Participant recruitment and retention in longitudinal preconception randomized trials: lessons learnt from the Calcium And Pre-eclampsia (CAP) trial.

BACKGROUND: The preconception period has the potential to influence pregnancy outcomes and randomized controlled trials (RCTs) are needed to evaluate a variety of potentially beneficial preconception interventions. However, RCTs commencing before pregnancy have significant participant recruitment and retention challenges. The Calcium And Pre-eclampsia trial (CAP trial) is a World Health Organization multi-country RCT of calcium supplementation commenced before pregnancy to prevent recurrent pre-eclampsia in which non-pregnant participants are recruited and followed up until childbirth. This sub-study explores recruitment methods and preconception retention of participants of the CAP trial to inform future trials. METHODS: Recruiters at the study sites in Argentina, South Africa and Zimbabwe completed post-recruitment phase questionnaires on recruitment methods used. Qualitative data from these questionnaires and quantitative data on pre-pregnancy trial visit attendance and pregnancy rates up to September 2016 are reported in this paper. RStudio (Version 0.99.903 https://www.rstudio.org ) statistical software was used for summary statistics. RESULTS: Between July 2011 and 8 September 2016, 1354 women with previous pre-eclampsia were recruited. Recruitment took 2 years longer than expected and was facilitated mainly through medical record/register and maternity ward/clinic-based strategies. Recruiters highlighted difficulties associated with inadequate medical records, redundant patient contact details, and follow-up of temporarily ineligible women as some of the challenges faced. Whilst the attendance rates at pre-pregnancy visits were high (78% or more), visits often occurred later than scheduled. Forty-five percent of participants became pregnant (614/1354), 33.5% (454/1354) within 1 year of randomization. CONCLUSIONS: In preconception trials, both retrospective and prospective methods are useful for recruiting eligible women with certain conditions. However, these are time-consuming in low-resource settings with suboptimal medical records and other challenges. Trial planners should ensure that trial budgets cover sufficient on-site researchers with pre-trial training, and should consider using mobile phone and web-based electronic tools to optimize recruitment and retention. This should lead to greater efficiency and shorter trial durations. TRIAL REGISTRATION: Pan-African Clinical Trials Registry, Registration Number: PACTR201105000267371 . The trial was registered on 6 December 2016

Quantifiable plasma tenofovir among South African women using daily oral pre-exposure prophylaxis during the ECHO trial

Access to data from the ECHO study may be requested through submission of a research concept to ude.wu@crci. The concept must include the research question, data requested, analytic methods, and steps taken to ensure ethical use of the data. Access will be granted if the concept is evaluated to have scientific merit and if sufficient data protections are in place. As of the time of publication, data access applications are in process with the governing institutional review boards of the ECHO study to make deidentified data publicly available.BACKGROUND : HIV endpoint–driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS : ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16–35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS : Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83–104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS : Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER : NCT02550067.The Bill & Melinda Gates Foundation, the American people through the United States Agency for International Development, the Swedish International Development Cooperation Agency, the South Africa Medical Research Council, and the United Nations Population Fund. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development.http://journals.lww.com/jaidshj2023Family MedicineMedical Microbiolog

Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia : a multicentre, double-blind, randomised, placebo-controlled trial

CITATION: Hofmeyr, G. J., et al. 2019. Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia : a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet, 393(10169):P330-339, doi:10.1016/S0140-6736(18)31818-X.The original publication is available at https://www.thelancet.comBackground: Reducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks’ gestation) prevents the development of pre-eclampsia Methods: We did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks’ gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks’ gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017. Findings: Between July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks’ gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks’ gestation (risk ratio [RR] 0·80, 95% CI 0·61–1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks’ gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44–0·98; p=0·037). There were no serious adverse effects of calcium reported. Interpretation: Calcium supplementation that commenced before pregnancy until 20 weeks’ gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention. ernal and Child Health.https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31818-X/fulltextPublisher's versio

High levels of pretreatment HIV-1 drug resistance mutations among South African women who acquired HIV during a prospective study

Access to data from the ECHO Study may be requested through submission of a research concept to [email protected]. The concept must include the research question, data requested, analytic methods, and steps taken to ensure ethical use of the data. Access will be granted if the concept is evaluated to have scientific merit and if sufficient data protections are in place. As of the time of publication, data access applications are in process with the governing institutional review boards of the ECHO Study to make de-identified data publicly available.BACKGROUND : Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS : HIV-uninfected, sexually active women, aged 18–35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database. RESULTS : We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs. CONCLUSIONS : The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.The Bill & Melinda Gates Foundation, the American people through the United States Agency for International Development, the Swedish International Development Cooperation Agency, the South Africa Medical Research Council, and the United Nations Population Fund.http://journals.lww.com/jaidshj2023Family MedicineMedical Microbiolog

Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage

Background: Delays in the detection or treatment of postpartum hemorrhage can result in complications or death. A blood-collection drape can help provide objective, accurate, and early diagnosis of postpartum hemorrhage, and delayed or inconsistent use of effective interventions may be able to be addressed by a treatment bundle.Methods: We conducted an international, cluster-randomized trial to assess a multicomponent clinical intervention for postpartum hemorrhage in patients having vaginal delivery. The intervention included a calibrated blood-collection drape for early detection of postpartum hemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy (intervention group). Hospitals in the control group provided usual care. The primary outcome was a composite of severe postpartum hemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Key secondary implementation outcomes were the detection of postpartum hemorrhage and adherence to the treatment bundle.Results: A total of 80 secondary-level hospitals across Kenya, Nigeria, South Africa, and Tanzania, in which 210,132 patients underwent vaginal delivery, were randomly assigned to the intervention group or the usual-care group. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval [CI], 0.32 to 0.50; P<0.001). Postpartum hemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI, 1.41 to 1.76), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI, 3.88 to 6.28).Conclusions: Early detection of postpartum hemorrhage and use of bundled treatment led to a lower risk of the primary outcome, a composite of severe postpartum hemorrhage, laparotomy for bleeding, or death from bleeding, than usual care among patients having vaginal delivery

Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage

Background: Delays in the detection or treatment of postpartum hemorrhage can result in complications or death. A blood-collection drape can help provide objective, accurate, and early diagnosis of postpartum hemorrhage, and delayed or inconsistent use of effective interventions may be able to be addressed by a treatment bundle.Methods: We conducted an international, cluster-randomized trial to assess a multicomponent clinical intervention for postpartum hemorrhage in patients having vaginal delivery. The intervention included a calibrated blood-collection drape for early detection of postpartum hemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy (intervention group). Hospitals in the control group provided usual care. The primary outcome was a composite of severe postpartum hemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Key secondary implementation outcomes were the detection of postpartum hemorrhage and adherence to the treatment bundle.Results: A total of 80 secondary-level hospitals across Kenya, Nigeria, South Africa, and Tanzania, in which 210,132 patients underwent vaginal delivery, were randomly assigned to the intervention group or the usual-care group. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval [CI], 0.32 to 0.50; P<0.001). Postpartum hemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI, 1.41 to 1.76), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI, 3.88 to 6.28).Conclusions: Early detection of postpartum hemorrhage and use of bundled treatment led to a lower risk of the primary outcome, a composite of severe postpartum hemorrhage, laparotomy for bleeding, or death from bleeding, than usual care among patients having vaginal delivery

Participant recruitment and retention in longitudinal preconception randomized trials: lessons learnt from the Calcium And Pre-eclampsia (CAP) trial

Abstract Background The preconception period has the potential to influence pregnancy outcomes and randomized controlled trials (RCTs) are needed to evaluate a variety of potentially beneficial preconception interventions. However, RCTs commencing before pregnancy have significant participant recruitment and retention challenges. The Calcium And Pre-eclampsia trial (CAP trial) is a World Health Organization multi-country RCT of calcium supplementation commenced before pregnancy to prevent recurrent pre-eclampsia in which non-pregnant participants are recruited and followed up until childbirth. This sub-study explores recruitment methods and preconception retention of participants of the CAP trial to inform future trials. Methods Recruiters at the study sites in Argentina, South Africa and Zimbabwe completed post-recruitment phase questionnaires on recruitment methods used. Qualitative data from these questionnaires and quantitative data on pre-pregnancy trial visit attendance and pregnancy rates up to September 2016 are reported in this paper. RStudio (Version 0.99.903 https://www.rstudio.org ) statistical software was used for summary statistics. Results Between July 2011 and 8 September 2016, 1354 women with previous pre-eclampsia were recruited. Recruitment took 2 years longer than expected and was facilitated mainly through medical record/register and maternity ward/clinic-based strategies. Recruiters highlighted difficulties associated with inadequate medical records, redundant patient contact details, and follow-up of temporarily ineligible women as some of the challenges faced. Whilst the attendance rates at pre-pregnancy visits were high (78% or more), visits often occurred later than scheduled. Forty-five percent of participants became pregnant (614/1354), 33.5% (454/1354) within 1 year of randomization. Conclusions In preconception trials, both retrospective and prospective methods are useful for recruiting eligible women with certain conditions. However, these are time-consuming in low-resource settings with suboptimal medical records and other challenges. Trial planners should ensure that trial budgets cover sufficient on-site researchers with pre-trial training, and should consider using mobile phone and web-based electronic tools to optimize recruitment and retention. This should lead to greater efficiency and shorter trial durations. Trial registration Pan-African Clinical Trials Registry, Registration Number: PACTR201105000267371 . The trial was registered on 6 December 2016