Intrauterine device use is safe among nulligravidas and adolescent girls.

The use of intrauterine devices (IUDs), including the copper-bearing device and the levonorgestrel intrauterine system (LNG-IUS), is safe among nulligravidas and adolescent girls. However, several misconceptions limit their use in clinical practice; health-care providers are hesitant to prescribe IUDs, and several myths associated with their usage in nulligravidas and adolescents exist among both providers and women themselves. The high rates of unplanned pregnancies (which in many settings constitute a public health issue, primarily among adolescent females) can be attributed at least partially to lack of awareness and limited use of highly effective contraceptives such as IUDs. In this review, we discuss the role of non-hormonal and hormonal IUDs as effective contraceptives in nulligravidas and adolescent girls. We present a literature review of data that highlight contraceptive efficacy, side effects (including reasons for discontinuation), and continuation rates with the method. We searched the PubMed/MEDLINE, Cochrane Library, Embase, and Scopus databases for all articles published in English between January 1990 through September 2020. A large body of evidence confirmed the effectiveness of IUD/IUS, independent of age and parity. Studies showed a high expulsion rate among adolescents but not among nulligravidas. Additionally, bleeding patterns among adolescents and nulligravidas were similar to those observed among adults and parous women. The high early removal rates observed in adolescents were attributable to bleeding and/or pain, which indicate that compared with adults, adolescents are less likely to accept IUD-induced side effects. IUD placement is an excellent strategy to avoid the high rates of unplanned pregnancies in adolescents and nulligravidas. IUDs are more effective than short-acting reversible contraceptives with failure rates that are equivalent to those observed with permanent contraception. However, few long-term studies have investigated this category of women to definitively establish the role of IUD/IUS as effective means of contraception.

Long-acting reversible contraceptive (LARCs) methods.

Unplanned pregnancy (UP) is a public health problem, which affects millions of women worldwide. Providing long-acting reversible contraceptive (LARC) methods is an excellent strategy to avoid or at least reduce UP, because the effectiveness of these methods is higher than other methods, and is indeed comparable to that of permanent contraception. As the initial introduction of the inert plastic intrauterine device (IUD) and of the six-rod implant, pharmaceutical companies have introduced a copper IUD (Cu-IUD), different models of levonorgestrel-releasing intrauterine system (LNG IUS), and one and two-rod implants, which certainly improved women's LARC options. The main characteristic of LARCs is that they provide high contraceptive effectiveness with a single intervention, and that they can be used for a long time. Emerging evidence from the last few years has demonstrated that it is possible to extend the use of the 52 mg LNG IUS and of the etonogestrel-implant beyond five- and three years, respectively, which adds new value to these LARCs.

Pregnancy outcomes associated with extended use of the 52-mg 20 µg/day levonorgestrel-releasing intrauterine system beyond 60 months: A chart review of 776 women in Brazil.

OBJECTIVE: To assess the contraceptive performance of the 52-mg 20 µg/day levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena; Bayer Oy, Turku, Finland) among women who maintain the same device without changes after 60 months. STUDY DESIGN: This is a chart review study in which we assessed the charts of 766 women who continue the same LNG-IUS for contraception beyond 60 months. The women were evaluated at the Family Planning clinic, University of Campinas Medical School, Campinas, SP, Brazil, from November 1990 to March 2011. We obtained sociodemographic data, duration of use, continuation and discontinuation rates and reasons, bleeding pattern at the recorded last visit. The statistical analysis was performed using Kaplan-Meier analysis. RESULTS: A total of 776 charts were identified of women who used the LNG-IUS beyond 60 months. The mean age (±S.E.M.) at LNG-IUS placement was 32.0±0.2 years (ranged 15 to 44 years; median was 32 years). The distribution of number of pregnancies was 0-1 (45%); 2-4 (54.1%) and≥5 (0.9%). The median length of the LNG-IUS' use was 73 months after placement (ranged 61-184 months). Zero pregnancies were reported and the main reasons for discontinuation were expiration of approved effective lifespan, menopause and planning pregnancy. The cumulative women-years (W-Y) of exposure were 967 and 1403 up to seven and 15 years, respectively. The main bleeding pattern reported by the women was amenorrhea. CONCLUSIONS: The 52-mg 20 µg/day LNG-IUD (Mirena) showed continue contraceptive efficacy beyond 5 years of use with no pregnancies detected over 967 and 1403 W-Y up to seven and 15 years after placement. IMPLICATIONS STATEMENT: The 52-mg 20 µg/day LNG-IUD presented a very high contraceptive efficacy beyond the first 5 years of lifetime labeled. Increasing data support that efficacy beyond 5 years of use, and new data suggested efficacy as long as 15 years. Healthcare professionals, policy makers and stakeholders could take advantage of the present information to decide to maintain the same device at least up to seven years. Furthermore, amenorrhea could be a good indicator of contraceptive effect.

A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.

STUDY QUESTION: Will the use of levonorgestrel (LNG) 1.5 mg taken at each day of coitus by women who have relatively infrequent sex be an efficacious, safe and acceptable contraceptive method? SUMMARY ANSWER: Typical use of LNG 1.5 mg taken pericoitally, before or within 24 h of sexual intercourse, provides contraceptive efficacy of up to 11.0 pregnancies per 100 women-years (W-Y) in the primary evaluable population and 7.1 pregnancies per 100 W-Y in the evaluable population. WHAT IS KNOWN ALREADY: LNG 1.5 mg is an effective emergency contraception following unprotected intercourse. Some users take it repeatedly, as their means of regular contraception. STUDY DESIGN, SIZE, DURATION: This was a prospective, open-label, single-arm, multicentre Phase III trial study with women who have infrequent coitus (on up to 6 days a month). Each woman had a follow-up visit at 2.5, 4.5 and 6.5 months after admission or until pregnancy occurs if sooner, or she decided to interrupt participation. The study was conducted between 10 January 2012 and 15 November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 330 healthy fertile women aged 18-45 years at risk of pregnancy who reported sexual intercourse on up to 6 days a month, were recruited from four university centres located in Bangkok, Thailand; Campinas, Brazil; Singapore and Szeged, Hungary to use LNG 1.5 mg pericoitally (24 h before or after coitus) as their primary method of contraception. The participants were instructed to take one tablet every day she had sex, without taking more than one tablet in any 24-h period, and to maintain a paper diary for recording date and time for every coital act and ingestion of the study tablet, use of other contraceptive methods and vaginal bleeding patterns. Anaemia was assessed by haemoglobin evaluation. Pregnancy tests were performed monthly and pregnancies occurring during product use were assessed by ultrasound. At the 2.5-month and final visit at 6.5 months, acceptability questions were administered. MAIN RESULTS AND THE ROLE OF CHANCE: There were 321 women included in the evaluable population (which includes all eligible women enrolled), with 141.9 woman-years (W-Y) of observation and with a rate (95% confidence interval [CI]) of 7.1 (3.8; 13.1) pregnancies per 100 W-Y of typical use (which reflects use of the study drug as main contraceptive method, but also includes possible use of other contraceptives from admission to end of study) and 7.5 (4.0; 13.9) pregnancies per 100 W-Y of sole use. In the primary evaluable population (which includes only eligible enrolled women <35 years old), the rate was 10.3 (5.4; 19.9) pregnancies per 100 W-Y of typical use, and 11.0 (5.7; 13.1) pregnancies per 100 W-Y of sole use. There were three reported severe adverse events and 102 other mild adverse events (most common were headache, nausea, abdominal and pelvic pain), with high recovery rate. The vaginal bleeding patterns showed a slight decrease in volume of bleeding and the number of bleeding-free days increased over time. There was only one case of severe anaemia, found at the final visit (0.4%). The method was considered acceptable, as over 90% of participants would choose to use it in the future or would recommend it to others. LIMITATIONS, REASONS FOR CAUTION: This was a single-arm study with small sample size, without a control group, designed as a proof of concept study to explore the feasibility of this type of contraception. WIDER IMPLICATIONS OF THE FINDINGS: A larger clinical study evaluating pericoital contraception with LNG is feasible and our data show that this method would be acceptable to many women. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR) and the World Health Organization. Gynuity and the Bill and Melinda Gates Foundation (BMGF) provided financial support for project monitoring. HRA Pharma donated the LNG product. N.K. was the initial project manager when she was with WHO/HRP and was employed by HRA Pharma, which distributes LNG for emergency contraception. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: This study was registered on ANZCTR, Trial ID ACTRN12611001037998. TRIAL REGISTRATION DATE: 4 October 2011. DATE OF FIRST PATIENT'S ENROLMENT: 10 January 2012.

Effect of vaginal administration of misoprostol before intrauterine contraceptive insertion following previous insertion failure: a double blind RCT.

STUDY QUESTION: Is pretreatment with misoprostol useful in insertion of intrauterine contraceptives (IUCs) after insertion failure at the first attempt? SUMMARY ANSWER: Pretreatment with intravaginal administration of 200 mcg of misoprostol after IUC insertion failure 10 and 4 h before the second attempt of IUC placement was significantly better than placebo at facilitating the insertion of an IUC. WHAT IS KNOWN ALREADY: One of the reasons for low use of IUCs is the concept that insertion is difficult. Misoprostol was used in several randomized clinical trials (RCT) before IUC insertion to facilitate the insertion. In general, the results showed no significant differences when compared with placebo. However, most previous studies have been carried out among unselected women whereas the present study is among women with previous insertion failure. STUDY DESIGN, SIZE, DURATION: This was a double blind RCT conducted between February 2013 and October 2014. Participants were 104 women who requested an insertion of an IUC and the insertion failed at the first attempt. After insertion failure, the women received a sealed envelope with misoprostol or placebo. The randomization system (1: 1) in one block size was computer-generated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a tertiary care centre. The women were instructed to insert vaginally one tablet of misoprostol 200 µg (Prostokos, Hebron, Cariacica, PE, Brazil) or placebo 10 and 4 h before the woman returned to the clinic for a new insertion attempt. The outcomes were successful IUC insertion and the use of a cervical dilator immediately prior to the insertion procedure. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2639 women requested the insertion of an IUC during the study period. The IUC was inserted at the first attempt in 2535 women (96%) and 104 women in whom we were unable to insert the device were eligible to participate in the RCT. Four women declined and 100 women were randomized (55 for the misoprostol group and 45 for the placebo group). From the 100 participating women, the levonorgestrel-releasing intrauterine system (LNG-IUS) was chosen by 55 and 37 women and the TCu380A intrauterine device (Cu-IUD) was chosen by none and 8 women in the misoprostol and placebo group, respectively. Seven and three women allocated to misoprostol and placebo, respectively, never returned to the clinic after randomization. We placed the IUC in 42 (87.5%) out of the 48 women and in 26 (61.9%) out of the 42 women randomized to misoprostol and placebo, respectively (P = 0.0066). Regarding the Evaluable Population the relative risk (RR) of successful insertions was 1.41 (95% confidence interval (CI) for absolute difference (8.2, 43.0), P = 0.0066); in the Intent-to-Treat Population the RR (95% CI) was 1.32 (0.3, 36.9). Multiple regression analysis showed that the significant variables associated with the insertion failure were the number of Caesarean section ≥1 (P = 0.020) and the use of placebo (P = 0.026). Dilators were used in 21 (43.7%) out of the 48 and 21 (50%) out of the 42 women randomized to misoprostol and placebo, respectively (P = 0.804). LIMITATIONS, REASONS FOR CAUTION: The limitations were that the majority of the women chose the LNG-IUS, and consequently the data for the Cu-IUD were limited, and there was a small number of nulligravidas. WIDER IMPLICATIONS OF THE FINDINGS: The results show that IUC insertion difficulties and failures are not common. Pretreatment with intravaginal misoprostol facilitated IUC insertion after failure of insertion at the first attempt, and insertion failure was associated with number of Caesarean sections. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant # 2012/10085-0, and from the National Research Council (CNPq), grant #573747/2008-3. All the TCu380A IUDs were donated by Injeflex, São Paulo, Brazil, and all the LNG-IUS were donated by the International Contraceptive Access Foundation (ICA), Turku, Finland. Both donations were provided in the form of unrestricted grants. The authors declare that there are no conflicts of interest associated with this study. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT01754649.

Prevalence of Low Bone Mass and Osteoporosis in Long-Term Users of the Injectable Contraceptive Depot Medroxyprogesterone Acetate.

BACKGROUND: Bone mineral density (BMD) loss among depot medroxyprogesterone acetate (DMPA) users is a controversial issue. Aspects under debate include whether the number of years of use has any effect on continuous BMD loss, whether this loss will stabilise over the years of use or if it will progress to low bone mass, osteoporosis and an increased fracture risk. The aim of this study was to compare the difference in osteoporosis and low bone mass between DMPA and copper intrauterine device (Cu-IUD) users. METHODS: This was a cross-sectional study that evaluated BMD at the lumbar spine and femoral neck in 47 long-term DMPA users and 41 Cu-IUD users as control group. BMD was measured by dual-energy X-ray absorptiometry. The participants were 27 to 57 years of age, had used either DMPA or a Cu-IUD uninterruptedly for at least ten years, had initiated use of the method prior to 40 years of age and had follicle stimulating hormone values <40 mIU/mL. RESULTS: Findings showed that 68.1% and 36.6% of the DMPA and Cu-IUD users, respectively, had low bone mass and 29.8% and 2.4% of DMPA and Cu-IUD users, respectively, had osteoporosis. BMD decreased as the number of years of DMPA use increased. CONCLUSION: Long-term DMPA use was associated with low bone mass and osteoporosis in women who had used the method for 10 years or more. DMPA users with longer time of use showed a greater bone mass loss.

Estimated disability-adjusted life years averted by long-term provision of long acting contraceptive methods in a Brazilian clinic.

STUDY QUESTION: What is the contribution of the provision, at no cost for users, of long acting reversible contraceptive methods (LARC; copper intrauterine device [IUD], the levonorgestrel-releasing intrauterine system [LNG-IUS], contraceptive implants and depot-medroxyprogesterone [DMPA] injection) towards the disability-adjusted life years (DALY) averted through a Brazilian university-based clinic established over 30 years ago. SUMMARY ANSWER: Over the last 10 years of evaluation, provision of LARC methods and DMPA by the clinic are estimated to have contributed to DALY averted by between 37 and 60 maternal deaths, 315-424 child mortalities, 634-853 combined maternal morbidity and mortality and child mortality, and 1056-1412 unsafe abortions averted. WHAT IS KNOWN ALREADY: LARC methods are associated with a high contraceptive effectiveness when compared with contraceptive methods which need frequent attention; perhaps because LARC methods are independent of individual or couple compliance. However, in general previous studies have evaluated contraceptive methods during clinical studies over a short period of time, or not more than 10 years. Furthermore, information regarding the estimation of the DALY averted is scarce. STUDY DESIGN, SIZE AND DURATION: We reviewed 50 004 medical charts from women who consulted for the first time looking for a contraceptive method over the period from 2 January 1980 through 31 December 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who consulted at the Department of Obstetrics and Gynaecology, University of Campinas, Brazil were new users and users switching contraceptive, including the copper IUD (n = 13 826), the LNG-IUS (n = 1525), implants (n = 277) and DMPA (n = 9387). Estimation of the DALY averted included maternal morbidity and mortality, child mortality and unsafe abortions averted. MAIN RESULTS AND THE ROLE OF CHANCE: We obtained 29 416 contraceptive segments of use including 25 009 contraceptive segments of use from 20 821 new users or switchers to any LARC method or DMPA with at least 1 year of follow-up. The mean (± SD) age of the women at first consultation ranged from 25.3 ± 5.7 (range 12-47) years in the 1980s, to 31.9 ± 7.4 (range 16-50) years in 2010-2011. The most common contraceptive chosen at the first consultation was copper IUD (48.3, 74.5 and 64.7% in the 1980s, 1990s and 2000s, respectively). For an evaluation over 20 years, the cumulative pregnancy rates (SEM) were 0.4 (0.2), 2.8 (2.1), 4.0 (0.4) and 1.3 (0.4) for the LNG-IUS, the implants, copper IUD and DMPA, respectively and cumulative continuation rates (SEM) were 15.1 (3.7), 3.9 (1.4), 14.1 (0.6) and 7.3 (1.7) for the LNG-IUS, implants, copper IUD and DMPA, respectively (P < 0.001). Over the last 10 years of evaluation, the estimation of the contribution of the clinic through the provision of LARC methods and DMPA to DALY averted was 37-60 maternal deaths; between 315 and 424 child mortalities; combined maternal morbidity and mortality and child mortality of between 634 and 853, and 1056-1412 unsafe abortions averted. LIMITATIONS, REASONS FOR CAUTION: The main limitations are the number of women who never returned to the clinic (overall 14% among the four methods under evaluation); consequently the pregnancy rate could be different. Other limitations include the analysis of two kinds of copper IUD and two kinds of contraceptive implants as the same IUD or implant, and the low number of users of implants. In addition, the DALY calculation relies on a number of estimates, which may vary in different parts of the world. WIDER IMPLICATIONS OF THE FINDINGS: LARC methods and DMPA are highly effective and women who were well-counselled used these methods for a long time. The benefit of averting maternal morbidity and mortality, child mortality, and unsafe abortions is an example to health policy makers to implement more family planning programmes and to offer contraceptive methods, mainly LARC and DMPA, at no cost or at affordable cost for the underprivileged population. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant # 2012/12810-4 and from the National Research Council (CNPq), grant #573747/2008-3. B.F.B., M.P.G., and V.M.C. were fellows from the scientific initiation programme from FAPESP. Since the year 2001, all the TCu380A IUD were donated by Injeflex, São Paulo, Brazil, and from the year 2006 all the LNG-IUS were donated by the International Contraceptive Access Foundation (ICA), Turku, Finland. Both donations are as unrestricted grants. The authors declare that there are no conflicts of interest associated with this study.

Exploratory study of the effect of lifestyle counselling on bone mineral density and body composition in users of the contraceptive depot-medroxyprogesterone acetate.

OBJECTIVES: To compare variations in bone mineral density (BMD) and body composition (BC) in depot-medroxyprogesterone acetate (DMPA) users and nonusers after providing counselling on healthy lifestyle habits. METHODS: An exploratory study in which women aged 18 to 40 years participated: 29 new DMPA users and 25 new non-hormonal contraceptive users. All participants were advised on healthy lifestyle habits: sun exposure, walking and calcium intake. BMD and BC were assessed at baseline and 12 months later. Statistical analysis included the Mann-Whitney test or Student's t-test followed by multiple linear regression analysis. RESULTS: Compared to the controls, DMPA users had lower BMD at vertebrae L1 and L4 after 12 months of use. They also had a mean increase of 2 kg in total fat mass and an increase of 2.2% in body fat compared to the non-hormonal contraceptive users. BMD loss at L1 was less pronounced in DMPA users with a calcium intake ≥ 1 g/day compared to DMPA users with a lower calcium intake. CONCLUSIONS: DMPA use was apparently associated with lower BMD and an increase in fat mass at 12 months of use. Calcium intake ≥ 1 g/day attenuates BMD loss in DMPA users. Counselling on healthy lifestyle habits failed to achieve its aims.

Body weight and body composition of depot medroxyprogesterone acetate users.

OBJECTIVES: Weight gain is a concern with the contraceptive depot-medroxyprogesterone acetate (DMPA); however, this issue remains controversial. The objective of this study was to compare body weight (BW) and body composition (BC) in DMPA and copper intrauterine device (IUD) users at baseline and after one year of use. STUDY DESIGN: We enrolled new DMPA users and age and weight matched new IUD users into this prospective study. Weight and height were measured, BC (fat and lean mass) was evaluated using dual-energy X-ray absorptiometry, and physical activity was assessed at baseline and at 12 months. Student's paired t test and the Wilcoxon paired test for matched samples were used. RESULTS: Ninety-seven women were enrolled for the study; 26 matched pairs continued using the initial method for at least one year, and completed the baseline and 12 month assessments. An increase of 1.9 kg occurred in BW (p=.02) in DMPA users at 12 months of use, resulting from an increase in fat mass of 1.6 kg (p=.03). Weight remained stable in IUD users; however, there was an increase in lean mass at 12 months of use (p=.001). The number of women practicing physical activity increased in this group. There was a significant difference between the groups regarding the variation in the percentage of central fat (p=.04). CONCLUSION: Weight gain in the DMPA group after the first year of use resulted from an increase in fat mass. Weight remained stable in the IUD group; however, an increase in lean mass and a reduction in localized abdominal fat mass occurred, possibly because more users were practicing physical activity. IMPLICATIONS STATEMENT: There was a greater increase in body weight in DMPA users compared to TCu380A IUD users in the first year of use of the contraceptive method. Furthermore, the weight increase in users of DMPA occurred principally as the result of an increase in fat mass. Physical activity probably could increase the lean mass in the users of TCu380A IUD.

A randomized clinical trial of the effect of intensive versus non-intensive counselling on discontinuation rates due to bleeding disturbances of three long-acting reversible contraceptives.

STUDY QUESTION: Does intensive counselling before insertion and throughout the first year of use have any influence on discontinuation rates due to unpredictable menstrual bleeding in users of three long-acting reversible contraceptives (LARCs)? SUMMARY ANSWER: Intensive counselling had a similar effect to routine counselling in terms of discontinuation rates due to unpredictable menstrual bleeding in new users of the contraceptives. WHAT IS KNOWN ALREADY: Contraceptive efficacy and satisfaction rates are very high with LARCs, including the etonogestrel (ENG)-releasing implant, the levonorgestrel-releasing intrauterine system (LNG-IUS) and the TCu380A intrauterine device (IUD). However, unpredictable menstrual bleeding constitutes the principal reason for premature discontinuation, particularly in the cases of the ENG-implant and the LNG-IUS. STUDY DESIGN, SIZE, DURATION: A randomized clinical trial was conducted between 2011 and 2013, and involved 297 women: 98 ENG-implant users, 99 LNG-IUS users and 100 TCu380A IUD users. PARTICIPANTS, SETTING, METHODS: Women accepting each contraceptive method were randomized into two groups after the women chose their contraceptive method. Group I received routine counselling at the clinic, including information on safety, efficacy and side effects, as well as what to expect regarding bleeding disturbances. Group II received 'intensive counselling'. In addition to the information provided to those in Group I, these women also received leaflets on their chosen method and were seen by the same three professionals, the most experienced at the clinic, throughout the year of follow-up. These three professionals went over all the information provided at each consultation. Women in both groups were instructed to return to the clinic after 45 (±7) days and at 6 and 12 (±1) months after insertion. They were instructed to record all bleeding episodes on a menstrual calendar specifically provided for this purpose. Additionally, satisfaction with the method was evaluated by a questionnaire completed by the women after 12 months of use of the contraceptive method. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences between the intensive and routine counselling groups on the discontinuation rates due to unpredictable menstrual bleeding of the three contraceptives under evaluation. The 1-year cumulative discontinuation rates due to menstrual bleeding irregularities were 2.1, 2.7 and 4.0% and the continuation rates were 82.6, 81.0 and 73.2%, for the ENG-implant, the LNG-IUS or the TCu380A IUD users, respectively. The main reasons for discontinuation of the methods were weight gain in users of the ENG-implant and expulsion of the TCu380A. LIMITATIONS, REASONS FOR CAUTION: The main limitations are that we cannot assure generalization of the results to another settings and that the routine counselling provided by our counsellors may already be appropriate for the women attending the clinic and so consequently intensive counselling including written leaflets was unable to influence the premature discontinuation rate due to unpredictable menstrual bleeding. Additionally, counselling could discourage some women from using the LARC methods offered in the study and consequently those women may have decided on other contraceptives. WIDER IMPLICATIONS OF THE FINDINGS: Routine counselling may be sufficient for many women to help reduce premature discontinuation rates and improve continuation rates and user satisfaction among new users of LARC methods. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01392157). STUDY FUNDING/COMPETING INTEREST(S): The study was partially funded by the Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP) grant # 2012/01379-0, the Brazilian National Research Council (CNPq) grant #573747/2008-3 and by Merck (MSD), Brazil under an unrestricted grant. The LNG-IUS were donated by the International Contraceptive Access Foundation (ICA) and the copper IUD by Injeflex, São Paulo, Brazil. L.B. has occasionally served on the Board of MSD, Bayer and Vifor.

Human vaginal histology in long-term users of the injectable contraceptive depot-medroxyprogesterone acetate.

OBJECTIVES: Apparently, depot-medroxyprogesterone acetate (DMPA) increases a woman's risk of acquiring HIV. The objective of this study was to test whether the vaginal mucosal thickness and Langerhans cell counts were significantly different in long-term DMPA users compared with women users of an intrauterine device (IUD) who had never used DMPA. STUDY DESIGN: Cross-sectional study. Twenty-three DMPA users were matched with 23 nonusers controlled for age, body mass index (BMI; kg/m²), and duration of contraceptive use. Four groups of women were evaluated according to the duration of DMPA use: >1, <5; ≥5, <10; ≥10, <15 or ≥15 years. Estradiol (E2) levels were compared between the two groups. Histologic sections of vaginal mucosal biopsies were evaluated to measure the mean epithelial thickness and S100 immunostained sections were used to count the number of Langerhans cells/mm. RESULTS: Mean (±S.D.) E2 levels were significantly lower in DMPA users (39.4±26.6 pg/mL) compared with nonusers (102.6±60.3 pg/mL) despite similar ages (42.3±7.4 and 42.4±7.4 years, respectively). Mean (±S.D.) vaginal thickness was 232.6±108.1 and 229.7±112.9 in DMPA users and nonusers, respectively. There were no differences in vaginal thickness or Langerhans cell count/mm between users and nonusers even after controlling for DMPA duration of use. CONCLUSIONS: Vaginal epithelial thinning or Langerhans cell count was not different between long-term DMPA users and copper-IUD users who had never used DMPA. IMPLICATIONS: No differences were found in vaginal epithelial thickness or in Langerhans cell count between long-term users of the injectable contraceptive DMPA and nonusers.

New and emerging contraceptives: a state-of-the-art review.

BACKGROUND: The first hormonal contraceptive was introduced onto the market in several countries 50 years ago; however, the portfolio of contraceptive methods remains restricted with regards to their steroid composition, their cost, and their ability to satisfy the requirements of millions of women/couples in accordance with their different reproductive intentions, behaviors, cultures, and settings. METHODS: A literature review was conducted using Medline, Embase, and Current Contents databases, up to September 1, 2013 to identify publications reporting new contraceptives in development using combinations of the search terms: contraception, contraceptives, oral contraceptives, patch, vaginal ring, implants, intrauterine contraceptives, and emergency contraception (EC). Also, several experts in the field were also consulted to document ongoing projects on contraception development. Additionally, the Clinicaltrial.gov website was searched for ongoing studies on existing contraceptive methods and new and emerging female contraceptives developed over the past 5 years. Information was also obtained from the pharmaceutical industry. RESULTS: Early sexual debut and late menopause means that women may require contraception for up to 30 years. Although oral, injectable, vaginal, transdermal, subdermal, and intrauterine contraceptives are already available, new contraceptives have been developed in an attempt to reduce side effects and avoid early discontinuation, and to fulfill women's different requirements. Research efforts are focused on replacing ethinyl-estradiol with natural estradiol to reduce thrombotic events. In addition, new, less androgenic progestins are being introduced and selective progesterone receptor modulators and new delivery systems are being used. In addition, research is being conducted into methods that offer dual protection (contraception and protection against human immunodeficiency virus transmission), and contraceptives for use "on demand." Studies are also investigating non-hormonal contraceptive methods that have additional, non-contraceptive benefits. CONCLUSION: The most pressing need worldwide is, first, that the highly effective contraceptive methods already available should be affordable to most of the population and also that these methods should fulfill the needs of women of different ages and with different reproductive requirements. The development of new contraceptive methods should also take advantage of the knowledge obtained over the past 30 years on gamete physiology and gamete interaction to avoid the use of steroid compounds.

Effect of hormonal contraceptives during breastfeeding on infant's milk ingestion and growth.

OBJECTIVE: To measure infants' breast milk intake and infant growth when their mothers initiated either combined oral contraceptive (COC), levonorgestrel-releasing intrauterine system, or etonogestrel-releasing implant, or copper intrauterine device (IUD) as a reference group. DESIGN: Prospective trial. SETTING: University-based hospital. PATIENT(S): On postpartum day 42, 40 women initiated a contraceptive method according to their choice. INTERVENTION(S): Deuterium (D2O; 0.5 g/kg mother's weight) was ingested by mothers on postpartum days 42, 52, and 63 as a marker of total body fluid. MAIN OUTCOME MEASURE(S): Infants' milk intake from 42 to 63 postpartum days was assessed by measurement of D2O levels in infants' saliva and infant growth by measuring their body weight, height, and tibia length. Women recorded all infant feed and changes of diapers wet with urine. Breastfeeding continuation was assessed at 6 months postpartum. RESULT(S): Infant mean milk intake, mean growth increase, mean number of breastfeeding episodes, daily wet diaper changes, and mean duration of exclusively breastfeeding (~5 months) were similar in the four groups. CONCLUSION(S): Use of a COC, the two progestin-only contraceptives, or copper IUD did not affect the amount of infant milk intake and growth up to 9 weeks of age. The incidence of full breastfeeding and breastfeeding continuation was similar with contraceptive hormonal use and no use. CLINICAL TRIALS REGISTRATION NUMBER: NCT01388582.

Pain at insertion of the levonorgestrel-releasing intrauterine system in nulligravida and parous women with and without cesarean section.

BACKGROUND: Despite the high contraceptive effectiveness and noncontraceptive benefits of the levonorgestrel-releasing intrauterine system (LNG-IUS) in nulligravidas, there are still concerns related to the use of this device. Pain at insertion is one of the limitations to the increased use of intrauterine contraceptives. The aim of the study was to evaluate the ease of insertion and occurrence of pain at insertion of the LNG-IUS in nulligravidas (women who never became pregnant) compared to parous women with and without cesarean section (c-section). We also assessed the difficulty at insertion in each group. METHODS: Three groups of new acceptors of the LNG-IUS were studied: one with 23 nulligravida women, one with 28 parous women who had undergone at least one c-section and one with 23 parous women who had no previous c-section. Pain at insertion was evaluated by using a pain visual analogue score (VAS). The ease of insertion was defined as easy or difficult by health care providers (HCPs) and classified according to the cause of difficulty: tight cervix, anatomically distorted uterus or pain. RESULTS: Almost all women reported pain at insertion, regardless of parity and form of delivery. The mean VAS was 6.6 for nulligravida women, 5.2 for parous women with c-section and 5.9 for parous women with no c-section. Although 93% of the women reported pain at insertion, they also reported a willingness to insert a new LNG-IUS again if needed. The most common difficulties were a tight cervix in nulligravidas, an anatomically distorted uterus in parous women with c-section and pain in parous women without c-section. There was no failure of insertion in any group. HCPs reported that it was easier to perform insertion in parous women who had undergone only vaginal deliveries than nulligravid women or parous women with a prior c-section. CONCLUSIONS: Although almost all women reported pain at insertion, they also reported a willingness to insert a new LNG-IUS if needed. This attitude reflects high satisfaction with the LNG-IUS. The type of difficulty at insertion was related to parity and type of delivery. The LNG-IUS was able to be inserted in all women; however, it was easier to do in parous women without c-section than nulligravid women or those with a prior C-section.

Assessment of the use of two new low-dose levonorgestrel-releasing intrauterine systems as contraceptives.

Evaluation of: Gemzell-Danielsson K, Schellschmidt I, Apter D. A randomized, Phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil. Steril. 97(3), 616-622.e3 (2012). A randomized, open-label, Phase II study was conducted in 37 centers in five European countries to assess the optimal dose for a new contraceptive levonorgestrel intrauterine system (LNG-IUS). Overall, 742 parous or nulliparous women aged 21-40 years were allocated to receive a LNG-IUS that initially releases 12 µg/day (LNG-IUS(12)) or 16 µg/day (LNG-IUS(16)) in vitro or the currently available device that releases 20 µg/day (LNG-IUS(20)). The two new devices are shorter than the current one. Pearl Indices of 0.17, 0.82 and 0.00 for the LNG-IUS(12), LNG-IUS(16) and LNG-IUS(20), respectively, reflect the contraceptive efficacy of these devices. The mean number of bleeding and spotting days decreased in all three groups; however, this decrease was more significant in LNG-IUS(20) users. Placement of the new shorter devices was considered simple by providers, while patients reported significantly less pain with the two new devices compared with the current one. This study provided further insight into the development of two new LNG-IUS devices as contraceptives, with the additional possibility of using them to treat heavy menstrual bleeding or as endometrial protection during estrogen therapy.

Body weight and composition in users of levonorgestrel-releasing intrauterine system.

BACKGROUND: There is little information about body weight and body composition (BC) among users of the levonorgestrel-releasing intrauterine system (LNG-IUS). The aim of this study was to evaluate body weight and BC in LNG-IUS users compared to users of the TCu380A intrauterine device (IUD). STUDY DESIGN: A prospective study was done with 76 new users of both contraceptive methods. Women were paired by age (±2 years) and body mass index (BMI, kg/m², ±2). Body weight and BC (% lean mass and % fat mass) were evaluated by a trained professional at baseline and at 1 year of contraceptive use. The BC measurements were obtained using Lunar DXA equipment. Weight and BC were evaluated in each woman at baseline and at 12 months and analyzed as the mean change within each woman. Then, the changes in weight and BC for each woman were calculated and then compared between LNG-IUS and TCu380A IUD users (paired data for each woman). The central-to-peripheral fat ratio was calculated by dividing trunk fat by the upper and lower limb fat. RESULTS: There were no significant differences at time of IUD insertion between LNG-IUS and TCu380A IUD users regarding age (mean±SD) (34.4±7.5 vs. 33.9±8.0 years), BMI (25.3±4.1 vs. 25.9±4.1) and number of pregnancies (1.9±0.2 vs. 1.7±0.2), respectively. Mean body weight gain of 2.9 kg was observed among LNG-IUS users at 12 months (p=.0012), whereas the body weight of TCu380A IUD users only increased by 1.4 kg (p=.067). There was no significant difference in body weight change between the two groups of users at 12 months. The variation in the central-to-peripheral fat ratio was the same between the two groups (-1.6% vs. -0.2%; p=.364). LNG-IUS users showed a 2.5% gain in fat mass (p=.0009) and a 1.4% loss of lean mass, whereas TCu380A IUD users showed a loss of 1.3% of fat mass (p=.159) and gain of 1.0% of lean mass (p=.120). TCu380A IUD users gained more lean mass than LNG-IUS users (p=.0270), although there was no significant difference between the two groups after 12 months of use. CONCLUSIONS: Although an increase in mean fat mass among LNG-IUS users at 12 months of use was observed, it should be noted that an increase of body weight was also observed in both groups after 1 year of insertion of the device. However, a study with a larger number of women and long-term evaluation is necessary to evaluate these body changes.

Resources and procedures in the treatment of heavy menstrual bleeding with the levonorgestrel-releasing intrauterine system (LNG-IUS) or hysterectomy in Brazil.

BACKGROUND: Heavy menstrual bleeding (HMB) is the most common complaint of women seeking gynecological care. Treatments included surgical or medical options including hysterectomy and the levonorgestrel-releasing intrauterine system (LNG-IUS) due to the profound suppression of endometrial growth that intrauterine LNG exerts which results in amenorrhea or in a reduction of blood loss. OBJECTIVE: The study was conducted to evaluate the resources and procedures involved in inserting an LNG-IUS compared to performing hysterectomy in women with HMB in a public sector hospital in Brazil. STUDY DESIGN: Two cohorts of women were studied: women who accepted an LNG-IUS (n=124) and matched women who underwent hysterectomy on the same day (n=122). We evaluate the number of procedures carried out in each group of women, including those performed before the decision was made to insert an LNG-IUS or to perform hysterectomy, the insertion of the device itself and the surgical procedure, in addition to the procedures and complications registered up to 1 year after LNG-IUS insertion or hysterectomy. RESULTS: Age and the duration of HMB were significantly lower in the LNG-IUS acceptors than women at the hysterectomy group. The numbers of gynecological consultations and Pap smears were similar in both groups; however, women in the hysterectomy group also underwent laboratory tests, ultrasonography, chest X-ray and electrocardiogram. In the hysterectomy group, the main complications were hemorrhage (six), bladder/bowel perforation (four), complications with anesthesia (one), ureteral reimplantation required (one) and abdominal pain (two). At 1 year, HMB was controlled in 83.1% of women in the LNG-IUS group, and 106 women continued with the device. CONCLUSIONS: Both treatments were effective in HMB control. Fewer resources and complications were observed in LNG-IUS acceptors when compared to hysterectomy. The LNG-IUS represents a good strategy for reducing the number of hysterectomies and the resources required for women with HMB.

In vitro assessment of some sperm function following exposure to levonorgestrel in human fallopian tubes.

BACKGROUND: The mechanism of action of levonorgestrel (LNG) as emergency contraception (EC) remains a subject of debate and its effect on sperm function has been only partially explained. The aim of this study was to assess whether LNG at a similar dose to those found in serum following oral intake for EC could affect spermatozoa when exposed to human fallopian tubes in vitro. METHODS: Fifteen mini-laparotomies were performed, the side on which ovulation occurred was recorded, and both tubes were removed and perfused with a suspension containing 1 × 10(6) motile spermatozoa, with or without LNG. Following 4-hour incubation, the tubes were sectioned to separate the isthmus and the ampulla. Each segment was flushed and the material was evaluated to quantify the number of motile sperm, the number of spermatozoa adhering to the oviductal epithelium and the acrosome reaction (AR) rate. RESULTS: The addition of LNG did not significantly alter the number of recovered motile spermatozoa either at the isthmus or at the ampulla, nor did it have any effect on the number of recovered spermatozoa adhered to the human tubal epithelium. Furthermore, LNG did not affect the AR rate. No significant differences were found even when the side on which ovulation occurred was taken into account. CONCLUSIONS: In a similar dose to that observed in serum following oral intake for EC, LNG had no effect on the number of motile spermatozoa recovered from the human fallopian tubes in vitro, on their adhesion to the tubal epithelium, distribution or AR rate. The possible effect of LNG as EC on sperm function remains poorly understood.

A cross-sectional study of the forearm bone mineral density in long-term current users of the injectable contraceptive depot medroxyprogesterone acetate.

BACKGROUND: One of the well-established effects of the use of depot medroxyprogesterone acetate (DMPA) contraception is on bone mineral density (BMD). However, little evidence assesses the skeletal impact of long-term DMPA use. The objective of this study was to assess BMD on a cohort of women who used DMPA uninterruptedly between 1 and 15 years. STUDY DESIGN: A cross-sectional study with 232 users of DMPA matched to a group of 232 copper intrauterine device (IUD) users by age (±1) (range 20-53 and 20-51 years for DMPA and IUD group, respectively), body mass index (BMI; kg/m(2)) (±1) (range 17.4-44.5 and 18.5-40.2 for DMPA and IUD group, respectively) and years of use (1-15 years) was performed. The women underwent forearm BMD evaluation using dual-energy X-ray absorptiometry. The women were divided into five groups (1-5) according to the length of DMPA use: 1-3, 4-6, 7-9, 10-12 and 13-15 years of use. RESULTS: The mean (±SEM) age was 38.3±0.5 and 38.1±0.57 years and the mean (±SEM) BMI (kg/m(2)) was 26.4±0.3 and 26.3±0.3 for the entire group of women in the DMPA and IUD group, respectively. Women who used DMPA or IUD for a short time were younger and had lower BMI (kg/m(2)) than the women who used either contraceptive method long term. White women were significantly more frequent among IUD users (p<.040) than DMPA users. In addition, parity (p<.053) and physical activity (p<.012) were significantly greater among IUD users, whereas the prevalence of washing clothes by hand (p<.025) was significantly greater among DMPA users. There was no significant difference in BMD measurements between the current users of DMPA and those who had used the IUD either at the distal or ultra-distal sections of the forearm. However, women who had used DMPA for 13-15 years showed significantly lower BMD at the distal and ultra-distal radius when compared to IUD users (p<.041 and .042, respectively). Otherwise, all other differences in BMD values between DMPA and IUD users were nonsignificant at the distal and ultra-distal radius. For both DMPA and IUD users, we noted a direct correlation between higher BMD and BMI (kg/m(2)) and an inverse correlation between BMD and age for distal and ultra-distal radius. CONCLUSIONS: Our study did not detect a deleterious effect on measurements of forearm BMD among long-term DMPA users with less than 13 years of use; however, a significantly lower BMD was observed at 13-15 years of use in DMPA users when compared to IUD users. Bone mineral density was inversely correlated to older age and directly correlated to BMI (kg/m(2)).