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Perforation risk and intra-uterine devices: results

of the EURAS-IUD 5-year extension study

Clare Barnett, Sabine Moehner, Thai Do Minh & Klaas Heinemann

To cite this article: Clare Barnett, Sabine Moehner, Thai Do Minh & Klaas Heinemann
(2018): Perforation risk and intra-uterine devices: results of the EURAS-IUD 5-year
extension study, The European Journal of Contraception & Reproductive Health Care, DOI:
10.1080/13625187.2017.1412427

To link to this article: https://doi.org/10.1080/13625187.2017.1412427

Published online: 11 Jan 2018.

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THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE, 2018
https://doi.org/10.1080/13625187.2017.1412427

ORIGINAL RESEARCH ARTICLE

Perforation risk and intra-uterine devices: results of the EURAS-IUD 5-year

extension study
Clare Barnett, Sabine Moehner, Thai Do Minh and Klaas Heinemann
ZEG Berlin – Berlin Center for Epidemiology and Health Research, Berlin, Germany

ABSTRACT ARTICLE HISTORY

Objectives: The objective of this analysis was to identify intra-uterine devices (IUD) perforations Received 24 November 2017
detected from 12 to 60 months following IUD insertion, and to combine this information with (our Accepted 28 November 2017
previously published) data about perforations detected in the first 12 months to calculate cumula- Published online 11 January
tive perforation rates. 2018
Methods and materials: Prospective, non-interventional cohort study with new users of levonor- KEYWORDS
gestrel-releasing intra-uterine systems (LNG-IUS) and copper-IUD. The original cohort included IUD; breastfeeding;
61,448 women followed for 12 months. Of these, we had sufficient resources to perform an add- prospective cohort study;
itional follow-up and analysis at 60 months in 39,009 women. Inclusion criteria for this analysis was active surveillance;
insertion prior to 31 July 2010. All potential cases were validated via the health care professional or levonorgestrel; childbirth;
medical records. Crude and adjusted relative risks were calculated using a logistic regression contraception
model.
Results: We identified 23 additional perforations (19 LNG-IUS and 4 copper-IUD) more than 12
months after insertion. Added to perforations detected at 12 months, the overall perforation rate
was 2.1 per 1000 insertions (95% CI: 1.6–2.8) for LNG-IUS users (40 þ 19 perforations/27,630 inser-
tions) and 1.6 per 1000 insertions (95% CI: 0.9–2.5) for copper-IUD users (14 þ 4 perforations/11,379
insertions). LNG-IUS users had a borderline higher risk of perforation compared with copper-IUD
users (ORadj 1.7; 95% CI: 1.0–2.8). Forty-five (58%) of the 77 perforations were associated with sus-
pected risk factors. Breastfeeding (RR 4.9, 95% CI: 3.0–7.8) and time since delivery (RR 3.0, CI:
1.5–5.4) remained significant risk factors in perforations detected after 12 months. No perforations
resulted in serious injury to intra-abdominal or pelvic structures.
Conclusions: The incidence of uterine perforations in this study was low, although higher than the
commonly reported rate. Approximately one third of perforations are detected 12 months after
insertion. Clinical sequalae of perforations are generally mild and associated with a very low risk of
injury to intra-abdominal and pelvic structures.

IMPLICATIONS
 Uterine perforation is a rare risk associated with intra-uterine device use. Late diagnosed perfora-
tions can occur, although women can be reassured that the morbidity associated with detection
and removal is low.

Introduction that up to one quarter of all IUD perforation cases were

diagnosed more than 1 year after insertion. Therefore, it
Levonorgestrel-releasing intrauterine systems (LNG-IUSs) are
was decided to prolong the follow-up phase of EURAS-IUD
an effective and safe contraceptive with additional non-
for a sub-cohort of women to capture IUD perforation cases
contraceptive benefits including treatment for menorrhagia,
detected between 12 and 60 months following insertion
endometriosis and endometrial hyperplasia. Concerns
and identify whether the safety and efficacy of LNG-IUS
remain regarding the overall safety of intra-uterine devices
and copper-IUDs change when late-perforation cases are
(IUDs), particularly regarding potential serious complications
included.
associated with uterine perforation. Until recently, the rela-
tive risk of uterine perforation with LNG-IUS compared to
copper-IUD was poorly studied. We found a relative risk of Methods
perforation in users of LNG-IUS compared to copper-IUD of
1.61 (95% CI: 0.96–2.70) at 12 months after insertion when EURAS IUD (NCT00461175) was a multinational, prospective,
adjusted for age, body mass index (BMI), breastfeeding at controlled cohort study that followed women for 12
time of insertion and parity [1]. Although low overall, per- months following an IUD insertion to measure incidence
foration rates were significantly higher among women who and risk factors associated with uterine perforation.
were breastfeeding at the time of insertion compared to Recruitment was based on an all-comer approach and the
those not breastfeeding, irrespective of the temporal rela- final proportion of LNG-IUS and copper-IUD users was
tionship to delivery. determined by prescribing practices. Further details on
In 2011, during the recruitment phase of the 12-month the study methodology can be found in previous publica-
study, van Grootheest et al. [2] published data suggesting tions [1,3].

CONTACT Klaas Heinemann [email protected] ZEG-Berlin – Berlin Center for Epidemiology and Health Research, Invalidenstr. 115, 10115
Berlin, Germany
ß 2018 The European Society of Contraception and Reproductive Health
2 C. BARNETT ET AL.

Baseline and 12-month follow-up data from all women Crude, as well as adjusted, relative risks were calculated
recruited into EURAS IUD before 31 July 2010 – in total using a logistic regression model. Based on the expectation
39,009 – formed the 12–60 month extension study of a small absolute number of perforations, confounding
cohort. Of these, all women with an IUD in situ at 12 variables were limited to a predefined set of risk factors as
months received a follow-up questionnaire 5 years after recommended by the independent Safety Monitoring and
IUD insertion (30,144 women). Women who had had their Advisory Council. In addition, sensitivity analyses were per-
IUDs removed at 12 months due to perforation, expulsion formed with other potential risk factors to verify the robust-
or personal preference were not sent 5-year follow-up ness of the primary analysis including the use of the
questionnaires, however, their data were included in the backward stepwise approach, where all prognostic factors
analyses of total incidence rates and risk factors for that did not change the point estimate of the risk ratio by
perforation. more than 10% or that had no statistically significant
Sample size was based on published data from four impact (p > .10) were removed. Data on time since delivery
national pharmacovigilance centres showing that approxi- were dichotomised at 36 weeks using a data-driven cut-
mately 25% of perforation cases were diagnosed more than point. All analyses were performed using the STATA 11.0
12 months after insertion [2]. Using this estimate, we calcu- (College Station, TX, USA) and SAS 9.1 (Cary, NC, USA). This
lated that approximately 30,000 women whose IUD was still report complies with the STROBE guidelines for observa-
in place at 12 months, would be required to estimate the tions studies [5].
anticipated proportion of additionally diagnosed perfora- The study was approved by the ethical committee of
tions with acceptable precision. This calculation assumed a the physicians’ association in Berlin, Germany and the
response rate of 2/3.
Ethics Committee of Hospital District of Southwest Finland.
The primary outcome for the 12-month and 60-month
analysis was the incidence of uterine perforation, including
the proportion of uterine perforations associated with ser- Results
ious clinical complications, the interval between IUD inser-
EURAS-IUD included 61,448 women with a newly inserted
tion and diagnosis of uterine perforation and the impact of
IUD insertion in close proximity to childbirth on the uterine IUD [1]. The 5-year sub-cohort included all women recruited
perforation rate. For each of these outcome measures, com- into the study prior to 31 July 2010 (39,009 women, 27,630
parisons were made between LNG and copper-IUDs. All LNG-IUS users and 11,379 copper-IUD users). At the time of
events reported by the participating health care providers recruitment, only one LNG-IUS containing 52 mg of LNG
(HCPs) and/or study participants where any part of the was prescribed in Europe. The exact number of different
device crossed the endometrium and entered the myome- copper-IUDs is unknown since the standard varieties are
trium was considered a perforation. Previously performed marketed under different names in different countries.
sensitivity analysis conducted on the 12-month data However, approximately 50 copper-IUDs of differing size,
showed that limiting events to perforations completely shape and metal content were included.
crossing the myometrium did not significantly alter risk A total of 30,114 women were sent 5-year follow-up ques-
ratios [4]. tionnaires, of which we received 23,896 valid datasets. The
Baseline data collected from study participants included non-response rate for the 5-year questionnaire was 20.7%;
information on medical and gynaecological history, medica- 506 women actively dropped out or withdrew consent for
tion, contraceptive use, age, BMI, lifestyle factors and edu- study participation and 5742 were lost to follow-up. A
cation [1,3]. Specific questions were asked on breastfeeding detailed explanation of the recruitment of study participants
and time since last delivery. Physicians provided informa- into the 5-year sub-cohort can be found in Appendix 1.
tion on the IUD insertion procedure and documented any The study population of the 5-year sub-cohort was com-
IUD perforations identified during or immediately following parable to the study population at 12 months [1]. Overall
insertion. At 12 and 60 months, women were contacted copper-IUD users were younger and more likely to be nulli-
and information obtained on IUD use and complications gravid or to have given birth in the 12 months prior to IUD
associated with IUD use. Physicians were also sent ques- insertion (see Table 1).
tionnaires for each woman they enrolled to capture add- At 5 years, data on the IUD status were missing for
itional perforation-related information. All perforation approximately 27% of the study population (24.8% of LNG-
reports were validated via medical chart review. Contact IUS users and 33.4% of copper-IUD users). In total 29.2% of
data were managed in compliance with data protection LNG-IUS users and 18.9% of copper-IUD users still had their
regulations. IUDs in situ. The remaining 46.0% of LNG-IUS users and

Table 1. Descriptive statistics by user cohorts, with comparison to 12-month study cohorts.
LNG-IUS Copper-IUD
Study 5-year study 12-month study 5-year study 12-month study
N (%) N ¼ 27,630 (70.8) N ¼ 43,078 (70.1) N ¼ 11,379 (29.2) N ¼ 18,370 (29.9)
Age, mean (SD) 37.3 (7.5) 37.4 (7.5) 33.5 (7.7) 33.3 (7.6)
Weight, mean (SD) 69.9 (14.5) 70.1 (14.7) 68.3 (14.0) 68.1 (13.8)
BMI, mean (SD) 25.3 (5.1) 25.4 (5.1) 24.9 (5.0) 24.9 (4.9)
Current smoker N ¼ 6630 (24.0) N ¼ 10,013 (23.2) N ¼ 2802 (24.6) N ¼ 4448 (24.2)
First-ever users of IUD (%) N ¼ 12,677 (45.9) N ¼ 19,932 (46.3) N ¼ 5643 (49.6) N ¼ 9559 (52.0)
Nulligravid N ¼ 1787 (6.5) N ¼ 3036 (7.0) N ¼ 1190 (10.5) N ¼ 2209 (12.0)
Birth in last 12 months N ¼ 5516 (20.0) N ¼ 12,423 (21.9) N ¼ 3,267 (28.7) N ¼ 5291 (34.7)
Breastfeeding at time of insertion N ¼ 2660 (9.6) N ¼ 3968 (9.2) N ¼ 1700 (14.9) N ¼ 2687 (14.63)
 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 3

47.7% of copper-IUD users had had their IUD removed at insertion and parity (preferred model) yielded an adjusted
the time of answering the 5-year follow-up questionnaire – risk ratio of 1.7 (95% CI: 1.0–2.8). ‘Model 2’ containing the
of these, approximately 1.5% (1.4% LNG-IUS and 1.6% cop- variables age, BMI, time since last delivery and HCP experi-
per-IUD) reported a spontaneous IUD expulsion. ence did not substantially change the risk ratio (RR 1.6;
We found 23 additional perforations (19 LNG-IUS and 4 95% CI: 1.0–2.8). Therefore, our results cannot exclude a
copper-IUD) identified more than 12 months after insertion. two-fold higher risk of uterine perforation with LNG-IUS use
Added to the perforations detected at 12 months, a total compared to copper-IUD use. Sensitivity analyses using a
of 77 perforations were identified, of which 59 (40 þ 19) backwards stepwise procedure yielded almost identical
occurred during LNG-IUS use and 18 (14 þ 4) during cop- results (results not shown).
per-IUD use. One perforation in each cohort occurred prior The time interval between insertions and perforation
to insertion of the IUD (during sounding). These cases do diagnosis did not differ substantially between cohorts
not contribute to the IUD perforation rates. The overall per- (Figure 1). A small proportion of perforations were diag-
foration rate was 2.1 per 1000 insertions (95% CI: 1.6–2.8) nosed during or immediately after insertion (2% of LNG-IUS
for LNG-IUS users (39 þ 19 perforations/27,630 insertions) and 17% of copper-IUD). Approximately 69% of perfora-
and 1.6 per 1000 insertions (95% CI: 0.9–2.5) for copper-IUD tions were diagnosed within 12 months of insertion, with
users (4 þ 13 perforations/11,379 insertions). The crude rela- the remaining perforations diagnosed between 1 and 5
tive risk for LNG-IUS versus copper-IUDs was 1.4 (95% CI: years. In two LNG-IUS users, the perforation was diagnosed
0.8–2.3). after the women became pregnant.
A logistic regression model containing the predefined Most early perforations were detected following symp-
prognostic factors age, BMI, breastfeeding at time of toms of pain and/or bleeding. However, in 29% of LNG-IUS
and 17% of copper-IUD perforations, the perforation was
100 asymptomatic (Table 2). This figure increases substantially
90 when data are limited to perforations diagnosed after 12
months, where 58% of LNG-IUS users and 75% of copper-
80
% of diagnosed perforaons

IUD users were asymptomatic at the time of diagnosis.

70 Proportions did not change when stratified by breastfeed-
60 ing status (data not shown). A small number (n ¼ 2, 3.4%)
50 of the LNG-IUS perforations were diagnosed only at the
time of planned IUD removal.
40
No perforation caused serious sequelae, such as bowel
30
or bladder injury, septicaemia, or peritonitis. Most IUDs
20 that perforated the uterus were removed laparoscopically
LNG-IUS
10 (66% of LNG-IUS and 59% of copper-IUD cases).
Copper IUD Approximately one quarter of IUDs could be removed vagi-
0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 nally via hysteroscopy or direct visualisation and removal
Months aer IUD inseron during clinical examination. Laparotomy was a rare proced-
ure (see Table 3).
Figure 1. Kaplan–Meier plot of time to IUD perforation diagnosis.

Table 2. Perforations: circumstances leading to diagnosis at 1 and 5 years of follow-up, stratified by IUS.
LNG-IUS Copper-IUD
1-y FU 5-y FU only 1-y FU 5-y FU only
(40 perforations) (19 perforations) (14 perforations) (4 perforations)
Category n % n % n % n %
Diagnosed at insertion 1 2.5 0 0.0 3 21.4 0 0.0
Pains and/or bleeding 27 67.5 8 42.1 7 50.0 1 25.0
Strings not felt by patient 0 0.0 0 0.0 1 7.1 1 25.0
Pregnancy 1 2.5 2 10.5 1 7.1 0 0.0
Incidental finding (e.g., during diagnostic procedure) 1 2.5 0 0.0 1 7.1 0 0.0
Routine check of IUD position 10 25.0 7 36.8 1 7.1 2 50.0
At planned removal 0 0.0 2 10.5 0 0.0 0 0.0
Total 40 100.0 19 100.0 14 100.0 4 100.0
Percent of perforations.

Table 3. Perforation reported and confirmed during follow-up, by removal technique.

LNG IUD Copper-IUD
Category 0–12 months n (%) 1–5 years n (%) Total n (%) 0–12 months n (%) 1–5 years n (%) Total n (%)
Total 39 (100.0) 19 (100.0) 58 (100.0) 13 (100.0) 4 (100.0) 17 (100.0)
Laparoscopy 29 (74.4) 9 (47.4) 38 (65.6) 8 (61.5) 2 (50.0) 10 (58.8)
Laparotomy 1 (2.6) 0 (0.0) 1 (1.7) 1 (7.7) 0 (0.0) 1 (5.9)
Hysteroscopy 4 (10.3) 6 (31.6) 10 (17.2) 1 (7.7) 0 (0.0) 1 (5.9)
Pulled out by the strings by the vaginal route 2 (5.1) 2 (10.5) 4 (6.9) 3 (23.1) 1 (25.0) 4 (23.5)
Not removed 1 (2.6) 1 (5.3) 2 (3.4) 0 (0.0) 0 (0.0) 0 (0.0)
Unknown 2 (5.1) 1 (5.3) 3 (5.2) 0 (0.0) 1 (25.0) 1 (5.9)
Perforations that occurred before IUD were introduced excluded (n ¼ 2).
4 C. BARNETT ET AL.

Perforations per 1,000 Insertions 14.0 insertion attempt leaving the consecutive user cohort with
12.0
a lower overall risk.
10.0
Some asymptomatic perforations may have been missed
in women whose IUD remained in situ at the 5-year follow-
8.0
up. Most of these women would have had a gynaecological
6.0
examination and IUD position check in the intervening 5
4.0
years. Nevertheless, a slight upward adjustment of the
2.0
overall perforation rate is possible.
0.0 EURAS-IUD was a large, epidemiological study. Although
Breast- Not Breast- Not
feeding Breast- feeding Breast- relative risk differences between LNG-IUS and Copper-IUD
feeding feeding
LNG-IUS Copper IUD
were observed, for an association of this magnitude, it is
not possible to discriminate among bias, confounding,
Figure 2. Perforations per 1000 IUD insertions stratified by cohorts and
breastfeeding at time of insertion (95% CI) (N of perforations/N of women). causation, and chance as alternative explanations [7–11].
When designing EURAS-IUD, we tried to address some
Perforation risk was higher for first-time IUD users issues commonly seen in observational research to more
(unAdj IR 3.55, 95% CI 2.59–4.75) for LNG-IUS and unAdj IR accurately approximate risks. The study was a prospective,
2.13, 95% CI 1.10–3.71) for copper-IUD. Breastfeeding and comparative cohort design in a study population of real
time since delivery remained independently associated with users. Co-variates were collected at baseline and outcomes
perforation risk. The relative perforation risk for women of interest were validated with the treating physician. Given
breastfeeding versus not breastfeeding was 4.9 (95% CI: the many potential threats to validity, it may be difficult to
3.0–7.8). Women who had delivered 36 weeks and were conclude that LNG-IUS has a higher perforation rate com-
pared to copper-IUD.
breastfeeding at the time of insertion had a relative risk of
Our non-response rate for the 5-year extension study
6.8 (95% CI: 4.5–9.9) per 1000 insertions compared to 5.1
was approximately 21%. In theory, a disproportionately
(95% CI: 0.6–18.4) for women who were breastfeeding and
high percentage of perforations could have occurred in
gave birth >36 weeks prior to insertion (Figure 2). Among
patients who were lost to follow-up, however, given that
women who were not breastfeeding at the time of inser-
the 5-year study results reflect both our results at 12
tion, the corresponding figures were 3.0 (95% CI: 1.5–5.4)
months and van Grootheest results, we believe this is
and 1.2 (95% CI: 0.8–1.7), respectively. unlikely to be the case [2].

Discussion Conclusion
There was no significant difference in the relative risk esti- No clinically relevant difference in uterine perforation risk
mate at 5 years in comparison to results at 12 months. At was evident between LNG-IUS and copper-IUDs during rou-
5 years the relative risk of uterine perforation with an LNG- tine clinical use at 12 months or at 5 years of follow-up.
IUS compared to a copper-IUD was 1.65 (95% CI: We found that approximately one third of IUD perforations
0.96–2.82). At 12 months, we found a relative risk of 1.61 were identified “late” (i.e., more than 12 months after the
(95% CI: 0.96–2.70) [1]. initial insertion date). Women with uterine perforations
The proportion of LNG-IUS perforations diagnosed at commonly present to their HCP with abdominal pain and
least 1 year after insertion was 32.7%. This is slightly higher irregular bleeding, however, in many cases they are discov-
than reported by van Grootheest et al. [2] (25.6%). No per- ered during routine gynaecological check-ups. From a pub-
foration caused serious sequalae. Only one IUD required lic health perspective, the rarity of perforation and the
laparotomy for removal and there were no cases of perfo- absence of serious sequelae are reassuring.
rated bowel or peritonitis.
While determining the temporal relationship between
perforation and diagnosis in an observational study of this
Disclosure statement
nature remain challenging, our assumption is that most The study was supervised by an independent Safety Monitoring and
perforations occurred at the time, or soon after, the date of Advisory Council with full authority over the study (including study
protocol, protocol amendments, data analysis, and stopping the
insertion. Breastfeeding at the time of insertion and time
study).
since delivery remained independently associated with the
risk of uterine perforation at 5 years. Moreover, most perfo-
rations diagnosed after 12 months were associated with no, Funding
or relatively few, symptoms. It is probable that due to their The study was funded by a manufacturer of hormonal contraceptives.
low morbidity, these ‘late-diagnosed’ perforations went Unconditional grant from Bayer AG, Germany. The funder had no
unnoticed, in some cases, for several years. access to the source data and did not participate in designing the
A reduced likelihood of perforations was seen in women study, analysing the data, or preparing this publication.
who had used an IUD before (repeat/consecutive users).
The most likely explanation is the “healthy-user” effect [6]. References
Women have inherently higher perforation risks due to ana-
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tomical factors such as cervical stenosis or unusual angula-
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Appendix 1
The EURAS-IUD study was conducted in six European countries (Austria, Finland, Germany, Poland, Sweden and the United Kingdom). The study
was implemented initially in Austria, Finland and Germany in 2006 and expanded to the United Kingdom, Sweden and Poland in the fall of 2009
(Figure A1). A total of 61,448 women were enrolled at baseline. There were no set inclusion criteria and recruitment was based on an all-comer
approach. All women with a newly inserted IUD were eligible for study inclusion with no limitation on age, parity or type of IUD fitted. A ‘non-
interference’ approach was used to provide standardised, comprehensive, reliable information under routine medical conditions. During the
recruitment period (2006–2012) the only levonorgestrel-IUD available in Europe contained 52 mg of levonorgestrel. Copper-IUDs are widely dis-
tributed and over 50 different devices formed the copper-IUD cohort.
Baseline data from all women recruited in EURAS-IUD prior to 30 July 2010 were included in the 5-year extension study (27,630 LNG-IUS users
and 11,379 copper-IUD users). Exclusion criteria was used to prevent women, where an additional questionnaire would not provide new data,
from receiving a 5-year follow-up questionnaire. Women were excluded if they dropped out, or withdrew their information consent during the
first 12 months of the study (433 women), if no follow-up information was available at 12 months (826 women), if only physician follow-up infor-
mation was available (2886 women), if there was missing data on IUD use (326 women) and finally, if the IUD was not in situ at 12 months
(4394). Of the 4394 women who had no IUD at 12 months, the IUD had been removed for personal reasons in 3831 cases. For 399 women, the
IUD had been expelled, 54 women had a perforation, and for 80 women the 12-month questionnaire stated that the IUD was no longer in place,
however, further details were missing (i.e., unclear whether the IUD was removed or expelled). These women were not sent 5-year follow-up
questionnaires, however, their data were included in the analysis of perforation incidence.
A total of 30,114 women were sent 5-year follow-up questionnaires from which we received 23,896 valid datasets. The non-response rate for
the 5-year questionnaire was 20.7%, of which 506 women actively dropped out or withdrew consent for study participation and 5742 were lost
to follow-up.

Baseline Recruited after

61.448 22.439
participants August 2010

Inclusion
Recruited prior
criteria for 5-year
39.009 to 1st August 8.865 4.394 No IUD at 12 months
questionnaire not
2010
fulfilled
No patient or HCP
826
follow-up available
Only 12 month HCP
2.886
follow-up available
Dropout (withdrawal
433
of informed consent)
Missing data on IUD
326
use at 12 months

Non-Responder: Dropout
5-year follow-up
30.144 6.248 dropout or Loss to 506 (Withdrawal IC, going
initiated
follow-up to live abroad)

5.742 Loss-to-follow-up

5-year follow-up
23.896
data obtained
Figure A1. Study flow in the 5-year extension study.