma level

which is short lasting. In contrast, vaginal treatment results in

lower plasma levels with a later peak level but the elevation

in misoprostol free acid is longer lasting (Zieman et al.,

1997). Sublingual administration results in a rapid uptake

similar to oral administration with the highest peak level andwith sustained levels similar to vaginal treatment (Tang and

Ho, 2001). Vaginal and sublingual administration has been

shown to be more effective than oral misoprostol to induce cer-

vical dilatation as well as uterine contractions in pregnant

women (Aronsson et al., 2004b; Hamoda et al., 2004; Tang

et al., 2004). The sublingual route was chosen based on the

pharmacokinetic studies. Following administration of sublin-

gual misoprostol there is a rapid increase in plasma levels of

misoprostol free acid. It was hypothesized that this would

also reflect in a shorter interval needed for cervical priming.

However, oral administration and a longer priming interval

may well be a better choice. In pregnant women the optimal

interval for priming following oral and vaginal administrationhas been shown to be 3 h. For the sublingual route the optimal

dose and interval remains to be investigated.

A potential advantage with the sublingual route is that sub-

lingual administration of misoprostol is usually more accepta-

ble to women than vaginal administration. It is easy to

self-administer at home prior to admission to the hospital.

Misoprostol has also been shown to induce cervical dilata-

tion in non-pregnant women when used prior to a hysteroscopy.

In these studies the route of administration was oral (Ngai

et al., 1997; Thomas et al., 2002).

Interestingly the height of the serum peak of misoprostol free

acid following misoprostol intake seems to be associated with

the side effects, while the sustained plasma levels are associ-ated with development of uterine contractions. Thus sublingual

administration shows more side effects than conventional oral

or vaginal administration in pregnant women.

The distribution of side effects showed no evidence of a

difference between the two groups in the present study.

However, shivering was significantly more common in the

misoprostol group.

Surprisingly, there was no reduction of pain experienced by

the patients in the misoprostol group during the insertion, in

spite of the decreased cervical resistance experienced by the

inserter. The women were not blinded to the treatment, b

the investigators were. This was due to the problem

finding an appropriate placebo-tablet to use sublingual

This could have introduced bias in the patients experience

pain during the insertion; however, the drug misoprostol w

explained to the patients as a potential facilitator, which pos

ibly could make the insertion less difficult. In spite of this, t

tendency was that the misoprostol group had a higher medi

value on the VAS scale (7.0 compared with 6.5 in the contr

group), although this showed no evidence of a difference.

The experience as a whole was also regarded as equally com

fortable or uncomfortable by the two groups. The pain in t

control group is likely to be related to the pain at inserti

through a narrow cervical canal and induction of uteri

contractions, while pain in the treatment group may be due

misoprostol induced uterine cramping. Based on the da

from pregnant women it is likely that these side effects cou

be reduced by administering misoprostol vaginally and/or reducing the dose.

Conclusions

The study shows that misoprostol can be used to facilitate th

insertion of an IUD in nulliparous women with a narro

cervix. However, the majority of insertions were uncomp

cated and the difficulties few in both groups. Shivering w

more common in the misoprostol group, which should be co

sidered before starting to treat on a routine basis. Probably th

could be reduced by using the vaginal route of misoprost

administration. The optimal dose of misoprostol and primin

interval remains to be defined.

Acknowledgements

The authors are grateful to research nurses Margareta Hellborg a

Lena Elffors-Soderlund, Karolinska University Hospital, StockholSweden, for taking excellent care of the patients. The study was suported by grants from the Swedish Medical Research Coun(2003-3869) and Stockholm city county/Karolinska Institutet (AL

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Submitted on January 26, 2007; resubmitted on June 21, 2007; accepted on

June 29, 2007

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