- Email: [email protected]
A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents
Contraception 79 (2009) 433 – 438
Original research article
A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents Helen Patersona,⁎, Janelle Ashtonb , Mira Harrison-Woolrychb b
a Dunedin School of Medicine, Department of Women's and Children's Health, University of Otago Dunedin 9054, New Zealand Department of Preventive and Social Medicine, Intensive Monitoring Programme (IMMP), University of Otago, Dunedin 9054, New Zealand Received 11 August 2008; revised 30 November 2008; accepted 1 December 2008
Abstract Background: While the use of the levonorgestrel intrauterine device (LNG-IUD) is well established in the adult population, there have been no research studies specifically on the use of the LNG-IUD in adolescents. Study Design: A nationwide cohort study of 179 adolescents in New Zealand using the LNG-IUD, by means of a follow-up questionnaire to their practitioner, was conducted to determine the indications for insertion of the LNG-IUD and to establish patterns of use, including duration of use and reasons for removal. Results: The study, with a 94% response rate, demonstrated that the most common indication for use was menorrhagia (17%); 29% of adolescents had an “off-label” primary indication. There was a 1-year continuation rate of 85%. The cumulative incidence of expulsion was 8%. Conclusion: The results of this study should be reassuring for practitioners and adolescents considering use of the LNG-IUD. However, further research is required into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications. © 2009 Elsevier Inc. All rights reserved. Keywords: Mirena; Adolescent; New Zealand; LNG-IUD
1. Introduction The Mirena® levonorgestrel intrauterine device (LNGIUD) is licensed in New Zealand for contraception, treatment of menorrhagia and endometrial protection during estrogen replacement therapy (http://www.medsafe.govt.nz/profs/ datasheet/m/Mirenaius.htm). The use of the LNG-IUD is well established in the adult population, but there have been no research studies specifically on the use of the LNG-IUD in adolescents. The majority of studies that have included adolescents had only a small number of 18- to 20-year-olds with no relevant subgroup analysis. Adolescence is a variable time period from the onset of puberty until the transition to adulthood. The World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use assigns the LNG-IUD to “Category 2” for women less than 20 years old, which indicates that the
⁎ Corresponding author. Tel.: +64 3 4797185; fax: +64 3 4770509. E-mail address: [email protected] (H. Paterson). 0010-7824/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.12.001
method may generally be used but that more careful followup is required [1]. Recent reviews and editorials have challenged long-held views that IUDs should not be used in young women [2–6]. The 2007 American College of Obstetrics and Gynaecology Committee Opinion Intrauterine Device and Adolescents concluded that data support the safety of IUDs for most women, including adolescents [7]. The primary aims of this nationwide cohort study were to determine the indications for insertion of the LNG-IUD in New Zealand adolescents (including comorbidities influential in the decision to use the device) and to establish patterns of use, including duration of use of the LNG-IUD in the adolescent population and reasons for removal.
2. Methods The Intensive Medicine Monitoring Program (IMMP) performs post-marketing surveillance of selected medicines, usually those newly introduced to the New Zealand market. Prospective observational cohort studies are conducted using
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prescription-event monitoring (PEM) methods in which cohorts of patients are established from prescription data and are then followed up, primarily by questionnaires to prescribers [8]. Spontaneous reports of adverse events for intensively monitored medicines are also assessed by the IMMP as a component of the PEM, along with events from follow-up questionnaires and data linkage to the New Zealand Health Information Service (NZHIS) morbidity and mortality databases [8–10]. This provides the IMMP with a unique intensive methodology for identification of adverse clinical events in patients taking monitored medicines [8]. The IMMP established a cohort of women using the LNG-IUD from insertion notification forms, which were included in the LNG-IUD packages with agreement from the sponsor company. Following the insertion of the device, doctors sent completed forms to the IMMP. This nationwide cohort also included patients identified by pharmacies from prescription data and documentation of insertions from hospital operating theaters. The notification form asked for an indication for use, listing options of contraception, menorrhagia or “other” please specify. It also asked for details of insertion including the timing of insertion of the device. These data were used to establish the timing of insertion options including within 7 days of menstruation, post-first-trimester termination, postpartum and other. The other factors were coded according to the IMMP Mirena® standard operating procedure, which included “at the time of other surgery”. The assumption was made that notifications from hospital theaters were documented as having had the device inserted at surgery, under general anesthetic, unless otherwise specified. For this study, the patient cohort was derived from the IMMP Mirena® Insertion Notification Database using the following inclusion criteria: (a) insertion of LNG-IUD reported to IMMP prior to January 1, 2007; (b) adolescents aged 10–19 years inclusive at date of insertion; and (c) an identifiable doctor to receive a follow-up questionnaire. Patients were excluded if they were recorded as deceased on the NZHIS database prior to January 1, 2007. The follow-up questionnaire was based on other IMMP questionnaires for the LNG-IUD used in previous IUD monitoring studies [11–13]. The questionnaire requested details of all new adverse events since insertion of the IUD, as well as the dates and reasons for removal of the device. Additional questions relevant to its use in adolescents were added to confirm indications for use and to identify other comorbidities in the patient that influenced the decision for LNG-IUD insertion. Further questions aimed to establish the frequency and methods of assessment of the device position after insertion. The questionnaire was tested in a small pilot sample of five practitioners. Only minor alterations were made to the questionnaire; therefore, the pilot cases were included in the analyses. All questionnaires were sent where possible to the patients' general practitioner (GP) or, otherwise, to the
inserting doctor, with a cover letter, an information sheet on the IMMP and a postage-paid addressed envelope for return to the researcher. A reminder fax was sent to all doctors who had not returned a questionnaire. 2.1. Analyses SAS® 8.0 and 9.1 and SAS® Enterprise Guide 4.1 were used in the analyses. Data were described as numbers, and percentages rounded to zero decimal places. Where nominal data followed a normal distribution, they were described with means and standard deviations. Skewed data were described as medians and interquartile ranges (IQRs). To enable analysis of the continuation rate of the LNGIUD, it was necessary to determine an “end date” for each case. This was done for the first device inserted for each adolescent, as detailed: If the LNG-IUD was still in situ, the questionnaire return date was taken to represent the end date; if the LNG-IUD was no longer in situ, then the end date equaled the date of removal; if this date was not given, estimation was made as per the IMMP SOP document for coding IUDs; where the inserter expressed doubt, but data suggested the device was in situ at the last doctor visit, the end date was recorded as the date the patient was last seen as reported on the questionnaire; for dates that included only a month and year, the 15th of the month was used as the estimate; for cases with inadequate information, an end date was not estimated. Product-limit survival estimates were used in the survival analysis; cases with end dates not equivalent to removal of the device were censured (statistically excluded) in the survival analysis. Gross discontinuation rates and the associated confidence intervals were estimated for all removals at 1 year following insertion of the LNG-IUD. 2.2. Ethical approval and privacy issues The IMMP is a long-standing national medical surveillance program, and its processes and practices have been approved by the New Zealand Privacy Commissioner. The monitoring program operates on the “opt-out” principle applied by other national programs. All people dispensed the medicines monitored by the IMMP are automatically included in the program; patients have the right to ask to have their information deleted from the database and still continue taking the medicine. Patients should have been informed at the time of insertion that the LNG-IUD device was being monitored, that their details were being sent to the IMMP and would be recorded in a database, and that details of any adverse events occurring at a later date would be sent to the IMMP. A leaflet should have been given to patients providing an explanation of the monitoring, the data being collected and contact details of the IMMP. This adolescent cohort study was carried out under the existing IMMP ethical approval, which covers the safe use of monitored medicines including assessment of specific populations [8].
H. Paterson et al. / Contraception 79 (2009) 433–438
3. Results A total of 179 adolescents with LNG-IUD insertions prior to January 1, 2007, were identified from the IMMP data sets. Of these 179 cases, 2 did not meet the inclusion criteria (Fig. 1), and therefore questionnaires were sent out for 177 adolescents. Because each case had a different insertion date, the duration of follow-up varied for each adolescent as is usual in PEM studies. The period to follow-up (time of insertion to date of questionnaire return) ranged from 7 months to 8.9 years. For the cohort with an end date, the median time of follow-up was 2.1 years (IQR=1.0–4.0). The characteristics of the cohort were determined from 175 cases with insertion information, defined as the “insertion population” (Fig. 1). Age at insertion of the
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device ranged from 11 to 19 years (there were no insertions in 10-year-olds) with a median age of 18 years (IQR=16– 19 years). Gravidity was available for 151 cases (86%) and ranged from 0 to 6; 114 (65%) were nulligravid. Parity was available for 149 cases (85%) and ranged from 0 to 3. The majority (73%) were nulliparous at the time of insertion. Timing of insertion was identified for 125 cases (71% of the 175 insertion population), with 52 of the 175 cases (30%) having the device inserted within 7 days of menstruation, 54 cases (31%) at the time of surgery, 14 cases (7%) posttermination of pregnancy and 5 cases (3%) postpartum. In 66 of the 175 cases (37%), the device was identified as being inserted under a general anesthetic. The designations of inserters of the LNG-IUD were available for 173 (99%) of the insertion population. The majority of devices (70%) were inserted by gynecology
Fig. 1. Flowchart of IMMP study.
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Table 1 Details of the identified primary indication for use Indication
n
Menorrhagia only Contraception only “Other” only Both contraception and menorrhagia Combination of “other” and contraception /menorrhagia Unknown Total a
Proportion of responder population (%)
22 18 38 21 33
17 14 29 16 25
1 133
1 101a
Percentages are rounded to zero decimal places.
specialists either in public or in private settings, 21% were inserted by GPs and 8% were inserted by other hospital doctors. Of the 175 eligible cases for whom a follow-up questionnaire was sent, 165 (94%) questionnaires were returned to the IMMP. Of these, 133 had sufficient information for assessment, and this group was defined as the “responder population” (Fig. 1). The primary indication for use was reported for 132 of the 133 patients in the responder population, and the results are displayed in Table 1. The most common indication for use, besides menorrhagia and contraception, was endometriosis, with 27 cases (20%) composed of 10 cases identifying endometriosis as the only indication and a further 17 as a combined indication. Dysmenorrhea (20 cases), menstrual management (17), pain (8), intellectual disability (4), metrorrhagia (1), low ferritin (1), polycystic ovarian syndrome (1) and post-termination of pregnancy (1) were also identified as “other” indications. Nine cases identified multiple “other” indications. The cases with an indication classified as “pain” included pelvic pain (4), pain with endometriosis (3) and pain not otherwise specified (1). A comorbidity was identified for 119 (89%) of the responder population. These comorbidities are shown in Table 2. Of the five cases identified as having a bleeding disorder, two were unspecified, one had idiopathic thrombocytopenia, one had thrombophilia and one had von Willebrand's disease. Of the 133 adolescents in the responder population, the LNG-IUD was the first-choice therapy for 43 (32%) cases;
54 (41%) had one prior treatment, 24 (18%) had two prior treatments and 6 had more than two prior treatments. The question was incomplete for six cases. In 59 (44%) cases, the oral contraceptive had been used as a treatment prior to insertion of the LNG-IUD. Depo Provera was used in 22 (17%) cases, progestagens in 11 (8%) cases, nonsteroidal anti-inflammatory drugs in 10 (8%) cases, other types of analgesia in 9 (7%) cases and surgery in 4 (3%) cases. Age at menarche was recorded for 69 (52%) of the responder population. The mean recorded age of menarche for this population was 11.9 years (SD=1.19). The average time from menarche to insertion of the device was 5 years (SD=2.46, range=0–9.8 years). In three cases (2%), the device was inserted prior to menarche; each of these cases was identified as having an intellectual disability. Six cases (5%) identified having considered hysterectomy prior to the use of the LNG-IUD. Five of these six were in adolescents with an intellectual disability. Seventy-three cases (55% of the responder population) were identified as being sexually active prior to insertion of the LNG-IUD, and 51 (38%) cases were identified as not having been sexually active. The answer was unknown or the question was not answered for nine cases. 3.1. Withdrawal/removal of the LNG-IUD There was a 1-year continuation rate of 85% (95% CI=77–90%). The mean time to withdrawal of the LNG-IUD in this population was 855 days (range=1–2561 days). Due to the number of censured cases, continuation rates were quoted only for the first year of use, which included 29 censured cases. In the responder population, 52 cases (40%) had details of the reasons for withdrawal or removal of the device as detailed in Table 3. Pain (n=8) and abnormal vaginal bleeding (n=8) were the most common “other adverse events” that led to removal of the device. Seven cases had multiple adverse events, which prompted removal of the device. 3.2. Perforation and expulsion There were no cases of uterine perforation identified within this study. Eleven cases of expulsion were identified. The cumulative incidence of expulsion was estimated at 8.3% (95% CI=4.2–14.3) in the responder population (n=133) and 6.3% (95% CI=3.2–10.9) in the total adolescent
Table 2 Details of comorbidities reported with insertion of the LNG-IUD
Table 3 Details of removal of the LNG-IUD
Comorbidity
n
Proportion of responder population (%)
Indication for removal
n
Dysmenorrhea Endometriosis Contraceptive compliance Intellectual disability Other Bleeding disorder
52 45 27 25 24 5
39 34 20 19 18 4
Expulsion Other adverse event Planned conception Renewal Other PID Total
11 19 8 7 6 1 52
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cohort (n=175). Five cases of expulsion were in nulligravid cases, giving an estimated cumulative incidence of expulsion from the 114 nulligravid cases of 4.4% (95% CI=1.4–9.9). The mean time to expulsion for the 11 cases identified was 403 days (SD=366 days, range=78–1128 days). There were no reported unintended pregnancies; however, the study was not powered to address this.
4. Discussion While it is estimated that the Mirena® IUD has been used by 7 million women worldwide (Bayer Schering Pharma web site: http://www.asia.mirena.com/scripts/en/1_what_is_the_ ius/is_it_safe/index.php; accessed 5/7/2008), this is the first study to specifically address its use in an adolescent population. Despite the limited research upon which to base clinical practice of LNG-IUD use in adolescents, approximately half of New Zealand gynecologists have used the device in an adolescent [14]. The IMMP cohorts, prospectively established from insertion notifications from throughout New Zealand, provided an excellent opportunity to study use of the LNG-IUD in a substantial number of adolescents. The methods by which IMMP cohorts are established reduce selection bias, and the high response rate (94%) to the followup questionnaires for this study is a further strength. A key finding of this study was the wide range of indications for use of the LNG-IUD in the adolescent population, with 29% having an “off-label” primary indication. An earlier IMMP study of the Mirena device in a largely adult population estimated that only about 4% of insertions were for an indication outside the product license [12]. One may expect that the high off-label use in adolescents was a result of failed “other” therapies; however, the LNG-IUD was the first choice of therapy for 32% of the (responder population) adolescents. Menorrhagia and contraception, the two licensed indications for use of the LNG-IUD in this population, were identified by 17% and 14%, respectively, as the primary indication for use in the adolescent population, as apposed to 48% and 24% reported in the 2002 LNG-IUD IMMP cohort study [12]. New Zealand subsidizes LNG-IUD funding solely for heavy menstrual bleeding (menorrhagia), which may explain why contraception is not the most common reported indication, despite this being the primary function for which the device was designed. The identification of endometriosis as a primary indication for 20% of the responder population and a comorbidity for 34% is surprising in this adolescent cohort. There is limited evidence supporting the use of the LNG-IUD for endometriosis. Bahamondes et al. [15] reviewed the use of the LNG-IUD in women with endometriosis, chronic pelvic pain and dysmenorrhea, and concluded that “the use of LNG-IUS is an alternative for the medical treatment of women suffering from endometriosis, adenomyosis, chronic pelvic pain or dysmenorrhoea, but experience is limited and
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long-term studies are necessary to reach definitive conclusions.” The identification of endometriosis as a comorbidity for 34% of the responder population may explain the 31% of the insertion population who had the LNG-IUD inserted at the time of surgery (i.e., for endometriosis). Dysmenorrhea is commonly described in adolescents, with rates of 20% to 90% depending on the measurement used [16], and therefore, the frequency of dysmenorrhea (39%) reported in this study is not surprising. However, there is limited evidence for the LNG-IUD as a treatment for dysmenorrhea. Suhonen et al. [17] showed (as a secondary outcome) a reduction in dysmenorrhea in comparison to the oral contraceptive in a randomized controlled trial, and French [16] described the LNG-IUD as having Level B evidence for the treatment of dysmenorrhea [16]. Further research on the use of the LNG-IUD in this area, particularly in adolescents for whom dysmenorrhea is so prevalent, is needed. Intellectual disability affects approximately 1% of the general population [18]; therefore, this subgroup of adolescents appears to be overrepresented with 19% in our study. The literature supports the use of the LNG-IUD in women with intellectual disability [19,20]; however, there are no published studies specifically on the LNG-IUD in adolescents with intellectual disability. The most likely reasons for use in this population are contraception, menorrhagia and menstrual management/hygiene [19]. Traditionally, Depo Provera has been used in this population for these same reasons [19], but the increasing concerns over bone mineral density reduction [21,22] may explain an increased use of the LNG-IUD in this population. There is, however, a shortage of evidence for the effect of the LNG-IUD on bone mineral density in adolescents. The identification of prior consideration of hysterectomy for five adolescents with intellectual disability may give insight into the reasons for use of the LNG-IUD in this population. The average age of menarche of approximately 12 years reported in this study is consistent with that reported elsewhere in New Zealand girls as “just under 13 years of age” [23]. A very small proportion (2%) of LNG-IUDs in this cohort was inserted pre-menarche, and the average time from menarche to insertion was 5 years. Clinically, there are concerns about perforation of the uterus and expulsion in small uterine cavities with the use of IUDs [5]. It is therefore interesting to note that there were no perforations reported despite the insertion of devices prior to or early after menarche, although this involved only a minority of cases. Explanations for the high rate of general anesthetic use at insertion (37%) may include the circumstance for use (e.g., intellectual disability), the fact that patients were having a related surgical procedure or the fact that they were not sexually active. However, these are assumptions and cannot be confidently deduced from this study. The cumulative incidence of expulsion of about 8% in the responder population is consistent with rates reported for the general population of LNG-IUD users (5.8% to 11.7%) [24].
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Interestingly, the expulsion rate in the IMMP adolescent study is lower than the 19.9% expulsion rate reported in a 1978 study of the copper IUD in adolescents [25]. The cumulative incidence of expulsion of the LNG-IUD in the nulligravid responder population was 4% compared with 8% in the total adolescent cohort. Other authors have not reported rates of IUD expulsion for a nulligravid population and further research in this area is needed. However, in the meantime, the results of this study should be reassuring to nulligravid adolescents and practitioners considering use of the LNG-IUD in this group. The 1-year continuation rate of 85% compares well with the WHO-quoted 1-year continuation rate of 81% for the LNG-IUD [3], which is based on studies of adult populations of women, and with continuation of rates in adolescents of implants (82%), Depo Provera (45%) and the oral contraceptive pill (12%) [26]. In view of the concerns expressed around the use of the LNG-IUD in adolescents and the lack of supporting evidence for these concerns [27], it is reassuring to see a continuation rate of the LNG-IUD in an adolescent population that is similar to that of adult women. This study was not designed to investigate the therapeutic efficacy of the LNG-IUD in real-life use, although it is reassuring that no contraceptive failures were reported in this population. Adverse events were collected as a secondary outcome of the study and will be reported as part of a future follow-up of the cohort. 5. Conclusion This nationwide study is the first specific assessment of LNG-IUD use in an adolescent population. The principal findings were as follows: the wide range of indications for insertion of the LNG-IUD in the adolescent population including endometriosis, dysmenorrhea and menstrual management; a low expulsion rate; and a high continuation rate of 85% at 1 year. Further research into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications is required. Acknowledgments This study was carried out in partial fulfillment of the requirements for a Masters of Medical Science degree with the University of Otago and with the support of the IMMP. There was no external funding source.
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[21]
[22]
[23]
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among women with sexually transmitted infection? A systematic review. Contraception 2006;73:145–53. Prager S, Darney PD. The levonorgestrel intrauterine system in nulliparous women. Contraception 2007;75(Suppl):S12–5. Hubacher D, Lara-Ricalde R, Taylor DJ, Guerra-Infante F, GuzmanRodriguez R. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 2001;345:561–7. ACOG. ACOG Committee Opinion No. 392, December 2007. Intrauterine device and adolescents. Obstet Gynecol 2007;110: 1493–5. Harrison-Woolrych M, Coulter DM. PEM in New Zealand. In: Mann R, Andrews EB, editors. Pharmacovigilance. 2nd ed. Chichester: John Wiley and Sons Ltd; 2006. p. 313–28. Coulter DM. The New Zealand Intensive Medicines Monitoring Programme. Pharmacoepidemiol Drug Saf 1998;7:79–90. Coulter D. PEM in New Zealand. Pharmacovigilance 2002:345–62. Harrison-Woolrych M, Ashton J, Coulter D. Insertion of the Multiload Cu375 intrauterine device; experience in over 16,000 New Zealand women. Contraception 2002;66(6):387–91. Harrison-Woolrych M, Zhou L, Coulter D. Insertion of intrauterine devices: a comparison of experience with Mirena and Multiload Cu 375 during post-marketing monitoring in New Zealand. N Z Med J 2003;116(1179):U538. Zhou L, Harrison-Woolrych M, Coulter DM. Use of the New Zealand Intensive Medicines Monitoring Programme to study the levonorgestrel-releasing intrauterine device (Mirena). Pharmacoepidemiol Drug Saf 2003;12:371–7. Paterson H, Miller D, Devenish C. Survey of RANZCOG Fellows practising in New Zealand and their use of intrauterine levonorgestrelreleasing system in adolescents. ANZJOG 2008;48:112–8. Bahamondes L, Petta CA, Fernandes A, Monteiro I. Use of the levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea. Contraception 2007;75 (Suppl):S134–9. French L. Dysmenorrhea. Am Fam Physician 2005;71:285–91. Suhonen S, Haukkamaa M, Jakobsson T, Rauramo I. Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception 2004;69:407–12. Paransky OI, Zurawin RK. Management of menstrual problems and contraception in adolescents with mental retardation: a medical, legal, and ethical review with new suggested guidelines. J Pediatr Adolesc Gynecol 2003;16:223–35. Albanese A, Hopper NW. Suppression of menstruation in adolescents with severe learning disabilities. Arch Dis Child 2007;92:629–32. Atkinson E, Bennett MJ, Dudley J, et al. Consensus statement: menstrual and contraceptive management in women with an intellectual disability. ANZJOG 2003;43:109–10. Cundy T, Cornish J, Roberts H, Elder H, Reid IR. Spinal bone density in women using depot medroxyprogesterone contraception. Obstet Gynecol 1998;92(4 Pt 1):569–73. Cromer BA, Scholes D, Berenson A, Cundy T, Clark MK, Kaunitz AM. Depot medroxyprogesterone acetate and bone mineral density in adolescents — the Black Box Warning: a Position Paper of the Society for Adolescent Medicine. J Adolesc Health 2006;39:296–301. Ministry of Health. Sexual and reproductive health: a resource book for New Zealand health care organisations. Wellington: Ministry of Health; 2003. Backman T. Benefit–risk assessment of the levonorgestrel intrauterine system in contraception. Drug Saf 2004;27:1185–204. Weiner E, Berg A, Johansson I. Copper intrauterine contraceptive devices in adolescent nulliparae. BJOG 1978;85:204–6. Zibners A, Cromer BA, Hayes J. Comparison of continuation rates for hormonal contraception among adolescents. J Pediatr Adolesc Gynecol 1999;12(2):90–4. McNaught J. Adolescents and IUCDs — not a contraindication. J Pediatr Adolesc Gynecol 2006;19:303–5.
Original research article
A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents Helen Patersona,⁎, Janelle Ashtonb , Mira Harrison-Woolrychb b
a Dunedin School of Medicine, Department of Women's and Children's Health, University of Otago Dunedin 9054, New Zealand Department of Preventive and Social Medicine, Intensive Monitoring Programme (IMMP), University of Otago, Dunedin 9054, New Zealand Received 11 August 2008; revised 30 November 2008; accepted 1 December 2008
Abstract Background: While the use of the levonorgestrel intrauterine device (LNG-IUD) is well established in the adult population, there have been no research studies specifically on the use of the LNG-IUD in adolescents. Study Design: A nationwide cohort study of 179 adolescents in New Zealand using the LNG-IUD, by means of a follow-up questionnaire to their practitioner, was conducted to determine the indications for insertion of the LNG-IUD and to establish patterns of use, including duration of use and reasons for removal. Results: The study, with a 94% response rate, demonstrated that the most common indication for use was menorrhagia (17%); 29% of adolescents had an “off-label” primary indication. There was a 1-year continuation rate of 85%. The cumulative incidence of expulsion was 8%. Conclusion: The results of this study should be reassuring for practitioners and adolescents considering use of the LNG-IUD. However, further research is required into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications. © 2009 Elsevier Inc. All rights reserved. Keywords: Mirena; Adolescent; New Zealand; LNG-IUD
1. Introduction The Mirena® levonorgestrel intrauterine device (LNGIUD) is licensed in New Zealand for contraception, treatment of menorrhagia and endometrial protection during estrogen replacement therapy (http://www.medsafe.govt.nz/profs/ datasheet/m/Mirenaius.htm). The use of the LNG-IUD is well established in the adult population, but there have been no research studies specifically on the use of the LNG-IUD in adolescents. The majority of studies that have included adolescents had only a small number of 18- to 20-year-olds with no relevant subgroup analysis. Adolescence is a variable time period from the onset of puberty until the transition to adulthood. The World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use assigns the LNG-IUD to “Category 2” for women less than 20 years old, which indicates that the
⁎ Corresponding author. Tel.: +64 3 4797185; fax: +64 3 4770509. E-mail address: [email protected] (H. Paterson). 0010-7824/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.12.001
method may generally be used but that more careful followup is required [1]. Recent reviews and editorials have challenged long-held views that IUDs should not be used in young women [2–6]. The 2007 American College of Obstetrics and Gynaecology Committee Opinion Intrauterine Device and Adolescents concluded that data support the safety of IUDs for most women, including adolescents [7]. The primary aims of this nationwide cohort study were to determine the indications for insertion of the LNG-IUD in New Zealand adolescents (including comorbidities influential in the decision to use the device) and to establish patterns of use, including duration of use of the LNG-IUD in the adolescent population and reasons for removal.
2. Methods The Intensive Medicine Monitoring Program (IMMP) performs post-marketing surveillance of selected medicines, usually those newly introduced to the New Zealand market. Prospective observational cohort studies are conducted using
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prescription-event monitoring (PEM) methods in which cohorts of patients are established from prescription data and are then followed up, primarily by questionnaires to prescribers [8]. Spontaneous reports of adverse events for intensively monitored medicines are also assessed by the IMMP as a component of the PEM, along with events from follow-up questionnaires and data linkage to the New Zealand Health Information Service (NZHIS) morbidity and mortality databases [8–10]. This provides the IMMP with a unique intensive methodology for identification of adverse clinical events in patients taking monitored medicines [8]. The IMMP established a cohort of women using the LNG-IUD from insertion notification forms, which were included in the LNG-IUD packages with agreement from the sponsor company. Following the insertion of the device, doctors sent completed forms to the IMMP. This nationwide cohort also included patients identified by pharmacies from prescription data and documentation of insertions from hospital operating theaters. The notification form asked for an indication for use, listing options of contraception, menorrhagia or “other” please specify. It also asked for details of insertion including the timing of insertion of the device. These data were used to establish the timing of insertion options including within 7 days of menstruation, post-first-trimester termination, postpartum and other. The other factors were coded according to the IMMP Mirena® standard operating procedure, which included “at the time of other surgery”. The assumption was made that notifications from hospital theaters were documented as having had the device inserted at surgery, under general anesthetic, unless otherwise specified. For this study, the patient cohort was derived from the IMMP Mirena® Insertion Notification Database using the following inclusion criteria: (a) insertion of LNG-IUD reported to IMMP prior to January 1, 2007; (b) adolescents aged 10–19 years inclusive at date of insertion; and (c) an identifiable doctor to receive a follow-up questionnaire. Patients were excluded if they were recorded as deceased on the NZHIS database prior to January 1, 2007. The follow-up questionnaire was based on other IMMP questionnaires for the LNG-IUD used in previous IUD monitoring studies [11–13]. The questionnaire requested details of all new adverse events since insertion of the IUD, as well as the dates and reasons for removal of the device. Additional questions relevant to its use in adolescents were added to confirm indications for use and to identify other comorbidities in the patient that influenced the decision for LNG-IUD insertion. Further questions aimed to establish the frequency and methods of assessment of the device position after insertion. The questionnaire was tested in a small pilot sample of five practitioners. Only minor alterations were made to the questionnaire; therefore, the pilot cases were included in the analyses. All questionnaires were sent where possible to the patients' general practitioner (GP) or, otherwise, to the
inserting doctor, with a cover letter, an information sheet on the IMMP and a postage-paid addressed envelope for return to the researcher. A reminder fax was sent to all doctors who had not returned a questionnaire. 2.1. Analyses SAS® 8.0 and 9.1 and SAS® Enterprise Guide 4.1 were used in the analyses. Data were described as numbers, and percentages rounded to zero decimal places. Where nominal data followed a normal distribution, they were described with means and standard deviations. Skewed data were described as medians and interquartile ranges (IQRs). To enable analysis of the continuation rate of the LNGIUD, it was necessary to determine an “end date” for each case. This was done for the first device inserted for each adolescent, as detailed: If the LNG-IUD was still in situ, the questionnaire return date was taken to represent the end date; if the LNG-IUD was no longer in situ, then the end date equaled the date of removal; if this date was not given, estimation was made as per the IMMP SOP document for coding IUDs; where the inserter expressed doubt, but data suggested the device was in situ at the last doctor visit, the end date was recorded as the date the patient was last seen as reported on the questionnaire; for dates that included only a month and year, the 15th of the month was used as the estimate; for cases with inadequate information, an end date was not estimated. Product-limit survival estimates were used in the survival analysis; cases with end dates not equivalent to removal of the device were censured (statistically excluded) in the survival analysis. Gross discontinuation rates and the associated confidence intervals were estimated for all removals at 1 year following insertion of the LNG-IUD. 2.2. Ethical approval and privacy issues The IMMP is a long-standing national medical surveillance program, and its processes and practices have been approved by the New Zealand Privacy Commissioner. The monitoring program operates on the “opt-out” principle applied by other national programs. All people dispensed the medicines monitored by the IMMP are automatically included in the program; patients have the right to ask to have their information deleted from the database and still continue taking the medicine. Patients should have been informed at the time of insertion that the LNG-IUD device was being monitored, that their details were being sent to the IMMP and would be recorded in a database, and that details of any adverse events occurring at a later date would be sent to the IMMP. A leaflet should have been given to patients providing an explanation of the monitoring, the data being collected and contact details of the IMMP. This adolescent cohort study was carried out under the existing IMMP ethical approval, which covers the safe use of monitored medicines including assessment of specific populations [8].
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3. Results A total of 179 adolescents with LNG-IUD insertions prior to January 1, 2007, were identified from the IMMP data sets. Of these 179 cases, 2 did not meet the inclusion criteria (Fig. 1), and therefore questionnaires were sent out for 177 adolescents. Because each case had a different insertion date, the duration of follow-up varied for each adolescent as is usual in PEM studies. The period to follow-up (time of insertion to date of questionnaire return) ranged from 7 months to 8.9 years. For the cohort with an end date, the median time of follow-up was 2.1 years (IQR=1.0–4.0). The characteristics of the cohort were determined from 175 cases with insertion information, defined as the “insertion population” (Fig. 1). Age at insertion of the
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device ranged from 11 to 19 years (there were no insertions in 10-year-olds) with a median age of 18 years (IQR=16– 19 years). Gravidity was available for 151 cases (86%) and ranged from 0 to 6; 114 (65%) were nulligravid. Parity was available for 149 cases (85%) and ranged from 0 to 3. The majority (73%) were nulliparous at the time of insertion. Timing of insertion was identified for 125 cases (71% of the 175 insertion population), with 52 of the 175 cases (30%) having the device inserted within 7 days of menstruation, 54 cases (31%) at the time of surgery, 14 cases (7%) posttermination of pregnancy and 5 cases (3%) postpartum. In 66 of the 175 cases (37%), the device was identified as being inserted under a general anesthetic. The designations of inserters of the LNG-IUD were available for 173 (99%) of the insertion population. The majority of devices (70%) were inserted by gynecology
Fig. 1. Flowchart of IMMP study.
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Table 1 Details of the identified primary indication for use Indication
n
Menorrhagia only Contraception only “Other” only Both contraception and menorrhagia Combination of “other” and contraception /menorrhagia Unknown Total a
Proportion of responder population (%)
22 18 38 21 33
17 14 29 16 25
1 133
1 101a
Percentages are rounded to zero decimal places.
specialists either in public or in private settings, 21% were inserted by GPs and 8% were inserted by other hospital doctors. Of the 175 eligible cases for whom a follow-up questionnaire was sent, 165 (94%) questionnaires were returned to the IMMP. Of these, 133 had sufficient information for assessment, and this group was defined as the “responder population” (Fig. 1). The primary indication for use was reported for 132 of the 133 patients in the responder population, and the results are displayed in Table 1. The most common indication for use, besides menorrhagia and contraception, was endometriosis, with 27 cases (20%) composed of 10 cases identifying endometriosis as the only indication and a further 17 as a combined indication. Dysmenorrhea (20 cases), menstrual management (17), pain (8), intellectual disability (4), metrorrhagia (1), low ferritin (1), polycystic ovarian syndrome (1) and post-termination of pregnancy (1) were also identified as “other” indications. Nine cases identified multiple “other” indications. The cases with an indication classified as “pain” included pelvic pain (4), pain with endometriosis (3) and pain not otherwise specified (1). A comorbidity was identified for 119 (89%) of the responder population. These comorbidities are shown in Table 2. Of the five cases identified as having a bleeding disorder, two were unspecified, one had idiopathic thrombocytopenia, one had thrombophilia and one had von Willebrand's disease. Of the 133 adolescents in the responder population, the LNG-IUD was the first-choice therapy for 43 (32%) cases;
54 (41%) had one prior treatment, 24 (18%) had two prior treatments and 6 had more than two prior treatments. The question was incomplete for six cases. In 59 (44%) cases, the oral contraceptive had been used as a treatment prior to insertion of the LNG-IUD. Depo Provera was used in 22 (17%) cases, progestagens in 11 (8%) cases, nonsteroidal anti-inflammatory drugs in 10 (8%) cases, other types of analgesia in 9 (7%) cases and surgery in 4 (3%) cases. Age at menarche was recorded for 69 (52%) of the responder population. The mean recorded age of menarche for this population was 11.9 years (SD=1.19). The average time from menarche to insertion of the device was 5 years (SD=2.46, range=0–9.8 years). In three cases (2%), the device was inserted prior to menarche; each of these cases was identified as having an intellectual disability. Six cases (5%) identified having considered hysterectomy prior to the use of the LNG-IUD. Five of these six were in adolescents with an intellectual disability. Seventy-three cases (55% of the responder population) were identified as being sexually active prior to insertion of the LNG-IUD, and 51 (38%) cases were identified as not having been sexually active. The answer was unknown or the question was not answered for nine cases. 3.1. Withdrawal/removal of the LNG-IUD There was a 1-year continuation rate of 85% (95% CI=77–90%). The mean time to withdrawal of the LNG-IUD in this population was 855 days (range=1–2561 days). Due to the number of censured cases, continuation rates were quoted only for the first year of use, which included 29 censured cases. In the responder population, 52 cases (40%) had details of the reasons for withdrawal or removal of the device as detailed in Table 3. Pain (n=8) and abnormal vaginal bleeding (n=8) were the most common “other adverse events” that led to removal of the device. Seven cases had multiple adverse events, which prompted removal of the device. 3.2. Perforation and expulsion There were no cases of uterine perforation identified within this study. Eleven cases of expulsion were identified. The cumulative incidence of expulsion was estimated at 8.3% (95% CI=4.2–14.3) in the responder population (n=133) and 6.3% (95% CI=3.2–10.9) in the total adolescent
Table 2 Details of comorbidities reported with insertion of the LNG-IUD
Table 3 Details of removal of the LNG-IUD
Comorbidity
n
Proportion of responder population (%)
Indication for removal
n
Dysmenorrhea Endometriosis Contraceptive compliance Intellectual disability Other Bleeding disorder
52 45 27 25 24 5
39 34 20 19 18 4
Expulsion Other adverse event Planned conception Renewal Other PID Total
11 19 8 7 6 1 52
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cohort (n=175). Five cases of expulsion were in nulligravid cases, giving an estimated cumulative incidence of expulsion from the 114 nulligravid cases of 4.4% (95% CI=1.4–9.9). The mean time to expulsion for the 11 cases identified was 403 days (SD=366 days, range=78–1128 days). There were no reported unintended pregnancies; however, the study was not powered to address this.
4. Discussion While it is estimated that the Mirena® IUD has been used by 7 million women worldwide (Bayer Schering Pharma web site: http://www.asia.mirena.com/scripts/en/1_what_is_the_ ius/is_it_safe/index.php; accessed 5/7/2008), this is the first study to specifically address its use in an adolescent population. Despite the limited research upon which to base clinical practice of LNG-IUD use in adolescents, approximately half of New Zealand gynecologists have used the device in an adolescent [14]. The IMMP cohorts, prospectively established from insertion notifications from throughout New Zealand, provided an excellent opportunity to study use of the LNG-IUD in a substantial number of adolescents. The methods by which IMMP cohorts are established reduce selection bias, and the high response rate (94%) to the followup questionnaires for this study is a further strength. A key finding of this study was the wide range of indications for use of the LNG-IUD in the adolescent population, with 29% having an “off-label” primary indication. An earlier IMMP study of the Mirena device in a largely adult population estimated that only about 4% of insertions were for an indication outside the product license [12]. One may expect that the high off-label use in adolescents was a result of failed “other” therapies; however, the LNG-IUD was the first choice of therapy for 32% of the (responder population) adolescents. Menorrhagia and contraception, the two licensed indications for use of the LNG-IUD in this population, were identified by 17% and 14%, respectively, as the primary indication for use in the adolescent population, as apposed to 48% and 24% reported in the 2002 LNG-IUD IMMP cohort study [12]. New Zealand subsidizes LNG-IUD funding solely for heavy menstrual bleeding (menorrhagia), which may explain why contraception is not the most common reported indication, despite this being the primary function for which the device was designed. The identification of endometriosis as a primary indication for 20% of the responder population and a comorbidity for 34% is surprising in this adolescent cohort. There is limited evidence supporting the use of the LNG-IUD for endometriosis. Bahamondes et al. [15] reviewed the use of the LNG-IUD in women with endometriosis, chronic pelvic pain and dysmenorrhea, and concluded that “the use of LNG-IUS is an alternative for the medical treatment of women suffering from endometriosis, adenomyosis, chronic pelvic pain or dysmenorrhoea, but experience is limited and
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long-term studies are necessary to reach definitive conclusions.” The identification of endometriosis as a comorbidity for 34% of the responder population may explain the 31% of the insertion population who had the LNG-IUD inserted at the time of surgery (i.e., for endometriosis). Dysmenorrhea is commonly described in adolescents, with rates of 20% to 90% depending on the measurement used [16], and therefore, the frequency of dysmenorrhea (39%) reported in this study is not surprising. However, there is limited evidence for the LNG-IUD as a treatment for dysmenorrhea. Suhonen et al. [17] showed (as a secondary outcome) a reduction in dysmenorrhea in comparison to the oral contraceptive in a randomized controlled trial, and French [16] described the LNG-IUD as having Level B evidence for the treatment of dysmenorrhea [16]. Further research on the use of the LNG-IUD in this area, particularly in adolescents for whom dysmenorrhea is so prevalent, is needed. Intellectual disability affects approximately 1% of the general population [18]; therefore, this subgroup of adolescents appears to be overrepresented with 19% in our study. The literature supports the use of the LNG-IUD in women with intellectual disability [19,20]; however, there are no published studies specifically on the LNG-IUD in adolescents with intellectual disability. The most likely reasons for use in this population are contraception, menorrhagia and menstrual management/hygiene [19]. Traditionally, Depo Provera has been used in this population for these same reasons [19], but the increasing concerns over bone mineral density reduction [21,22] may explain an increased use of the LNG-IUD in this population. There is, however, a shortage of evidence for the effect of the LNG-IUD on bone mineral density in adolescents. The identification of prior consideration of hysterectomy for five adolescents with intellectual disability may give insight into the reasons for use of the LNG-IUD in this population. The average age of menarche of approximately 12 years reported in this study is consistent with that reported elsewhere in New Zealand girls as “just under 13 years of age” [23]. A very small proportion (2%) of LNG-IUDs in this cohort was inserted pre-menarche, and the average time from menarche to insertion was 5 years. Clinically, there are concerns about perforation of the uterus and expulsion in small uterine cavities with the use of IUDs [5]. It is therefore interesting to note that there were no perforations reported despite the insertion of devices prior to or early after menarche, although this involved only a minority of cases. Explanations for the high rate of general anesthetic use at insertion (37%) may include the circumstance for use (e.g., intellectual disability), the fact that patients were having a related surgical procedure or the fact that they were not sexually active. However, these are assumptions and cannot be confidently deduced from this study. The cumulative incidence of expulsion of about 8% in the responder population is consistent with rates reported for the general population of LNG-IUD users (5.8% to 11.7%) [24].
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Interestingly, the expulsion rate in the IMMP adolescent study is lower than the 19.9% expulsion rate reported in a 1978 study of the copper IUD in adolescents [25]. The cumulative incidence of expulsion of the LNG-IUD in the nulligravid responder population was 4% compared with 8% in the total adolescent cohort. Other authors have not reported rates of IUD expulsion for a nulligravid population and further research in this area is needed. However, in the meantime, the results of this study should be reassuring to nulligravid adolescents and practitioners considering use of the LNG-IUD in this group. The 1-year continuation rate of 85% compares well with the WHO-quoted 1-year continuation rate of 81% for the LNG-IUD [3], which is based on studies of adult populations of women, and with continuation of rates in adolescents of implants (82%), Depo Provera (45%) and the oral contraceptive pill (12%) [26]. In view of the concerns expressed around the use of the LNG-IUD in adolescents and the lack of supporting evidence for these concerns [27], it is reassuring to see a continuation rate of the LNG-IUD in an adolescent population that is similar to that of adult women. This study was not designed to investigate the therapeutic efficacy of the LNG-IUD in real-life use, although it is reassuring that no contraceptive failures were reported in this population. Adverse events were collected as a secondary outcome of the study and will be reported as part of a future follow-up of the cohort. 5. Conclusion This nationwide study is the first specific assessment of LNG-IUD use in an adolescent population. The principal findings were as follows: the wide range of indications for insertion of the LNG-IUD in the adolescent population including endometriosis, dysmenorrhea and menstrual management; a low expulsion rate; and a high continuation rate of 85% at 1 year. Further research into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications is required. Acknowledgments This study was carried out in partial fulfillment of the requirements for a Masters of Medical Science degree with the University of Otago and with the support of the IMMP. There was no external funding source.
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[21]
[22]
[23]
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