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 INTEREST(S) 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 200

Antenatal care packages with reduced visits and perinatal mortality: a secondary analysis of the WHO Antenatal Care Trial

BACKGROUND: In 2001, the WHO Antenatal Care Trial (WHOACT) concluded that an antenatal care package of evidence-based screening, therapeutic interventions and education across four antenatal visits for low-risk women was not inferior to standard antenatal care and may reduce cost. However, an updated Cochrane review in 2010 identified an increased risk of perinatal mortality of borderline statistical significance in three cluster-randomized trials (including the WHOACT) in developing countries. We conducted a secondary analysis of the WHOACT data to determine the relationship between the reduced visits, goal-oriented antenatal care package and perinatal mortality. METHODS: Exploratory analyses were conducted to assess the effect of baseline risk and timing of perinatal death. Women were stratified by baseline risk to assess differences between intervention and control groups. We used linear modeling and Poisson regression to determine the relative risk of fetal death, neonatal death and perinatal mortality by gestational age. RESULTS: 12,568 women attended the 27 intervention clinics and 11,958 women attended the 26 control clinics. 6,160 women were high risk and 18,365 women were low risk. There were 161 fetal deaths (1.4%) in the intervention group compared to 119 fetal deaths in the control group (1.1%) with an increased overall adjusted relative risk of fetal death (Adjusted RR 1.27; 95% CI 1.03, 1.58). This was attributable to an increased relative risk of fetal death between 32 and 36 weeks of gestation (Adjusted RR 2.24; 95% CI 1.42, 3.53) which was statistically significant for high and low risk groups. CONCLUSION: It is plausible the increased risk of fetal death between 32 and 36 weeks gestation could be due to reduced number of visits, however heterogeneity in study populations or differences in quality of care and timing of visits could also be playing a role. Monitoring maternal, fetal and neonatal outcomes when implementing antenatal care protocols is essential. Implementing reduced visit antenatal care packages demands careful monitoring of maternal and perinatal outcomes, especially fetal death

Comparative effectiveness of single and dual rapid diagnostic tests for syphilis and HIV in antenatal care services in Colombia

ABSTRACT Objective To assess the effectiveness of a dual rapid test compared to a single rapid test for syphilis and HIV screening. Methods A cluster-randomized open-label clinical trial was performed in 12 public antenatal care (ANC) centers in the cities of Bogotá and Cali, Colombia. Pregnant women who were over 14 years of age at their first antenatal visit and who had not been previously tested for HIV and syphilis during the current pregnancy were included. Pregnant women were randomized to single HIV and single syphilis rapid diagnostic tests (Arm A) or to dual HIV and syphilis rapid diagnostic tests (Arm B). The four main outcomes measured were: (1) acceptability of the test, (2) uptake in testing, (3) treatment on the same day (that is, timely treatment), and (4) treatment at any time for positive rapid test cases. Bivariate and multivariate analyses were calculated to adjust for the clustering effect and the period. Results A total of 1 048 patients were analyzed in Arm A, and 1 166 in Arm B. Acceptability of the rapid tests was 99.8% in Arm A and 99.6% in Arm B. The prevalence of positive rapid tests was 2.21% for syphilis and 0.36% for HIV. Timely treatment was provided to 20 of 29 patients (69%) in Arm A and 16 of 20 patients (80%) in Arm B (relative risk (RR), 1.10; 95% confidence interval (CI): (1.00 −1.20). Treatment at any time was given to 24 of 29 patients (83%) in Arm A and to 20 of 20 (100%) in Arm B (RR, 1.11; 95% CI: 1.01−1.22). Conclusions There were no differences in patient acceptability, testing and timely treatment between dual rapid tests and single rapid tests for HIV and syphilis screening in the ANC centers. Same-day treatment depends also on the interpretation of and confidence in the results by the health providers