Abstract
BackgroundMaternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.MethodsWe developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed.FindingsAccounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%.InterpretationSome clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.
Highlights
Maternal and neonatal mortality in Sub-Saharan Africa present a major barrier to achievement of Millennium Development Goals 4 and 5
If a two-arm trial demonstrates a significant decrease in the rate of small for gestational age (SGA) in vaccine group A compared to group B, does this indicate that vaccine A has reduced the incidence of SGA or that vaccine B has increased the incidence of SGA [15]? knowledge of the background rates of adverse pregnancy outcomes is crucial to interpret the results of clinical trials in Sub-Saharan Africa
Further adaptations of these data to yield the number of expected adverse events based on the amount of person-time observed before and after delivery can provide an important context to inform interim decisions made by independent Data Safety Monitoring Boards (DSMB) and researchers involved with clinical trials in such vulnerable populations
Summary
Maternal and neonatal mortality in Sub-Saharan Africa present a major barrier to achievement of Millennium Development Goals 4 and 5. Several randomized controlled trials of maternal immunization with influenza vaccine are underway in developing countries, including in Sub-Saharan Africa. Knowledge of the background rates of adverse pregnancy outcomes is crucial to interpret the results of clinical trials in Sub-Saharan Africa. Further adaptations of these data to yield the number of expected adverse events based on the amount of person-time observed before and after delivery can provide an important context to inform interim decisions made by independent Data Safety Monitoring Boards (DSMB) and researchers involved with clinical trials in such vulnerable populations.
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