Pregnancy cohorts and biobanking in sub-Saharan Africa: a systematic review

Background: Technological advances and high throughput biological assays can facilitate discovery science in biobanks from population cohorts, including pregnant women. Biological pathways associated with health outcomes differ depending on geography, and high-income country data may not generalise to low-resource settings. We conducted a systematic review to identify prospective pregnancy cohorts in sub-Saharan Africa (SSA) that include biobanked samples with potential to enhance discovery science opportunity. Methods: Inclusion criteria were prospective data collection during pregnancy, with associated biobanking in SSA. Data sources included: scientific databases (with comprehensive search terms), grey literature, hand searching applicable reference lists and expert input. Results were screened in a three-stage process based on title, abstract and full text by two independent reviewers. The review is registered on PROSPERO (CRD42019147483). Results: Fourteen SSA studies met the inclusion criteria from database searches (n=8), reference list searches (n=2) and expert input (n=4). Three studies have ongoing data collection. The most represented countries were South Africa and Mozambique (Southern Africa) (n=3), Benin (Western Africa) (n=4) and Tanzania (Eastern Africa) (n=4); including an estimated 31 763 women. Samples commonly collected were blood, cord blood and placenta. Seven studies collected neonatal samples. Common clinical outcomes included maternal and perinatal mortality, malaria and preterm birth. Conclusions: Increasingly numerous pregnancy cohorts in SSA that include biobanking are generating a uniquely valuable resource for collaborative discovery science, and improved understanding of the high regional risks of maternal, fetal and neonatal morbidity and mortality. Future studies should align protocols and consider their added value and distinct contributions

Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings

BACKGROUND: The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy.METHODS/DESIGN:Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed.DISCUSSION:In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improve maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy

The feasibility of community level interventions for pre-eclampsia in South Asia and sub-saharan Africa: A mixed-methods design

Background: Globally, pre-eclampsia and eclampsia are major contributors to maternal and perinatal mortality; of which the vast majority of deaths occur in less developed countries. In addition, a disproportionate number of morbidities and mortalities occur due to delayed access to health services. The Community Level Interventions for Pre-eclampsia (CLIP) Trial aims to task-shift to community health workers the identification and emergency management of pre-eclampsia and eclampsia to improve access and timely care. Literature revealed paucity of published feasibility assessments prior to initiating large-scale community-based interventions. Arguably, well-conducted feasibility studies can provide valuable information about the potential success of clinical trials prior to implementation. Failure to fully understand the study context risks the effective implementation of the intervention and limits the likelihood of post-trial scale-up. Therefore, it was imperative to conduct community-level feasibility assessments for a trial of this magnitude.Methods: A mixed methods design guided by normalization process theory was used for this study in Nigeria, Mozambique, Pakistan, and India to explore enabling and impeding factors for the CLIP Trial implementation. Qualitative data were collected through participant observation, document review, focus group discussion and in-depth interviews with diverse groups of community members, key informants at community level, healthcare providers, and policy makers. Quantitative data were collected through health facility assessments, self-administered community health worker surveys, and household demographic and health surveillance.Results: Refer to CLIP Trial feasibility publications in the current and/or forthcoming supplement.Conclusions: Feasibility assessments for community level interventions, particularly those involving task-shifting across diverse regions, require an appropriate theoretical framework and careful selection of research methods. The use of qualitative and quantitative methods increased the data richness to better understand the community contexts

Is this pill an antibiotic or a painkiller? Improving the identification of oral antibiotics for better use

In this Viewpoint, we discuss how the identification of oral antibiotics and their distinction from other commonly used medicines can be challenging for consumers, suppliers, and health-care professionals. There is a large variation in the names that people use to refer to antibiotics and these often relate to their physical appearance, although antibiotics come in many different physical presentations. We also reflect on how the physical appearance of medicine influences health care and public health by affecting communication between patients and health-care professionals, dispensing , medicine use, and the public understanding of health campaigns. Furthermore, we report expert and stakeholder consultations on improving the identification of oral antibiotics and discuss next steps towards a new identification system for antibiotics. We propose to use the physical appearance as a tool to support and nudge awareness about antibiotics and their responsible use

Causes and circumstances of maternal death:a secondary analysis of the Community-Level Interventions for (CLIP) trials cohort

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12–49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193–268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43–0·66]) or InterVA-5 (κ=0·44 [0·30–0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60–0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38–0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27–0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59–0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00–0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation)

Safety of Artemether-Lumefantrine Exposure in First Trimester of Pregnancy: An Observational Cohort.

There is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy. Pregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery. 2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and premature birth (OR 2.6; 1.3-5.3) as opposed to AL with (OR 1.4; 0.8-2.5) for miscarriage/stillbirth and (OR 0.9; 0.5-1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]). Exposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.\u

Maternal and neonatal data collection systems in low- and middle-income countries: Scoping review protocol

Background: Pregnant women and neonates represent one of the most vulnerable groups, especially in low- and middle-income countries (LMICs). A recent analysis reported that most vaccine pharmacovigilance systems in LMICs consist of spontaneous (passive) adverse event reporting. Thus, LMICs need effective active surveillance approaches, such as pregnancy registries. We intend to identify currently active maternal and neonatal data collection systems in LMICs, with the potential to inform active safety electronic surveillance for novel vaccines using standardized definitions. Methods: A scoping review will be conducted based on established methodology. Multiple databases of indexed and grey literature will be searched with a specific focus on existing electronic and paper-electronic systems in LMICs that collect continuous, prospective, and individual-level data from antenatal care, delivery, neonatal care (up to 28 days), and postpartum (up to 42 days) at the facility and community level, at the national and district level, and at large hospitals. Also, experts will be contacted to identify unpublished information on relevant data collection systems. General and specific descriptions of Health Information Systems (HIS) extracted from the different sources will be combined and duplicated HIS will be removed, producing a list of unique statements. We will present a final list of Maternal, Newborn, and Child Health systems considered flexible enough to be updated with necessary improvements to detect, assess and respond to safety concerns during the introduction of vaccines and other maternal health interventions. Selected experts will participate in an in-person consultation meeting to select up to three systems to be further explored in situ. Results and knowledge gaps will be synthesized after expert consultation.Fil: Berrueta, Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bardach, Ariel Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Xiong, Xu. University of Tulane; Estados UnidosFil: Stergachis, Andy. University of Washington; Estados UnidosFil: Zaraa, Sabra. University of Washington; Estados UnidosFil: Buekens, Pierre. University of Tulane; Estados UnidosFil: Absalon, Judith. No especifíca;Fil: Anderson, Steve. No especifíca;Fil: Althabe, Fernando. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Madhi, Shabir A.. No especifíca;Fil: McClure, Elizabeth. No especifíca;Fil: Munoz, Flor M.. No especifíca;Fil: Mwamwitwa, Kissa W.. No especifíca;Fil: Nakimuli, Annettee. No especifíca;Fil: Clark Nelson, Jennifer. No especifíca;Fil: Noguchi, Lisa. No especifíca;Fil: Panagiotakopoulos, Lakshmi. No especifíca;Fil: Sevene, Esperanca. No especifíca;Fil: Zuber, Patrick. No especifíca;Fil: Belizan, Maria. No especifíca;Fil: Bergel, Eduardo. No especifíca;Fil: Rodriguez Cairoli, Federico. No especifíca;Fil: Castellanos, Fabricio. No especifíca;Fil: Ciganda, Alvaro. No especifíca;Fil: Comande, Daniel. No especifíca;Fil: Pingray, Veronica. No especifíca

Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials

Background Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy—parasitaemia and clinical disease—than adult women. Methods and findings An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian–Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value &lt; 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value &lt; 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data—12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. Conclusions In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant

Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post-Licensure in African Public Hospitals with Electrocardiograms.

The antimalarial drug piperaquine is associated with delayed ventricular depolarization, causing prolonged QT interval (time taken for ventricular de-polarisation and re-polarisation). There is a lack of safety data regarding dihydroartemisinin/piperaquine (DHA/PPQ) for the treatment of uncomplicated malaria, which has limited its use. We created a platform where electrocardiograms (ECG) were performed in public hospitals for the safety assessment of DHA/PPQ, at baseline before the use of dihydroartemisinin/piperaquine (Eurartesim®), and on day 3 (before and after administration of the final dose) and day 7 post-administration. Laboratory analyses included haematology and clinical chemistry. The main objective of the ECG assessment in this study was to evaluate the effect of administration of DHA/PPQ on QTc intervals and the association of QTc intervals with changes in blood biochemistry, full and differential blood count over time after the DHA/PPQ administration. A total of 1315 patients gave consent and were enrolled of which 1147 (87%) had complete information for analyses. Of the enrolled patients 488 (42%), 323 (28%), 213 (19%) and 123 (11%) were from Ghana, Burkina Faso, Tanzania and Mozambique, respectively. Median (lower-upper quartile) age was 8 (5-14) years and a quarter of the patients were children under five years of age (n = 287). Changes in blood biochemistry, full and differential blood count were temporal which remained within clinical thresholds and did not require any intervention. The mean QTcF values were significantly higher than on day 1 when measured on day 3 before and after administration of the treatment as well as on day 7, four days after completion of treatment (12, 22 and 4 higher, p < 0.001). In all age groups the values of QT, QTcF and QTcB were highest on day 3 after drug intake. The mean extreme QTcF prolongation from baseline was lowest on day 3 before drug intake (33 ms, SD = 19) and highest on day 3 after the last dose (60 ms, SD = 31). There were 79 (7%) events of extreme mean QTcF prolongation which were not clinically significant. Nearly a half of them (n = 37) were grade 3 and mainly among males (33/37). Patients in Burkina Faso, Mozambique and Tanzania had significantly lower mean QTcF than patients in Ghana by an average of 3, 4 and 11 ms, respectively. We found no evidence that Eurartesim® administered in therapeutic doses in patients with uncomplicated malaria and no predisposing cardiac conditions in Africa was associated with adverse clinically significant QTc prolongation

Pooled Multicenter Analysis of Cardiovascular Safety and Population Pharmacokinetic Properties of Piperaquine in African Patients with Uncomplicated Falciparum Malaria.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456?ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation?of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.)