Saikat Deb

Malaria incidence and prevalence on Pemba Island before the onset of the successful control intervention on the Zanzibar Archipelago

BackgroundMalaria incidence has been reported to decrease substantially in parts of sub-Saharan Africa, including the Zanzibar Archipelago in East Africa. A cohort study with an intensive follow-up on Pemba Island just before the onset of the highly successful malaria control intervention was conducted. The reported estimates of parasite prevalence and incidence can serve as a robust baseline to evaluate the effect size of the successful interventions and the potential contribution of quality controls and other factors associated with research studies in the decreased estimate of transmission.MethodsIn a rural clinic, two successive cohorts of 537 children total aged 2-23 months were followed for six months each with an intensive visitation schedule of bi-weekly follow-up. Robust estimates of incidence and prevalence according to four different malaria definitions were obtained.ResultsMalaria incidence and prevalence placed Pemba Island in a hyperendemic rather than holoendemic setting for the years 2003-2005. Overall parasite prevalence was estimated to be 39% - with monthly estimates varying between 30% and 50%. Incidence of malaria varied between 2.3 and 3.8 malaria episodes per year based on a diagnosis of fever and various microscopy-based parasite thresholds and between 4.8 and 5.7 based on a diagnosis of fever and 100 parasites/microliter analogous to detection by rapid diagnostic tests. Both parasite densities and malaria incidence increased with age and rainy season. Malaria incidence also varied substantially between the individual villages within the study area.ConclusionsPemba Island was previously considered holo-endemic for Malaria. The data suggest that the transmission situation on Pemba Island was significantly lower in 2003-2005 suggesting a hyper-endemic or meso-endemic transmission environment. The figures were obtained just before the onset of the highly successful malaria control intervention by impregnated bed nets and IRS on the Zanzibar Archipelago and provide robust estimates of the malaria transmission situation prior to the control programme. Together with other published data, the results suggest that malaria transmission had started to decrease before the onset of the control programme. The local heterogeneity in malaria incidence highlights the importance of a micro-epidemiological approach in the context of malaria control and elimination.

Efficacy of chlorhexidine application to umbilical cord on neonatal mortality in Pemba, Tanzania: a community-based randomised controlled trial

BACKGROUND In low-income countries, including the east African region, a third of neonatal deaths are due to infections. A substantial proportion of these have been attributed to sepsis, which can result from umbilical cord infections. Evidence from Asia suggests that chlorhexidine application to the neonatal umbilical cord reduces mortality, but no data from Africa are available. We aimed to assess the effect of umbilical cord cleansing with 4% chlorhexidine solution on neonatal mortality and omphalitis in rural settings of sub-Saharan Africa. METHODS We did a community-based randomised controlled trial on Pemba Island, Zanzibar, Tanzania. All eligible babies (aged 1 h to 48 h, without congenital malformations) from hospital-based and community-based deliveries on Pemba Island were enrolled. Participants were randomly assigned to either 4% free chlorhexidine for cord care or to dry cord care using a computer-generated random sequence. For babies allocated to the chlorhexidine group, mothers or caretakers were advised to apply the solution to the cord every day until 3 days after the cord had dropped off. Cord stumps were examined for redness, pus, swelling, and foul odour on day 0, 1, 4, 10, and 28. The primary outcome for this study was mortality until day 28 on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, number NCT01528852. FINDINGS Between May 19, 2011, and Aug 31, 2014, 36 911 newborn babies were enrolled into the chlorhexidine (n=18 015) and dry cord care study (n=18 896) groups. 17 468 (96·9%) of 18 015 neonates in the chlorhexidine group were available for complete follow-up (28 days) compared with 18 384 (97·3%) of 18 896 neonates in the dry cord care group. Mortality rate in the chlorhexidine group (10·5 deaths per 1000 livebirths) was not significantly lower than that in the dry cord care group (11·7 per 1000 livebirths; relative risk 0·90, 0·74-1·09; p=0·27). INTERPRETATION Our findings do not support the use of chlorhexidine for reduction of neonatal mortality in this east African setting, which might not justify a change in the WHO policy. To inform global policy, a detailed meta-analysis and pooled analysis needs to be undertaken using data from both African and Asian settings. FUNDING Bill & Melinda Gates Foundation.

4 Trials of Improved Practices - A Pilot Study Evaluating the Acceptability and Preferences for a Chlorhexidine Cord Care Intervention

Background Chlorhexidine, a broad-spectrum topical antiseptic with strong residual activity, has a potential to reduce infections during the neonatal period. However, the challenge remains what would be the best mode to deliver the intervention. As a part of formative research, we evaluated three possible modes of chlorhexidine delivery i.e. 100ml bottle with cotton swab, 10ml single use dropper bottle and 3g single application squeeze tube containing gel, as an umbilical cord care intervention using Trials for Improved Practices (TIPS) methodology in preparation for a large double-blind randomized controlled trial evaluating the impact of chlorhexidine. in Pemba, Tanzania. Methods 204 mother-newborn pairs were enrolled from hospital and community setting. Three different modes of application of intervention were tested (3 days for each preparation) in a cross over design. Mothers (on day 10), MCH, TBA and hospital staff was interviewed about their experience and feedback of their preference among the three delivery modes. Convenient and preference scores were calculated based on their feedback. Results 97% mothers applied intervention for all 9 days. 10ml dropper bottle (49.7%) was rated as most convenient by the mothers, gel tube (32.2%) and 100ml bottle (19.8%). Mothers opted 10ml dropper bottle (44.6%) as their first choice over the 100ml bottle (21.5%) or gel tube (33.9%). MCH/hospital staff’s choice was to use gel tube (84%) or 10ml dropper bottle (82%). Conclusions Overall acceptability was high, in terms of convenience and preference 10ml dropper bottle was a winner. Based on their choice the 10ml dropper bottle was selected for RCT.

Population-based rates, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: a multi-country prospective cohort study

Summary Background Modelled mortality estimates have been useful for health programmes in low-income and middle-income countries. However, these estimates are often based on sparse and low-quality data. We aimed to generate high quality data about the burden, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa. Methods In this prospective cohort study done in 11 community-based research sites in south Asia and sub-Saharan Africa, between July, 2012, and February, 2016, we conducted population-based surveillance of women of reproductive age (15–49 years) to identify pregnancies, which were followed up to birth and 42 days post partum. We used standard operating procedures, data collection instruments, training, and standardisation to harmonise study implementation across sites. Verbal autopsies were done for deaths of all women of reproductive age, neonatal deaths, and stillbirths. Physicians used standardised methods for cause of death assignment. Site-specific rates and proportions were pooled at the regional level using a meta-analysis approach. Findings We identified 278 186 pregnancies and 263 563 births across the study sites, with outcomes ascertained for 269 630 (96·9%) pregnancies, including 8761 (3·2%) that ended in miscarriage or abortion. Maternal mortality ratios in sub-Saharan Africa (351 per 100 000 livebirths, 95% CI 168–732) were similar to those in south Asia (336 per 100 000 livebirths, 247–458), with far greater variability within sites in sub-Saharan Africa. Stillbirth and neonatal mortality rates were approximately two times higher in sites in south Asia than in sub-Saharan Africa (stillbirths: 35·1 per 1000 births, 95% CI 28·5–43·1 vs 17·1 per 1000 births, 12·5–25·8; neonatal mortality: 43·0 per 1000 livebirths, 39·0–47·3 vs 20·1 per 1000 livebirths, 14·6–27·6). 40–45% of pregnancy-related deaths, stillbirths, and neonatal deaths occurred during labour, delivery, and the 24 h postpartum period in both regions. Obstetric haemorrhage, non-obstetric complications, hypertensive disorders of pregnancy, and pregnancy-related infections accounted for more than three-quarters of maternal deaths and stillbirths. The most common causes of neonatal deaths were perinatal asphyxia (40%, 95% CI 39–42, in south Asia; 34%, 32–36, in sub-Saharan Africa) and severe neonatal infections (35%, 34–36, in south Asia; 37%, 34–39 in sub-Saharan Africa), followed by complications of preterm birth (19%, 18–20, in south Asia; 24%, 22–26 in sub-Saharan Africa). Interpretation These results will contribute to improved global estimates of rates, timing, and causes of maternal and newborn deaths and stillbirths. Our findings imply that programmes in sub-Saharan Africa and south Asia need to further intensify their efforts to reduce mortality rates, which continue to be high. The focus on improving the quality of maternal intrapartum care and immediate newborn care must be further enhanced. Efforts to address perinatal asphyxia and newborn infections, as well as preterm birth, are critical to achieving survival goals in the Sustainable Development Goals era. Funding Bill & Melinda Gates Foundation.

Understanding biological mechanisms underlying adverse birth outcomes in developing countries: protocol for a prospective cohort (AMANHI bio–banking) study

Objectives The AMANHI study aims to seek for biomarkers as predictors of important pregnancy–related outcomes, and establish a biobank in developing countries for future research as new methods and technologies become available. Methods AMANHI is using harmonised protocols to enrol 3000 women in early pregnancies (8–19 weeks of gestation) for population–based follow–up in pregnancy up to 42 days postpartum in Bangladesh, Pakistan and Tanzania, with collection taking place between August 2014 and June 2016. Urine pregnancy tests will be used to confirm reported or suspected pregnancies for screening ultrasound by trained sonographers to accurately date the pregnancy. Trained study field workers will collect very detailed phenotypic and epidemiological data from the pregnant woman and her family at scheduled home visits during pregnancy (enrolment, 24–28 weeks, 32–36 weeks & 38+ weeks) and postpartum (days 0–6 or 42–60). Trained phlebotomists will collect maternal and umbilical blood samples, centrifuge and obtain aliquots of serum, plasma and the buffy coat for storage. They will also measure HbA1C and collect a dried spot sample of whole blood. Maternal urine samples will also be collected and stored, alongside placenta, umbilical cord tissue and membrane samples, which will both be frozen and prepared for histology examination. Maternal and newborn stool (for microbiota) as well as paternal and newborn saliva samples (for DNA extraction) will also be collected. All samples will be stored at –80°C in the biobank in each of the three sites. These samples will be linked to numerous epidemiological and phenotypic data with unique study identification numbers. Importance of the study AMANHI biobank proves that biobanking is feasible to implement in LMICs, but recognises that biobank creation is only the first step in addressing current global challenges.

Development and validation of a simplified algorithm for neonatal gestational age assessment – protocol for the Alliance for Maternal Newborn Health Improvement (AMANHI) prospective cohort study

Objective The objective of the Alliance for Maternal and Newborn Health Improvement (AMANHI) gestational age study is to develop and validate a programmatically feasible and simple approach to accurately assess gestational age of babies after they are born. The study will provide accurate, population–based rates of preterm birth in different settings and quantify the risks of neonatal mortality and morbidity by gestational age and birth weight in five South Asian and sub–Saharan African sites. Methods This study used on–going population–based cohort studies to recruit pregnant women early in pregnancy (<20 weeks) for a dating ultrasound scan. Implementation is harmonised across sites in Ghana, Tanzania, Zambia, Bangladesh and Pakistan with uniform protocols and standard operating procedures. Women whose pregnancies are confirmed to be between 8 to 19 completed weeks of gestation are enrolled into the study. These women are followed up to collect socio–demographic and morbidity data during the pregnancy. When they deliver, trained research assistants visit women within 72 hours to assess the baby for gestational maturity. They assess for neuromuscular and physical characteristics selected from the Ballard and Dubowitz maturation assessment scales. They also measure newborn anthropometry and assess feeding maturity of the babies. Computer machine learning techniques will be used to identify the most parsimonious group of signs that correctly predict gestational age compared to the early ultrasound date (the gold standard). This gestational age will be used to categorize babies into term, late preterm and early preterm groups. Further, the ultrasound–based gestational age will be used to calculate population–based rates of preterm birth. Importance of the study The AMANHI gestational age study will make substantial contribution to improve identification of preterm babies by frontline health workers in low– and middle– income countries using simple evaluations. The study will provide accurate preterm birth estimates. This new information will be crucial to planning and delivery of interventions for improving preterm birth outcomes, particularly in South Asia and sub–Saharan Africa.

1177 Impact of 4% Chlorhexidine Cord Cleansing of Umbilical Cord on Bacterial Growth of Newborns in Pemba, Tanzania

Introduction Studies in Nepal, Pakistan, and Bangladesh have shown using 4% CHX solution for umbilical cord cleansing reduces neonatal mortality and omphalitis. Data evaluating the effect of 4% Chlorhexidine umbilical cord cleansing from the Sub-Saharan region is lacking. Considering this need we are undertaking a double blind, controlled study in Eastern Africa. Before starting the trial, in this pilot we tested the impact of 4% Chlorhexidine and control solution specially prepared for the trial on colonization and colony count. Methods Total 512 newborns in both the hospital and community were enrolled in the study. Newborns were randomly assigned the Chlorhexidine, placebo or dry cord care group. Umbilical swabs were collected at baseline (before the application of intervention), 2 hour and 48 hour after application of the assigned intervention. Presence of growth, identification to gram positive/negative groups and semi-quantitative colony count was estimated for all samples. Results The positivity was high baseline swabs 30% (154 of 512 samples). In 2 hour post intervention group Chlorhexidine significantly reduced the growth of pathogens compared to placebo (OR 0.15, p< 0.01) and dry cord [OR 0.07, p=0.00]. In 48-hour swabs reduction in growth and density of organisms was observed in Chlorhexidine group (OR 0.11, p<0.01). There was no difference between the control solution and dry cord group (OR 0.97, p=0.92). Conclusions Chlorhexidine preparation was effective in reducing the growth and density of pathogens over the umbilical cord. The control preparation did not increase colonization but was similar to dry cord care group.

Contributions of Polyclonal Malaria, Gametocytemia, and Pneumonia to Infant Severe Anemia Incidence in Malaria Hyperendemic Pemba, Tanzania

The causative factors for severe anemia incidence in sub-Saharan Africa are multifactorial. In an observational, longitudinal study of two cohorts of about 300 infants followed-up for six months in a malaria hyperendemic area, the risk factors for severe anemia incidence were clinical malaria and pneumonia, which outweighed nutritional and sociodemographic factors. Severe anemia incidence was 1-2/year at age 2 months, peaked around 6-7/year at age 7-12 months, and decreased back to 1-2/year at age 16-22 months. The age-dependent increase of severe anemia incidence was shown to be parallel to the age-dependent increase of clinical malaria. Previous clinical malaria episodes increased the severe anemia risk by 80%, and gametocyte carriage and pneumonia at prior visit was associated with a six-fold increase and a > 10-fold increase, respectively. The role of pneumonia and malaria as risk factors, and areas for interventions for severe anemia, should not be underestimated.

1408 Evaluating Variation in Colonization from Different Parts of Umbilical Cord Among Neonates in Hospital Setting in Delhi and Pemba Tanzania

Background Umbilical cord is a potential portal of entry for invasive bacteria causing neonatal sepsis and death from serious infections. Studies have used a single swab covering tip, stump and base region for identifying umbilical cord colonization. Information for bacteriological profile of the cord evaluating variation from tip, stump and base is lacking. As a pilot for a large randomized controlled trial of Chlorhexidine intervention the present study aimed to evaluate the variation in colonization at three sites of cord tip/stump/base. Methods Newborns enrolled from hospitals in Delhi (n=56) and Pemba (n=68), three swabs were collected one each from tip, stump and base of the cord. Swabs were sent to laboratory within 6 hours of collection for identification of pathogens. Results Positivity for bacterial colonization at tip was lower than stump and base. Highest positivity for bacterial growth was found at base (Delhi 0hr-16%; 24hrs-23%; Pemba 0hr-20%) followed by stump (Delhi 0hr-7%; 24hrs-27%; Pemba 0hr-11%). Percentage of newborns with positivity at tip was lowest with 5–6%, 3% and 1.97% among Delhi 0hr, 24hrs and Pemba 0hr respectively. At 24hr, the bacterial colonization for stump and base combination increased from 5% (at baseline) to 21.4%. Conclusion With non-significant variation between the three sites for bacterial isolation, for clinical trials evaluating association of colonization with clinical outcomes taking two swabs (one from tip and other from stump and base of the cord) should be adequate. Association between bacterial isolation at each of two sites with clinical events and mortality needs investigation.

1178 Evaluating Optimal Quantity of Chlorhexidine Solution Needed for Application to Umbilical Cord of Neonates in First 10 Days of Life

Background Efficacy studies of application of chlorhexidine on umbilical cord have suggested significant improvement in neonatal outcomes. An important question for new trials and programs however is what should be the quantity used. There are concerns about the increased risk of hypothermia resulting from spillage or over use of any cleansing liquid solution in newborn. In context of a randomized controlled trial evaluating impact of cord cleansing in Africa, on recommendation of DSMB we undertook a pilot study, which aimed to determine the optimal quantity of the intervention solution required for application on umbilical cord of newborn. Methods Children were enrolled from both community and hospital in Pemba (n=62) and only from Hospitals in Delhi (n=50). Trained Hospital staff/MCH applied the intervention solution from a dropper bottle filled with 10 ml, on the umbilical cord of the baby generously such that it covered umbilical cord and periumbilical area. A study supervisor to maintain consistency supervised the process. After application the unused volume from each of the containers was measured to determine the actual usage. Results The mean volume of usage did not differ between Pemba and Delhi (4.58±0.8 ml and 4.79±1.88 ml respectively). The quantity of solution used ranged from 3ml to 7.5ml with a median of 4.5ml. Conclusions The optimal requirement for application was found to be 5 ml. However to be little conservative we recommend use 6 ml to adjust for any spillage and/or any abnormally long cord.