Jennifer B. Griffin

High-Throughput Pooling and Real-Time PCR-Based Strategy for Malaria Detection

ABSTRACT Molecular assays can provide critical information for malaria diagnosis, speciation, and drug resistance, but their cost and resource requirements limit their application to clinical malaria studies. This study describes the application of a resource-conserving testing algorithm employing sample pooling for real-time PCR assays for malaria in a cohort of 182 pregnant women in Kinshasa. A total of 1,268 peripheral blood samples were collected during the study. Using a real-time PCR assay that detects all Plasmodium species, microscopy-positive samples were amplified individually; the microscopy-negative samples were amplified after pooling the genomic DNA (gDNA) of four samples prior to testing. Of 176 microscopy-positive samples, 74 were positive by the real-time PCR assay; the 1,092 microscopy-negative samples were initially amplified in 293 pools, and subsequently, 35 samples were real-time PCR positive (3%). With the real-time PCR result as the referent standard, microscopy was 67.9% sensitive (95% confidence interval [CI], 58.3% to 76.5%) and 91.2% specific (95% CI, 89.4% to 92.8%) for malaria. In total, we detected 109 parasitemias by real-time PCR and, by pooling samples, obviated over 50% of reactions and halved the cost of testing. Our study highlights both substantial discordance between malaria diagnostics and the utility and parsimony of employing a sample pooling strategy for molecular diagnostics in clinical and epidemiologic malaria studies.

Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study

BackgroundDuring early pregnancy, the placenta develops to meet the metabolic demands of the foetus. The objective of this analysis was to examine the effect of malaria parasitaemia prior to 20 weeks’ gestation on subsequent changes in uterine and umbilical artery blood flow and intrauterine growth restriction.MethodsData were analysed from 548 antenatal visits after 20 weeks’ gestation of 128 women, which included foetal biometric measures and interrogation of uterine and umbilical artery blood flow. Linear mixed effect models estimated the effect of early pregnancy malaria parasitaemia on uterine and umbilical artery resistance indices. Log-binomial models with generalized estimating equations estimated the effect of early pregnancy malaria parasitaemia on the risk of intrauterine growth restriction.ResultsThere were differential effects of early pregnancy malaria parasitaemia on uterine artery resistance by nutritional status, with decreased uterine artery resistance among nourished women with early pregnancy malaria and increased uterine artery resistance among undernourished women with early pregnancy malaria. Among primigravidae, early pregnancy malaria parasitaemia decreased umbilical artery resistance in the late third trimester, likely reflecting adaptive villous angiogenesis. In fully adjusted models, primigravidae with early pregnancy malaria parasitaemia had 3.6 times the risk of subsequent intrauterine growth restriction (95% CI: 2.1, 6.2) compared to the referent group of multigravidae with no early pregnancy malaria parasitaemia.ConclusionsEarly pregnancy malaria parasitaemia affects uterine and umbilical artery blood flow, possibly due to alterations in placentation and angiogenesis, respectively. Among primigravidae, early pregnancy malaria parasitaemia increases the risk of intrauterine growth restriction. The findings support the initiation of malaria parasitaemia prevention and control efforts earlier in pregnancy.

Resuscitation and Obstetrical Care to Reduce Intrapartum-Related Neonatal Deaths: A MANDATE Study

To evaluate the impact of neonatal resuscitation and basic obstetric care on intrapartum-related neonatal mortality in low and middle-income countries, using the mathematical model, Maternal and Neonatal Directed Assessment of Technology (MANDATE). Using MANDATE, we evaluated the impact of interventions for intrapartum-related events causing birth asphyxia (basic neonatal resuscitation, advanced neonatal care, increasing facility birth, and emergency obstetric care) when implemented in home, clinic, and hospital settings of sub-Saharan African and India for 2008. Total intrapartum-related neonatal mortality (IRNM) was acute neonatal deaths from intrapartum-related events plus late neonatal deaths from ongoing intrapartum-related injury. Introducing basic neonatal resuscitation in all settings had a large impact on decreasing IRNM. Increasing facility births and scaling up emergency obstetric care in clinics and hospitals also had a large impact on decreasing IRNM. Increasing prevalence and utilization of advanced neonatal care in hospital settings had limited impact on IRNM. The greatest improvement in IRNM was seen with widespread advanced neonatal care and basic neonatal resuscitation, scaled-up emergency obstetric care in clinics and hospitals, and increased facility deliveries, resulting in an estimated decrease in IRNM to 2.0 per 1,000 live births in India and 2.5 per 1,000 live births in sub-Saharan Africa. With more deliveries occurring in clinics and hospitals, the scale-up of obstetric care can have a greater effect than if modeled individually. Use of MANDATE enables health leaders to direct resources towards interventions that could prevent intrapartum-related deaths. A lack of widespread implementation of basic neonatal resuscitation, increased facility births, and emergency obstetric care are missed opportunities to save newborn lives.

Reducing maternal mortality from preeclampsia and eclampsia in low-resource countries - what should work?

Preeclampsia/eclampsia (PE/E) remains a major cause of maternal death in low‐income countries. We evaluated interventions to reduce PE/E‐related maternal mortality in sub‐Saharan Africa.

The MANDATE model for evaluating interventions to reduce postpartum hemorrhage.

To create a comprehensive model of the comparative impact of various interventions on maternal, fetal, and neonatal (MFN) mortality.

Tranexamic acid to reduce postpartum hemorrhage: A MANDATE systematic review and analyses of impact on maternal mortality.

OBJECTIVE Postpartum hemorrhage (PPH) is a major cause of maternal mortality, with almost 300,000 cases and ~72,000 PPH deaths annually in sub-Saharan Africa. Novel prevention methods practical in community settings are required. Tranexamic acid, a drug to reduce bleeding during surgical cases including postpartum bleeding, is potentially suitable for community settings. Thus, we sought to determine the impact of tranexamic acid on PPH-related maternal mortality in sub-Saharan Africa. STUDY DESIGN We created a mathematical model to determine the impact of interventions on PPH-related maternal mortality. The model was populated with baseline birth rates and mortality estimates based on a review of current interventions for PPH in sub-Saharan Africa. Based on a systematic review of literature on tranexamic acid, we assumed 30% efficacy of tranexamic acid to reduce PPH; the model assessed prophylactic and treatment tranexamic acid use, for deliveries at homes, clinics, and hospitals. RESULTS With tranexamic acid only in the hospitals, less than 2% of the PPH mortality would be reduced. However, if tranexamic acid were available in the home and clinic settings for PPH prophylaxis and treatment, a nearly 30% reduction (nearly 22,000 deaths per year) in PPH mortality is possible. CONCLUSION These analyses point to the importance of preventive and treatment interventions compatible with home and clinic use, especially for sub-Saharan Africa, where the majority of births occur at home or community health clinics. Given its feasibility to be given in the home, tranexamic acid has potential to save many lives.

Clinical interventions to reduce stillbirths in sub‐Saharan Africa: a mathematical model to estimate the potential reduction of stillbirths associated with specific obstetric conditions

Stillbirths are among the most common adverse pregnancy outcomes, with 98% occurring in low‐income countries. More than one‐third occur in sub‐Saharan Africa (SSA). However, the medical conditions causing stillbirths and interventions to reduce stillbirths from these conditions are not well documented. We estimated the reductions in stillbirths possible with combinations of interventions.

Interventions to reduce neonatal mortality: a mathematical model to evaluate impact of interventions in sub‐Saharan Africa

To determine which interventions would have the greatest impact on reducing neonatal mortality in sub‐Saharan Africa in 2012.

Maternal and Neonatal Directed Assessment of Technologies (MANDATE): Methods and Assumptions for a Predictive Model for Maternal, Fetal, and Neonatal Mortality Interventions

MANDATE is a mathematical model designed to estimate the relative impact of different interventions on maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. A key advantage is that it allows users to explore the contribution of preventive interventions, diagnostics, treatments, and transfers to higher levels of care to mortality reductions, and at different levels of penetration, utilization, and efficacy. MANDATE is a mathematical model designed to estimate the relative impact of different interventions on maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. A key advantage is that it allows users to explore the contribution of preventive interventions, diagnostics, treatments, and transfers to higher levels of care to mortality reductions, and at different levels of penetration, utilization, and efficacy. Maternal, fetal, and neonatal mortality disproportionately impact low- and middle-income countries, and many current interventions that can save lives are often not available nor appropriate for these settings. Maternal and Neonatal Directed Assessment of Technologies (MANDATE) is a mathematical model designed to evaluate which interventions have the greatest potential to save maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. The MANDATE decision-support model includes interventions such as preventive interventions, diagnostics, treatments, and transfers to different care settings to compare the relative impact of different interventions on mortality outcomes. The model is calibrated and validated based on historical and current rates of disease in sub-Saharan Africa and India. In addition, each maternal, fetal, or newborn condition included in MANDATE considers disease rates specific to sub-Saharan Africa and India projected to intervention rates similar to those seen in high-income countries. Limitations include variance in quality of data to inform the estimates and generalizability of findings of the effectiveness of the interventions. The model serves as a valuable resource to compare the potential impact of multiple interventions, which could help reduce maternal, fetal, and neonatal mortality in low-resource settings. The user should be aware of assumptions in evaluating the model and interpret results accordingly.

Pertussis Immunisation in Pregnancy Safety (PIPS) Study: A retrospective cohort study of safety outcomes in pregnant women vaccinated with Tdap vaccine

BACKGROUND New Zealand has funded the administration of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy to prevent infant pertussis since 2013. The aim of this study was to assess the safety of Tdap vaccine administered to pregnant women as part of a national maternal immunisation programme. METHODS We conducted a national retrospective observational study using linked administrative New Zealand datasets. The study population consisted of pregnant women eligible to receive funded Tdap vaccination from 28 to 38 weeks gestation in 2013. Primary study outcomes were based on prioritised adverse events for the assessment of vaccine safety in pregnant women, as defined by WHO and Brighton Collaboration taskforces. We examined the effect of Tdap vaccination on prioritised maternal outcomes using Cox proportional hazard models. Adjusted hazard ratios controlled for key confounding variables. RESULTS In the cohort of 68,550 women eligible to receive funded antenatal Tdap vaccination during 2013, 8178 (11.9%) were vaccinated and 60,372 (88.1%) were unvaccinated. The use of Tdap in pregnancy was not associated with an increase in the rate of primary outcomes, including preterm labour; pre-eclampsia; pre-eclampsia with severe features; eclampsia; gestational hypertension; fetal growth restriction; or post-partum haemorrhage. Tdap also did not increase secondary outcomes, including gestational diabetes mellitus; antenatal bleeding; placental abruption; premature rupture of membranes; preterm delivery; fetal distress; chorioamnionitis; or, maternal fever during or after labour. Lactation disorders was the only secondary maternal outcome with a significantly increased hazard ratio. Tdap vaccine had a protective effect on pre-eclampsia with severe features, preterm labour, preterm delivery, and antenatal bleeding. CONCLUSION We did not detect any biologically plausible adverse maternal outcomes following Tdap vaccination during pregnancy. This study provides further assurance that Tdap administration during pregnancy is not associated with unexpected safety risks.