Neonatal and child mortality data in retrospective population-based surveys compared with prospective demographic surveillance: EN-INDEPTH study.

BACKGROUND: Global mortality estimates remain heavily dependent on household surveys in low- and middle-income countries, where most under-five deaths occur. Few studies have assessed the accuracy of mortality data or determinants of capturing births in surveys. METHODS: The Every Newborn-INDEPTH study (EN-INDEPTH) included a large, multi-country survey of women aged 15-49 interviewed about livebirths and their survival status in five Health and Demographic Surveillance Systems (HDSSs). The HDSSs undertake regular household visits to register births and deaths for a given population. We analysed EN-INDEPTH survey data to assess background factors associated with not recalling a complete date-of-birth. We calculated Kaplan-Meier survival estimates for both survey and HDSS data and describe age-at-death distributions during the past 5 years for children born to the same women. We assessed the proportion of HDSS-births that could be matched on month-of-birth to survey-births and used regression models to identify factors associated with matching. RESULTS: 69,176 women interviewed in the survey reported 109,817 births and 3064 deaths in children under 5 years in the 5 years prior to the survey. In the HDSS data, the same women had 83,768 registered births and 2335 under-five deaths in the same period. A complete date-of-birth was not reported for 1-7% of survey-births. Birthdates were less likely to be complete for dead children and children born to women of higher parity or with little/no education. Distributions of reported age-at-death indicated heaping at full weeks (neonatal period) and at 12 months. Heaping was more pronounced in the survey data. Survey estimates of under-five mortality rates were similar to HDSS estimates of under-five mortality in two of five sites, higher in the survey in two sites (15%, 41%) and lower (24%) in one site. The proportion of HDSS-births matched to survey-births ranged from 51 to 89% across HDSSs and births of children who had died were less likely to be matched. CONCLUSIONS: Mortality estimates in the survey and HDSS were not markedly different for most sites. However, neither source is a "gold standard" and both sources miss some events. Research is required to improve capture and accuracy to better track newborn and child survival targets.

Pregnancy intention data completeness, quality and utility in population-based surveys: EN-INDEPTH study.

BACKGROUND: An estimated 40% of pregnancies globally are unintended. Measurement of pregnancy intention in low- and middle-income countries relies heavily on surveys, notably Demographic and Health Surveys (DHS), yet few studies have evaluated survey questions. We examined questions for measuring pregnancy intention, which are already in the DHS, and additional questions and investigated associations with maternity care utilisation and adverse pregnancy outcomes. METHODS: The EN-INDEPTH study surveyed 69,176 women of reproductive age in five Health and Demographic Surveillance System sites in Ghana, Guinea-Bissau, Ethiopia, Uganda and Bangladesh (2017-2018). We investigated responses to survey questions regarding pregnancy intention in two ways: (i) pregnancy-specific intention and (ii) desired-versus-actual family size. We assessed data completeness for each and level of agreement between the two questions, and with future fertility desire. We analysed associations between pregnancy intention and number and timing of antenatal care visits, place of delivery, and stillbirth, neonatal death and low birthweight. RESULTS: Missing data were <2% in all questions. Responses to pregnancy-specific questions were more consistent with future fertility desire than desired-versus-actual family size responses. Using the pregnancy-specific questions, 7.4% of women who reported their last pregnancy as unwanted reported wanting more children in the future, compared with 45.1% of women in the corresponding desired family size category. Women reporting unintended pregnancies were less likely to attend 4+ antenatal care visits (aOR 0.73, 95% CI 0.64-0.83), have their first visit during the first trimester (aOR 0.71, 95% CI 0.63-0.79), and report stillbirths (aOR 0.57, 95% CI 0.44-0.73) or neonatal deaths (aOR 0.79, 95% CI 0.64-0.96), compared with women reporting intended pregnancies. We found no associations for desired-versus-actual family size intention. CONCLUSIONS: We found the pregnancy-specific intention questions to be a much more reliable assessment of pregnancy intention than the desired-versus-actual family size questions, despite a reluctance to report pregnancies as unwanted rather than mistimed. The additional questions were useful and may complement current DHS questions, although these are not the only possibilities. As women with unintended pregnancies were more likely to miss timely and frequent antenatal care, implementation research is required to improve coverage and quality of care for those women.

Paradata analyses to inform population-based survey capture of pregnancy outcomes: EN-INDEPTH study.

BACKGROUND: Paradata are (timestamped) records tracking the process of (electronic) data collection. We analysed paradata from a large household survey of questions capturing pregnancy outcomes to assess performance (timing and correction processes). We examined how paradata can be used to inform and improve questionnaire design and survey implementation in nationally representative household surveys, the major source for maternal and newborn health data worldwide. METHODS: The EN-INDEPTH cross-sectional population-based survey of women of reproductive age in five Health and Demographic Surveillance System sites (in Bangladesh, Guinea-Bissau, Ethiopia, Ghana, and Uganda) randomly compared two modules to capture pregnancy outcomes: full pregnancy history (FPH) and the standard DHS-7 full birth history (FBH+). We used paradata related to answers recorded on tablets using the Survey Solutions platform. We evaluated the difference in paradata entries between the two reproductive modules and assessed which question characteristics (type, nature, structure) affect answer correction rates, using regression analyses. We also proposed and tested a new classification of answer correction types. RESULTS: We analysed 3.6 million timestamped entries from 65,768 interviews. 83.7% of all interviews had at least one corrected answer to a question. Of 3.3 million analysed questions, 7.5% had at least one correction. Among corrected questions, the median number of corrections was one, regardless of question characteristics. We classified answer corrections into eight types (no correction, impulsive, flat (simple), zigzag, flat zigzag, missing after correction, missing after flat (zigzag) correction, missing/incomplete). 84.6% of all corrections were judged not to be problematic with a flat (simple) mistake correction. Question characteristics were important predictors of probability to make answer corrections, even after adjusting for respondent's characteristics and location, with interviewer clustering accounted as a fixed effect. Answer correction patterns and types were similar between FPH and FBH+, as well as the overall response duration. Avoiding corrections has the potential to reduce interview duration and reproductive module completion by 0.4 min. CONCLUSIONS: The use of questionnaire paradata has the potential to improve measurement and the resultant quality of electronic data. Identifying sections or specific questions with multiple corrections sheds light on typically hidden challenges in the survey's content, process, and administration, allowing for earlier real-time intervention (e.g.,, questionnaire content revision or additional staff training). Given the size and complexity of paradata, additional time, data management, and programming skills are required to realise its potential.

Electronic data collection in a multi-site population-based survey: EN-INDEPTH study.

BACKGROUND: Electronic data collection is increasingly used for household surveys, but factors influencing design and implementation have not been widely studied. The Every Newborn-INDEPTH (EN-INDEPTH) study was a multi-site survey using electronic data collection in five INDEPTH health and demographic surveillance system sites. METHODS: We described experiences and learning involved in the design and implementation of the EN-INDEPTH survey, and undertook six focus group discussions with field and research team to explore their experiences. Thematic analyses were conducted in NVivo12 using an iterative process guided by a priori themes. RESULTS: Five steps of the process of selecting, adapting and implementing electronic data collection in the EN-INDEPTH study are described. Firstly, we reviewed possible electronic data collection platforms, and selected the World Bank's Survey Solutions® as the most suited for the EN-INDEPTH study. Secondly, the survey questionnaire was coded and translated into local languages, and further context-specific adaptations were made. Thirdly, data collectors were selected and trained using standardised manual. Training varied between 4.5 and 10 days. Fourthly, instruments were piloted in the field and the questionnaires finalised. During data collection, data collectors appreciated the built-in skip patterns and error messages. Internet connection unreliability was a challenge, especially for data synchronisation. For the fifth and final step, data management and analyses, it was considered that data quality was higher and less time was spent on data cleaning. The possibility to use paradata to analyse survey timing and corrections was valued. Synchronisation and data transfer should be given special consideration. CONCLUSION: We synthesised experiences using electronic data collection in a multi-site household survey, including perceived advantages and challenges. Our recommendations for others considering electronic data collection include ensuring adaptations of tools to local context, piloting/refining the questionnaire in one site first, buying power banks to mitigate against power interruption and paying attention to issues such as GPS tracking and synchronisation, particularly in settings with poor internet connectivity.

Termination of pregnancy data completeness and feasibility in population-based surveys: EN-INDEPTH study.

BACKGROUND: Termination of pregnancy (TOP) is a common cause of maternal morbidity and mortality in low- and middle-income countries. Population-based surveys are the major data source for TOP data in LMICs but are known to have shortcomings that require improving. The EN-INDEPTH multi-country survey employed a full pregnancy history approach with roster and new questions on TOP and Menstrual Restoration. This mixed methods paper assesses the completeness of responses to questions eliciting TOP information from respondents and reports on practices, barriers, and facilitators to TOP reporting. METHODS: The EN-INDEPTH study was a population-based cross-sectional study. The Full Pregnancy History arm of the study surveyed 34,371 women of reproductive age between 2017 and 2018 in five Health and Demographic Surveillance System (HDSS) sites of the INDEPTH network: Bandim, Guinea-Bissau; Dabat, Ethiopia; IgangaMayuge, Uganda; Kintampo, Ghana; and Matlab, Bangladesh. Completeness and time spent in answering TOP questions were evaluated using simple tabulations and summary statistics. Exact binomial 95% confidence intervals were computed for TOP rates and ratios. Twenty-eight (28) focus group discussions were undertaken and analysed thematically. RESULTS: Completeness of responses regarding TOP was between 90.3 and 100.0% for all question types. The new questions elicited between 2.0% (1.0-3.4), 15.5% (13.9-17.3), and 11.5% (8.8-14.7) lifetime TOP cases over the roster questions from Dabat, Ethiopia; Matlab, Bangladesh; and Kintampo, Ghana, respectively. The median response time on the roster TOP questions was below 1.3 minutes in all sites. Qualitative results revealed that TOP was frequently stigmatised and perceived as immoral, inhumane, and shameful. Hence, it was kept secret rendering it difficult and uncomfortable to report. Miscarriages were perceived to be natural, being easier to report than TOP. Interviewer techniques, which were perceived to facilitate TOP disclosure, included cultural competence, knowledge of contextually appropriate terms for TOP, adaptation to interviewee's individual circumstances, being non-judgmental, speaking a common language, and providing detailed informed consent. CONCLUSIONS: Survey roster questions may under-represent true TOP rates, since the new questions elicited responses from women who had not disclosed TOP in the roster questions. Further research is recommended particularly into standardised training and approaches to improving interview context and techniques to facilitate TOP reporting in surveys.

A Two-Center Randomized Trial of an Additional Early Dose of Measles Vaccine: Effects on Mortality and Measles Antibody Levels.

Background: In addition to protecting against measles, measles vaccine (MV) may have beneficial nonspecific effects. We tested the effect of an additional early MV on mortality and measles antibody levels. Methods: Children aged 4-7 months at rural health and demographic surveillance sites in Burkina Faso and Guinea-Bissau were randomized 1:1 to an extra early standard dose of MV (Edmonston-Zagreb strain) or no extra MV 4 weeks after the third diphtheria-tetanus-pertussis-hepatitis B-Haemophilus influenzae type b vaccine. All children received routine MV at 9 months. We assessed mortality through home visits and compared mortality from enrollment to age 3 years using Cox proportional hazards models, censoring for subsequent nontrial MV. Subgroups of participants had blood sampled to assess measles antibody levels. Results: Among 8309 children enrolled from 18 July 2012 to 3 December 2015, we registered 145 deaths (mortality rate: 16/1000 person-years). The mortality was lower than anticipated and did not differ by randomization group (hazard ratio, 1.05; 95% confidence interval, 0.75-1.46). At enrollment, 4% (16/447) of children in Burkina Faso and 21% (90/422) in Guinea-Bissau had protective measles antibody levels. By age 9 months, no measles-unvaccinated/-unexposed child had protective levels, while 92% (306/333) of early MV recipients had protective levels. At final follow-up, 98% (186/189) in the early MV group and 97% (196/202) in the control group had protective levels. Conclusions: Early MV did not reduce all-cause mortality. Most children were susceptible to measles infection at age 4-7 months and responded with high antibody levels to early MV. Clinical Trials Registration: NCT01644721.

Overall effect of a campaign with measles vaccine on the composite outcome mortality or hospital admission: A cluster-randomized trial among children aged 9-59 months in rural Guinea-Bissau.

OBJECTIVES: Campaigns with measles vaccine (C-MV) are conducted to eradicate measles, but prior studies indicate that MV reduces non-measles mortality and hospital admissions too. We hypothesized that C-MV reduces death/hospital admission by 30%. METHODS: Between 2016-2019, we conducted a non-blinded cluster-randomized trial randomizing village clusters in rural Guinea-Bissau to a C-MV targeting children aged 9-59 months. In Cox proportional hazards models, we assessed the effect of C-MV, obtaining hazard ratios (HR) for the composite outcome (death/hospital admission). We also examined potential effect modifiers. RESULTS: Among 18,411 children (9636 in 111 intervention clusters/8775 in 110 control clusters), 379 events occurred (208 intervention/171 control) during a median follow-up period of 22 months. C-MV did not reduce the composite outcome (HR 1.12, 95% confidence interval 0.88-1.41). Mortality among enrolled children (5.3 intervention and 4.6 control, per 1000 person-years) was approximately half the pre-trial mortality rate (11.1 intervention and 8.9 control, per 1000 person-years). Neither planned nor explorative analyses of potential effect modifiers explained the contrasting results to prior studies. CONCLUSION: C-MV did not reduce overall mortality or hospital admission. This might be explained by changes in disease patterns, baseline differences in health status, and/or modifying effects of other campaigns during follow-up.

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

Health effects of utilising hospital contacts to provide measles vaccination to children 9-59 months-a randomised controlled trial in Guinea-Bissau.

BACKGROUND: Measles vaccination coverage in Guinea-Bissau is low; fewer than 80% of children are currently measles vaccinated before 12 months of age. The low coverage hampers control of measles. Furthermore, accumulating evidence indicates that measles vaccine has beneficial non-specific effects, strengthening the resistance towards other infections. Thus, even if children are not exposed to measles virus, measles-unvaccinated children may be worse off. To increase vaccination coverage, WHO recommends that contacts with the health system for mild illness are utilised to vaccinate. Currently, in Guinea-Bissau, curative health system contacts are not utilised. METHODS: Bandim Health Project registers out-patient consultations and admissions at the paediatric ward of the National Hospital in Guinea-Bissau. Measles-unvaccinated children aged 9-59 months consulting for milder illness or being discharged from the paediatric ward will be invited to participate in a randomised trial. Among 5400 children, randomised 1:1 to receive standard measles vaccine or a saline placebo, we will test the hypothesis that providing a measles vaccine at discharge lowers the risk of admission/mortality (composite outcome) during the subsequent 6 months by 25%. All enrolled children are followed through the Bandim Health Project registration system and through telephone follow-up. The first 1000 enrolled children are furthermore followed through interviews on days 2, 4, 7 and 14 after enrolment. DISCUSSION: Utilising missed vaccination opportunities can increase vaccination coverage and may improve child health. However, without further evidence for the safety and potential benefits of measles vaccination, these curative contacts are unlikely to be used for vaccination in Guinea-Bissau. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT04220671 . Registered on 5 January 2020.

Impact of COVID-19 Disruptions on Global BCG Coverage and Paediatric TB Mortality: A Modelling Study.

The impact of COVID-19 disruptions on global Bacillus Calmette-Guérin (BCG) coverage and paediatric tuberculosis (TB) mortality is still unknown. To fill this evidence-gap and guide mitigation measures, we estimated the impact of COVID-19 disruptions on global BCG coverage and paediatric TB mortality. First, we used data from multiple sources to estimate COVID-19-disrupted BCG vaccination coverage. Second, using a static mathematical model, we estimated the number of additional paediatric TB deaths in the first 15 years of life due to delayed/missed vaccinations in 14 scenarios-varying in duration of disruption, and magnitude and timing of catch-up. We estimated a 25% reduction in global BCG coverage within the disruption period. The best-case scenario (3-month disruption, 100% catch-up within 3 months) resulted in an additional 886 (0.5%) paediatric TB deaths, and the worst-case scenario (6-month disruption with no catch-up) resulted in an additional 33,074 (17%) deaths. The magnitude of catch-up was found to be the most influential variable in minimising excess paediatric TB mortality. Our results show that ensuring catch-up vaccination of missed children is a critical priority, and delivery of BCG alongside other routine vaccines may be a feasible way to achieve catch-up. Urgent action is required to support countries with recovering vaccination coverages to minimise paediatric deaths.

Disregarding the restrictive vial-opening policy for BCG vaccine in Guinea-Bissau: impact and cost-effectiveness for tuberculosis mortality and all-cause mortality in children aged 0-4 years.

OBJECTIVE: BCG vaccination is frequently delayed in low-income countries. Restrictive vial-opening policies, where a vial of BCG vaccine is not opened for few children, are a major reason for delay. During delays, children are unprotected against tuberculosis (TB) and deprived of non-specific effects of BCG. We assessed the potential effect and cost-effectiveness of disregarding the restrictive vial-opening policy, on TB and all-cause mortality, in children aged 0-4 years in Guinea-Bissau. METHODS: Using static mathematical models, we estimated the absolute and percentage change in TB and all-cause deaths, in children aged 0-4 years, between the current BCG vaccine restrictive-opening policy scenario, and a non-restrictive policy scenario where all children were vaccinated in the first health-facility contact. Incremental cost-effectiveness was estimated by integration of vaccine and treatment costs. FINDINGS: Disregarding the restrictive BCG vial-opening policy was estimated to reduce TB deaths by 11.0% (95% uncertainty range (UR):0.5%-28.8%), corresponding to 4 (UR:0-15) TB deaths averted per birth cohort in Guinea-Bissau, resulting in incremental cost-effectiveness of US$ 911 per discounted life-year gained (LYG) (UR:145-9142). For all-cause deaths, the estimated reduction was 8.1% (UR: 3.3%-12.7%) corresponding to 392 (UR:158-624) fewer all-cause deaths and an incremental cost-effectiveness of US$ 9 (UR:5-23) per discounted LYG. CONCLUSIONS: Disregarding the restrictive BCG vial-opening policy was associated with reductions in TB deaths and all-cause deaths and low cost-effectiveness ratios. Our results suggest that it would be cost-effective to disregard the restrictive vial-opening policy. Other settings with similar practice are also likely to gain from disregarding this policy.

Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study.

OBJECTIVES: To assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children. DESIGN: Prospective cohort study. SETTING: Bandim Health Project runs an urban Health and Demographic Surveillance site in Guinea-Bissau with registration of mortality, vaccination status and TB cases. PARTICIPANTS: Children entered the analysis when their vaccination card was inspected after 28 days of age and remained under surveillance to 3 years of age. Children residing in the same house as a TB case were classified as TB-exposed from 3 months prior to case registration to the end of follow-up. METHODS: Using Cox-proportional hazards models with age as underlying time scale, we compared mortality of children with and without neonatal BCG between October 2003 and September 2017. MAIN OUTCOME MEASURE: HR for neonatal BCG compared with no neonatal BCG by TB-exposure status. RESULTS: Among the 39 421 children who entered the analyses, 3022 (8%) had observation time as TB-exposed. In total, 84% of children received neonatal BCG. Children with neonatal BCG had lower mortality both in TB-exposed (adjusted HR: 0.57 (0.26 to 1.27)) and in TB-unexposed children (HR: 0.57 (95% CI 0.47 to 0.69)) than children without neonatal BCG. Children exposed to TB had higher mortality than TB-unexposed children if they had not received neonatal BCG. CONCLUSION: Neonatal BCG vaccination was associated with lower mortality among both TB-exposed and TB-unexposed children, consistent with neonatal BCG vaccination having beneficial non-specific effects. Interventions to increase timely BCG vaccination are urgently warranted.

Randomised comparison of two household survey modules for measuring stillbirths and neonatal deaths in five countries: the Every Newborn-INDEPTH study.

BACKGROUND: An estimated 5·1 million stillbirths and neonatal deaths occur annually. Household surveys, most notably the Demographic and Health Survey (DHS), run in more than 90 countries and are the main data source from the highest burden regions, but data-quality concerns remain. We aimed to compare two questionnaires: a full birth history module with additional questions on pregnancy losses (FBH+; the current DHS standard) and a full pregnancy history module (FPH), which collects information on all livebirths, stillbirths, miscarriages, and neonatal deaths. METHODS: Women residing in five Health and Demographic Surveillance System sites within the INDEPTH Network (Bandim in Guinea-Bissau, Dabat in Ethiopia, IgangaMayuge in Uganda, Matlab in Bangladesh, and Kintampo in Ghana) were randomly assigned (individually) to be interviewed using either FBH+ or FPH between July 28, 2017, and Aug 13, 2018. The primary outcomes were stillbirths and neonatal deaths in the 5 years before the survey interview (measured by stillbirth rate [SBR] and neonatal mortality rate [NMR]) and mean time taken to complete the maternity history section of the questionnaire. We also assessed between-site heterogeneity. This study is registered with the Research Registry, 4720. FINDINGS: 69 176 women were allocated to be interviewed by either FBH+ (n=34 805) or FPH (n=34 371). The mean time taken to complete FPH (10·5 min) was longer than for FBH+ (9·1 min; p<0·0001). Using FPH, the estimated SBR was 17·4 per 1000 total births, 21% (95% CI -10 to 62) higher than with FBH+ (15·2 per 1000 total births; p=0·20) in the 5 years preceding the survey interview. There was strong evidence of between-site heterogeneity (I2=80·9%; p<0·0001), with SBR higher for FPH than for FBH+ in four of five sites. The estimated NMR did not differ between modules (FPH 25·1 per 1000 livebirths vs FBH+ 25·4 per 1000 livebirths), with no evidence of between-site heterogeneity (I2=0·7%; p=0·40). INTERPRETATION: FPH takes an average of 1·4 min longer to complete than does FBH+, but has the potential to increase reporting of stillbirths in high burden contexts. The between-site heterogeneity we found might reflect variations in interviewer training and survey implementation, emphasising the importance of interviewer skills, training, and consistent implementation in data quality. FUNDING: Children's Investment Fund Foundation.

Out-of-sequence DTP and measles vaccinations and child mortality in Guinea-Bissau: a reanalysis.

OBJECTIVES: To assess whether the sequence of diphtheria-tetanus-pertussis vaccine (DTP) and measles vaccine (MV) was associated with child survival in a dataset previously used to assess non-specific effects of vaccines with no consideration of vaccination sequence. DESIGN: Prospective cohort study analysed using the landmark approach. SETTING: Bandim Health Project's Health and Demographic Surveillance System covering 100 village clusters in rural Guinea-Bissau. The recommended vaccination schedule was BCG and oral polio vaccine (OPV) at birth, DTP and OPV at 6, 10 and 14 weeks, MV at 9 months and booster DTP and OPV at 18 months of age. PARTICIPANTS: Children aged 9-17 months (main analysis) and 18-35 months (secondary analysis: age of booster DTP) with vaccination status assessed between April 1991 and April 1996. METHODS: Survival during the 6 months after assessing vaccination status was compared by vaccination sequence in Cox-proportional hazards models with age as underlying time. Analyses were stratified by sex and village cluster. MAIN OUTCOME MEASURE: Mortality rate ratio (MRR) for out-of-sequence vaccinations compared with in-sequence vaccinations. RESULTS: Among children aged 9-17 months, 60% of observations (3574/5937) were from children who had received both MV and DTP. Among these, 1590 observations were classified as in-sequence vaccinations (last DTP before MV), and 1984 observations were out-of-sequence vaccinations (1491: MV with DTP and 493: MV before DTP). Out-of-sequence vaccinations were associated with higher mortality than in-sequence vaccinations (MRR 2.10, 95% CI 1.07 to 4.11); the MRR was 2.30 (95% CI 1.15 to 4.58) for MV with DTP and 1.45 (95% CI 0.50 to 4.22) for DTP after MV. Associations were similar for boys and girls (p=0.77). Between 18 and 35 months the mortality rate increased among children vaccinated in-sequence and the differential effect of out-of-sequence vaccinations disappeared. CONCLUSION: Out-of-sequence vaccinations may increase child mortality. Hence, sequence of vaccinations should be considered when planning vaccination programmes or introducing new vaccines into the current vaccination schedule.

Can earlier BCG vaccination reduce early infant mortality? Study protocol for a cluster randomised trial in Guinea-Bissau.

INTRODUCTION: The BCG vaccine is designed to protect against tuberculosis, but the vaccine may have broader effects. In 2014, the Strategic Advisory Group of Experts on Immunization reviewed the literature on non-specific effects of BCG, and concluded that the evidence was consistent with beneficial non-specific effects and requested further randomised trials. METHODS AND ANALYSES: Within the Bandim Health Project's urban and rural health and demographic surveillance systems, we will conduct a cluster-randomised trial in six suburban districts and 55 rural villages. Infants are enrolled at a home visit before 72 hours of life. In intervention clusters, children are vaccinated with BCG and oral polio vaccine (OPV). In control clusters, the caregivers are informed about vaccination opportunities. Using Cox-proportional hazards models, we will test whether BCG and OPV provided at a single home visit can reduce early infant mortality up to 60 days.The trial was initiated with a pilot study in Biombo region in June 2015. The trial was scaled up to full study including Oio and Cacheu regions in July 2016. The trial was expanded to include the urban study area in July 2017. ETHICS AND DISSEMINATION: BCG vaccination is delayed in many low-income settings. WHO-recommended home visits are resource demanding and vaccines are not part of the recommendation. Utilising the home visits to provide BCG and OPV may provide countries with a further incentive to introduce a single home visit. In countries, where home visits are already in place, vaccines can easily be added to reduce early infant mortality. The trial is approved by the Guinean Ethical Committee (Reference number: 0016/CNES/INASA/2015) and the Danish Ethics Committee has given its consultative approval. The results of the trial will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02504203; Pre-results.

Household costs of seeking BCG vaccination in rural Guinea-Bissau.

In Guinea-Bissau, a vial of BCG vaccine is often not opened unless 10 infants are present for vaccination, with the aim of reducing vaccine wastage. This causes delays in vaccination, as previously demonstrated in Guinea-Bissau and other low-income countries. Reducing wastage of BCG vaccine to save money may deprive infants of important health benefits and transfer costs from the vaccination programme to mothers. Using the Bandim Health Project's rural Health and Demographic Surveillance System, we interviewed mothers of infants aged 1-11 months about household costs of seeking BCG vaccination. On average mothers took their infant for BCG vaccination 1.26 times before obtaining the vaccine. For mothers who had sought BCG vaccine for their infants the average cost was 1.89 USD for each BCG-vaccinated infant. Among BCG-unvaccinated infants at the time of interview, 42% had brought their infant for BCG vaccination in vain at an average cost of 2.83 USD.

"Every Newborn-INDEPTH" (EN-INDEPTH) study protocol for a randomised comparison of household survey modules for measuring stillbirths and neonatal deaths in five Health and Demographic Surveillance sites.

BACKGROUND: Under-five and maternal mortality were halved in the Millennium Development Goals (MDG) era, with slower reductions for 2.6 million neonatal deaths and 2.6 million stillbirths. The Every Newborn Action Plan aims to accelerate progress towards national targets, and includes an ambitious Measurement Improvement Roadmap. Population-based household surveys, notably Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys, are major sources of population-level data on child mortality in countries with weaker civil registration and vital statistics systems, where over two-thirds of global child deaths occur. To estimate neonatal/child mortality and pregnancy outcomes (stillbirths, miscarriages, birthweight, gestational age) the most common direct methods are: (1) the standard DHS-7 with Full Birth History with additional questions on pregnancy losses in the past 5 years (FBH+) or (2) a Full Pregnancy History (FPH). No direct comparison of these two methods has been undertaken, although descriptive analyses suggest that the FBH+ may underestimate mortality rates particularly for stillbirths. METHODS: This is the protocol paper for the Every Newborn-INDEPTH study (INDEPTH Network, International Network for the Demographic Evaluation of Populations and their Health Every Newborn, Every Newborn Action Plan), aiming to undertake a randomised comparison of FBH+ and FPH to measure pregnancy outcomes in a household survey in five selected INDEPTH Network sites in Africa and South Asia (Bandim in urban and rural Guinea-Bissau; Dabat in Ethiopia; IgangaMayuge in Uganda; Kintampo in Ghana; Matlab in Bangladesh). The survey will reach >68 000 pregnancies to assess if there is ≥15% difference in stillbirth rates. Additional questions will capture birthweight, gestational age, birth/death certification, termination of pregnancy and fertility intentions. The World Bank's Survey Solutions platform will be tailored for data collection, including recording paradata to evaluate timing. A mixed methods assessment of barriers and enablers to reporting of pregnancy and adverse pregnancy outcomes will be undertaken. CONCLUSIONS: This large-scale study is the first randomised comparison of these two methods to capture pregnancy outcomes. Results are expected to inform the evidence base for survey methodology, especially in DHS, regarding capture of stillbirths and other outcomes, notably neonatal deaths, abortions (spontaneous and induced), birthweight and gestational age. In addition, this study will inform strategies to improve health and demographic surveillance capture of neonatal/child mortality and pregnancy outcomes.

Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. METHODS: Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). RESULTS: From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal <3 mm were more likely to not develop a scar (RR = 9.05 (3.69-22.20) and RR = 4.74 (1.96-11.45), respectively). Nutritional status and socioeconomic status were not associated with scarification. CONCLUSION: Vaccination technique and vaccine strain were associated with BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.