Ndema Habib

A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls

STUDY QUESTION Is there any difference in the clinical performance of the 3-year one-rod etonogestrel (ENG)- and the 5-year two-rod levonorgestrel (LNG)-releasing contraceptive implants during 3 years of insertion, and between implant and intrauterine device (IUD) contraception, in particular complaints possibly related to hormonal contraceptives? SUMMARY ANSWER The cumulative contraceptive effectiveness after 3 years and method continuation through 2.5 years were not significantly different between ENG and LNG implants, but both outcomes were significantly worse in the non-randomized age-matched group of IUD users than in the combined implant group. WHAT IS KNOWN ALREADY ENG- and LNG-releasing implants are safe and highly efficacious contraceptives with pregnancy rates reported to be 0.0-0.5 per 100 women-years (W-Y). No head-to-head comparative study of the two implants has been undertaken, and little information is available on comparisons of complaints of side effects of implant and copper IUD users. STUDY DESIGN, SIZE, DURATION This was an open parallel group RCT with 1:1 allocation ratio of the ENG and the LNG implants with non-randomized control group of women choosing TCu380A IUD to address lack of reliable data on common side effects typically attributed to the use of progestogen-only contraceptives. After device(s) placement, follow-ups were at 2 weeks, 3 and 6 months, and semi-annually thereafter for 3 years or until pregnancy, removal or expulsion of the implant/IUD occurred. PARTICIPANTS, SETTING, METHODS The study took place in family planning clinics in Brazil, Chile, Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Women seeking long-term contraception were enlisted after an eligibility check and informed consent, and 2982 women were enrolled: 1003, 1005 and 974 in the ENG-implant, LNG-implant and IUD groups, respectively; 995, 997 and 971, respectively, were included in the per protocol analysis reported here. MAIN RESULTS AND THE ROLE OF CHANCE ENG and LNG implants each had the same 3-year cumulative pregnancy rate of 0.4 per 100 W-Y [95% confidence interval (CI) 0.1-1.4]. A weight of ≥70 kg at admission was unrelated to pregnancy. Method continuation rates for ENG and LNG implants at 2.5 years were 69.8 (95% CI 66.8-72.6) and 71.8 per 100 W-Y (68.8-74.5), and at 3 years 12.1 (95% CI 5.2-22.0) and 52.0 per 100 W-Y (95% CI 41.8-61.2), respectively. Bleeding disturbances, the most frequent reason for method discontinuation, were significantly more common in the ENG group [16.7 (95% CI 14.4-19.3)] than in the LNG group [12.5 (95% CI 10.5-14.9)] (P 0.019). The 3-year cumulative loss to follow-up was lower in the ENG- than in the LNG-implant group, 8.1 (95% CI 6.4-10.2) and 14.4 per 100 W-Y (95% CI 12.1-17.1), respectively. The median duration of implant removal was 50 s shorter among women with ENG than among women with LNG implant (P < 0.0001). In the observational comparison between IUD and implant users, the 3-year relative risk for pregnancy in IUD group compared with the combined implant group was 5.7 per 100 W-Y (95% CI 4.4-7.3) (P = 0.0003). The 3-year expulsion rate of the IUD was 17.8 per 100 W-Y (95% CI 14.5-21.9), while the discontinuation rate for bleeding disturbances was 8.5 (95% CI 6.7-10.9). Frequency of complaints of headache and dizziness was not significantly different between implant and IUD users (P = 0.16 and 0.77, respectively), acne and bleeding irregularities were more frequent among implant users (P < 0.0001), while heavy bleeding and lower abdominal pain occurred more often among IUD than implant users (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION Few women were ≤19 years old or nulligravida, the proportion of implant users ≥70 kg was <20% and <8% were obese. WIDER IMPLICATIONS OF THE FINDINGS Findings of the study can inform policy makers and clinicians about choice of implant, but also about TCu380A IUD in relation to implants. STUDY FUNDING/COMPETING INTERESTS UNDP/UNFPA/WHO/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization (WHO). This report contains the views of an international expert group and does not necessarily represent the decisions or the stated policy of the WHO. TRIAL REGISTRATION ISRCTN33378571 registered on 22 March 2004. The first participant was enrolled on 12 May 2003.

Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant

STUDY QUESTION Is it possible to extend the use of the 3-year one-rod etonogestrel (ENG)-releasing subdermal contraceptive implant to 5 years? SUMMARY ANSWER The extended use of the one-rod ENG-releasing subdermal contraceptive implant showed 100% efficacy in years 4 and 5. WHAT IS KNOWN ALREADY The initial regulated trials on the ENG-releasing subdermal contraceptive implant conducted in the 1990 s were designed to measure cumulative 3-year efficacy. The ENG-implant has both well established safety and efficacy for up to 3 years. Pharmacokinetic data on ENG show high levels at 3 years and some previous clinical research confirms efficacy beyond the current approved duration of 3 years. Today, many women, because the labeled duration has been reached, have the ENG implant removed at 3 years, increasing costs, inconvenience and risks. STUDY DESIGN SIZE, DURATION For the first 3 years, this study was an open-label, multi-centre randomized trial comparing the 3-year ENG implant to the 5-year levonorgestrel (LNG)-releasing implant. After 3 years, a subset of 390 ENG participants, consented to extended use. We compared efficacy, side effects and removal procedures of both implants. We used Kaplan–Meier (K–M) analysis. We included an observational cohort of copper intrauterine device (IUD) users as non-users of hormonal contraceptive method for comparative purposes. PARTICIPANTS/MATERIALS, SETTING, METHODS The study took place in family planning clinics in seven countries worldwide. Women were enlisted after an eligibility check and informed consent, and 1328 women were enrolled: 390, 522 and 416 in the ENG-implant, LNG-implant and IUD groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Over 200 women used the ENG implant for at least 5 years. No pregnancies occurred during the additional 2 years of follow up in the ENG or LNG implant group. The overall 5-year K–M cumulative pregnancy rates for ENG- and LNG- implants were 0.6 per 100 women-years (W-Y) [95% confidence interval (CI): 0.2–1.8] and 0.8 per 100 W-Y [95% CI: 0.2–2.3], respectively. Complaints of bleeding changes were similar; however, ENG-users were more likely than LNG-users to experience heavy bleeding (p < 0.05). The median duration of the implant removal procedure was 64 seconds shorter for the one-rod ENG-implant (inter-quartile range (IQR) = 30.5, 117.5) compared to the two-rod LNG product (IQR = 77.0, 180.0). The 2-year rate for pregnancy in the IUD group compared with the two implant groups combined was 4.1 per 100 W-Y [95% CI: 2.5–6.5]. LIMITATIONS, REASONS FOR CAUTION Few women were ≤19 years old or nulligravida. Although there was no weight limit for enrolment in the study, the number of women ≥70 kg were few. WIDER IMPLICATIONS OF THE FINDINGS The results from this study corroborate previous evidence showing high contraceptive efficacy through 4 years for the ENG-implant. Data through 5 years are a novel contribution and further proof of the products capability to provide safe and effective contraception that rivals the current 5-year LNG-subdermal implant. The findings provide valuable information for policy makers, family planning programmers and clinicians that the ENG-releasing subdermal implant is still highly effective up to 5 years after insertion. Compared to previous efforts, our study population was geographically diverse and our study had the highest number of participants completing at least 5 years of use. TRIAL REGISTRATION The trial was registered as ISRCTN33378571. STUDY FUNDING/COMPETING INTEREST(S) The contraceptive devices and funds for conduct of the study were provided by the United Nations Development Programme/United Nations Population Fund/World Health Organization (WHO)/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), WHO. This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the WHO. All stated authors have no conflict of interest, except Dr Hubacher who reported grants from United States Agency for International Development, during the conduct of the study; other from Advisory Boards (Teva, Bayer, OCON), outside the submitted work.

A multicenter randomized clinical trial of one-rod etonogestrel and two-rod levonorgestrel contraceptive implants with nonrandomized copper-IUD controls: methodology and insertion data☆☆☆★★★

BACKGROUND Comparative data on etonogestrel and two-rod levonorgestrel contraceptive implants are lacking. STUDY DESIGN A multicenter, open, parallel-group trial with random allocation of implants was performed. For every second implant user, an age-matched woman choosing an intrauterine device (IUD) (TCu380A) was admitted. Methods and data on implant/IUD insertion and 6-week follow-up are reported. RESULTS A total of 2008 women were randomized to an implant, and 974 women were enrolled in the IUD group. Results from 997 etonogestrel implant users, 997 levonorgestrel implant users and 971 IUD users were analyzed. In the etonogestrel and levonorgestrel groups, respectively, mean insertion durations were 51 (SD 50.2) s and 88 (SD 60.8) s; complication rates at insertion were 0.8% and 0.2%; and at follow-up, 27.2% and 26.7% of women, respectively, had signs or symptoms at the insertion site. At follow-up within 6 weeks after insertion, all implants were in situ, while 2.1% of IUDs were expelled. CONCLUSION Performance of etonogestrel and levonorgestrel implants at insertion and within the first 6 weeks is similar. Short-term (6 weeks) continuation rates appear higher for implants than TCu380A.

Accuracy of Assessment of Eligibility for Early Medical Abortion by Community Health Workers in Ethiopia, India and South Africa

Objective To assess the accuracy of assessment of eligibility for early medical abortion by community health workers using a simple checklist toolkit. Design Diagnostic accuracy study. Setting Ethiopia, India and South Africa. Methods Two hundred seventeen women in Ethiopia, 258 in India and 236 in South Africa were enrolled into the study. A checklist toolkit to determine eligibility for early medical abortion was validated by comparing results of clinician and community health worker assessment of eligibility using the checklist toolkit with the reference standard exam. Results Accuracy was over 90% and the negative likelihood ratio <0.1 at all three sites when used by clinician assessors. Positive likelihood ratios were 4.3 in Ethiopia, 5.8 in India and 6.3 in South Africa. When used by community health workers the overall accuracy of the toolkit was 92% in Ethiopia, 80% in India and 77% in South Africa negative likelihood ratios were 0.08 in Ethiopia, 0.25 in India and 0.22 in South Africa and positive likelihood ratios were 5.9 in Ethiopia and 2.0 in India and South Africa. Conclusion The checklist toolkit, as used by clinicians, was excellent at ruling out participants who were not eligible, and moderately effective at ruling in participants who were eligible for medical abortion. Results were promising when used by community health workers particularly in Ethiopia where they had more prior experience with use of diagnostic aids and longer professional training. The checklist toolkit assessments resulted in some participants being wrongly assessed as eligible for medical abortion which is an area of concern. Further research is needed to streamline the components of the tool, explore optimal duration and content of training for community health workers, and test feasibility and acceptability.

A multicenter randomized clinical trial of etonogestrel and levonorgestrel contraceptive implants with nonrandomized copper intrauterine device controls: effect on weight variations up to 3 years after placement

OBJECTIVES To evaluate weight changes in women randomized to either the etonogestrel (ENG)- or the levonorgestrel (LNG)-releasing contraceptive implants and to compare with users of the TCu380A intrauterine device (IUD). STUDY DESIGN A multicenter randomized trial with 1:1 allocation ratio of the ENG and the LNG implants with nonrandomized, age-matched control group of women choosing TCu380A IUD. The primary objective was to assess contraceptive efficacy and method continuation rates and, secondarily, the incidence of common complaints and side effects (including weight changes) associated with use of the three contraceptives. All women were enrolled in nine centers at seven countries. Weight change was evaluated from time at device(s) placement. Confounders were sociodemographic, baseline weight and body mass index, center and time from insertion. We used a linear mixed-effects regression modeling with random intercept and slope. Weight was compared between the two implants groups and between the implants and the IUD groups through linear mixed multivariable regression model. RESULTS A total of 995, 997 and 971 users in the ENG implant, LNG implant and IUD groups, respectively, were included. At 36 months of use, ENG and LNG implant users had similar significant mean weight increase of 3.0 kg [95% confidence interval (CI) 2.5-3.5] and 2.9 kg (95% CI 2.4-3.4), respectively (p<.0001), while IUD users had an increase of 1.1 kg (95% CI 0.5-1.7) (p=.0003). On adding the group-time interaction term to the stratified baseline weight models, implant users gained 0.759 kg (standard error [SE] .11) and 0.787 kg (SE .22) more weight than their IUD-user counterparts per year since placement if their baseline weight was in the category 51-69 kg (p<.0001) or ≥70 kg (p=.0005), respectively. CONCLUSIONS ENG and LNG implant as well as IUD users had a small but significant weight increase with little clinical significance during the 3 years of follow-up, and it was slightly higher among implant than IUD users weighing >50 kg. IMPLICATIONS These findings must be useful for clinicians to counsel implant users which could improve method continuation.

Does gentle assisted pushing or giving birth in the upright position reduce the duration of the second stage of labour? A three-arm, open-label, randomised controlled trial in South Africa

Introduction Gentle assisted pushing (GAP) is an innovative method of applying gentle, steady pressure to a woman’s uterine fundus during second stage of labour. This randomised trial evaluated GAP in an upright position, compared with upright position alone or routine practice (recumbent posture). Methods An open-label, hospital-based, randomised trial was conducted in Eastern Cape, South Africa. Randomisation occurred following at least 15 min in second stage of labour. Participants were randomly assigned (1:1:1) using computer-generated block randomisation of variable size using opaque, sealed, numbered envelopes. Primary analysis was intention to treat. Participants were healthy, nulliparous, consenting women with a singleton pregnancy in cephalic presentation where vaginal birth was anticipated. The primary outcome was mean time from randomisation to birth. Results 1158 participants were randomly allocated to GAP (n=388), upright position (n=386) and routine practice (n=384), with no loss to follow-up. Baseline characteristics were largely similar. In the experimental arm, GAP was applied a median of two times (IQR 1.0–3.0). Women in upright position alone spent a median of 6 min (IQR 3.0–10.0) upright. Mean duration from randomisation to birth was not different across groups (mean (SD) duration: 24.1 (34.9) min in GAP group, 24.6 (30.5) min in upright group, 25.0 (39.3) min in routine practice group). There were no differences in secondary outcomes, except that at two sites maternal discomfort was greater for both GAP and upright position compared with routine practice; at the other sites there were no differences. Conclusion No benefit was identified from GAP in the second stage; some women found the position uncomfortable. The use of fundal pressure should be limited to further research to determine techniques or settings in which it can safely assist vaginal birth. Women should be encouraged to assume the position they find most comfortable. Trial registration number PACTR201502001034448.

Two prophylactic medication approaches in addition to a pain control regimen for early medical abortion < 63 days’ gestation with mifepristone and misoprostol: study protocol for a randomized, controlled trial

BackgroundPain is often cited as one of the worst features of medical abortion. Further, inadequate pain management may motivate some women to seek unnecessary clinical care. There is a need to identify effective methods for pain control in this setting.Methods/DesignWe propose a randomized, placebo-controlled trial. 576 participants (288 nulliparous; 288 parous) from study sites in Nepal, South Africa and Vietnam will be randomly allocated to one of three treatments: (1) ibuprofen 400 mg PO and metoclopramide 10 mg PO; (2) tramadol 50 mg PO and a placebo; or (3) two placebo pills, to be taken immediately before misoprostol and repeated once four hours later. All women will be provided with supplementary analgesia for use as needed during the medical abortion. We hypothesize that women receiving prophylactic analgesia will report lower maximal pain scores in the first 8 h following misoprostol administration compared to women receiving placebos for medical abortion through 63 days’ gestation. Our primary objective is to determine whether prophylactic administration of ibuprofen and metoclopramide or tramadol provides superior pain relief compared to analgesia administration after pain begins, measured during the first eight hours after misoprostol administration. Secondary objectives include identifying covariates associated with higher reported pain scores; determining any impact of the study medicines on medical abortion success; and, qualitatively exploring women’s physical experiences of medical abortion, especially related to pain, and how can they be improved. Data sources include medical records, participant symptom diaries and interview data obtained on the day of enrollment, during the medical abortion, and at follow-up. Participants will be contacted via telephone on day 3 and return for follow-up will occur approximately 14 days after mifepristone, concluding study participation. A subset of 42 women will also be invited to undergo in-depth qualitative interviews following study completion.DiscussionAlthough pain is one of the most common side effects encountered with medical abortion, little is known about optimal pain management for this process. This multi-arm trial design offers an efficient approach to evaluating two prophylactic pain management regimens compared to use of pain medication as needed.Trial registrationACTRN12613000017729 (Prospectively registered 8/1/2013).