Feiko O. ter Kuile

Protective effects of the sickle cell gene against malaria morbidity and mortality

The high frequency of the sickle-cell haemoglobin (HbS) gene in malaria endemic regions is believed to be due to a heterozygote (HbAS) advantage against fatal malaria. Data to prospectively confirm the protection associated with HbAS against mortality are lacking. We show that HbAS provides significant protection against all-cause mortality, severe malarial anaemia, and high-density parasitaemia. This significant reduction in mortality was detected between the ages of 2 and 16 months, the highest risk period for severe malarial anaemia in this area. These data are important in understanding the role of malaria in the selection and maintenance of the sickle cell gene.

Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study

By combining data from the Malaria Atlas Project with country-specific data, Feiko ter Kuile and colleagues provide the first contemporary global estimates of the annual number of pregnancies at risk of malaria.

HIV-1/AIDS and the control of other infectious diseases in Africa.

The effect of HIV-1 on other infectious diseases in Africa is an increasing public health concern. In this review, we describe the role that three major infectious diseases--malaria, sexually transmitted diseases (STDs), and tuberculosis--have had in the HIV-1 epidemic. The high prevalence of untreated STD infections has been a major factor facilitating the spread of HIV-1 in Africa; with the synergistic interaction between HIV-1 transmission and genital herpes being of special concern for control of both diseases. Increased susceptibility to tuberculosis after infection with HIV-1 has led to a rising incidence and threat of increased transmission of tuberculosis. Clinical malaria occurs with an increased frequency and severity in HIV-1-infected individuals, especially during pregnancy. As with tuberculosis, STDs, and other communicable HIV-1-associated diseases, the net effect of HIV-1 might include increased rates of malaria transmission across communities. In addition to enhancing access to HIV-1 prevention and care, public health surveillance and control programmes should be greatly intensified to cope with the new realities of infectious disease control in Africa.

Reducing the burden of malaria in pregnancy by preventive strategies

Malaria is one of the most common and preventable causes of adverse birth outcomes. In Africa, important progress has been made in the past decade with the introduction of a preventive strategy for malaria in pregnancy consisting of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets, yet their coverage is still unacceptably low and malaria continues to demand a huge toll on pregnant women and their newborn babies. Increasing the frequency of dosing of IPTp with sulfadoxine-pyrimethamine might provide temporary respite, but increasing resistance to sulfadoxine-pyrimethamine makes research into safe, efficacious, and affordable alternatives for IPTp one of the highest priorities for the control of malaria in pregnancy. A number of promising alternatives are, or will soon be, available that need to be evaluated as IPTp after their safety and pharmacokinetics in pregnancy have first been assessed in parasitaemic women. Little is known about appropriate control strategies in Asia and Latin America for Plasmodium falciparum and Plasmodium vivax malaria in pregnancy, which in most countries rely on responsive case management approaches. The role of case management based on proactive screening for malaria infection of women attending antenatal care or preventive approaches with insecticide-treated nets or IPTp are urgently needed. To achieve these objectives, multicentre and multidisciplinary approaches are required across the range of malaria transmission settings that include assessment of immunological effect of successful preventions, the perceptions and acceptability of different preventive approaches, and their cost-effectiveness.

Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries

BACKGROUND Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30-40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain. METHODS Using extant longitudinal birth cohorts (n=19) with data on birthweight, gestational age and child anthropometry (12-60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth. RESULTS We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5-3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively. CONCLUSIONS This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.

CNS adverse events associated with antimalarial agents. Fact or fiction

SummaryCNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult.CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too toxic for humans, has been the antimalarial of choice for 40 years. While a range of serious CNS effects have been documented during chloroquine therapy, the incidence is unclear (extrapyramidal symptoms occur with an incidence of 1 in 5000). Amodiaquine has a higher incidence of mild CNS effects than chloroquine. Mefloquine therapy causes dose-related transient dizziness. Serious CNS events during mefloquine therapy occur in 1: 1200 Asians and 1: 200 Caucasians/Africans. Risk factors include dosage, concomitant drug use/interactions, previous history of a CNS event and disease severity. Retreatment (within a month) increases the risk in Asians 7-fold. Studies indicate that the frequency of serious CNS events with mefloquine prophylaxis (1: 10 000) is similar to that with chloroquine (1: 13 600). Quinine causes cinchonism at standard therapeutic doses. High-tone hearing loss occurs, but irreversible auditory or ocular effects are very rare.The artemisinin derivatives are associated with dose-dependent brain lesions in rodent, canine and nonhuman primates. At low doses, histological injury has been demonstrated, without clinical neurological signs. No significant toxicity has been reported in humans. Other antimalarial drugs are seldom associated with CNS adverse events.Data do not suggest a need to diminish the correct use of the quinoline derivatives. Irreversible effects are extremely rare and usually associated with overdosing or prior history of a serious CNS event. Concomitant therapeutic use of 2 drugs from the same family, or retreatment with the same drug, should be avoided. Onset of drug-associated serious CNS events requires drug discontinuation and future avoidance of the drug.

Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa: Systematic Review and Meta-analysis

IMPORTANCE Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain. OBJECTIVE To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens. DATA SOURCES AND STUDY SELECTION ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy. DATA EXTRACTION Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models. RESULTS Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events. CONCLUSIONS AND RELEVANCE Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.

The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya

Objective: To determine the effect of dual infection with HIV and malaria on birth outcomes and maternal anaemia among women delivering at a large public hospital in Kisumu, western Kenya. Subjects and methods: Data on obstetric and neonatal characteristics, maternal and placental parasitaemia, and postpartum haemoglobin levels were collected from women enrolled in a cohort study of the interaction between malaria and HIV during pregnancy. Results: Between 1996 and 1999, data were available from 2466 singleton deliveries. The maternal HIV seroprevalence was 24.3%, and at delivery 22.0% of the women had evidence of malaria. Low birthweight, preterm delivery (PTD), intrauterine growth retardation (IUGR) and maternal anaemia (haemoglobin < 8 g/dl) occurred in 4.6, 6.7, 9.8 and 13.8% of deliveries, respectively. Maternal HIV, in the absence of malaria, was associated with a 99 g (95% CI 52–145) reduction in mean birthweight among all gravidae. Malaria was associated with both IUGR and PTD, resulting in a reduction in mean birthweight of 145 g (95% CI 82–209) among HIV-seronegative and 206 g (95% CI 115–298) among HIV-seropositive primigravidae, but not among multigravidae. Both HIV and malaria were significant risk factors for postpartum maternal anaemia, and HIV-seropositive women with malaria were twice as likely to have anaemia than HIV-seronegative women with or without malaria. Conclusion: Women with dual infection are at particular risk of adverse birth outcomes. In areas with a moderate or high prevalence of HIV and malaria, all pregnant women should be the focus of malaria and anaemia control efforts to improve birth outcomes.

Profile: The KEMRI/CDC Health and Demographic Surveillance System—Western Kenya

The KEMRI/Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS) is located in Rarieda, Siaya and Gem Districts (Siaya County), lying northeast of Lake Victoria in Nyanza Province, western Kenya. The KEMRI/CDC HDSS, with approximately 220 000 inhabitants, has been the foundation for a variety of studies, including evaluations of insecticide-treated bed nets, burden of diarrhoeal disease and tuberculosis, malaria parasitaemia and anaemia, treatment strategies and immunological correlates of malaria infection, and numerous HIV, tuberculosis, malaria and diarrhoeal disease treatment and vaccine efficacy and effectiveness trials for more than a decade. Current studies include operations research to measure the uptake and effectiveness of the programmatic implementation of integrated malaria control strategies, HIV services, newly introduced vaccines and clinical trials. The HDSS provides general demographic and health information (such as population age structure and density, fertility rates, birth and death rates, in- and out-migrations, patterns of health care access and utilization and the local economics of health care) as well as disease- or intervention-specific information. The HDSS also collects verbal autopsy information on all deaths. Studies take advantage of the sampling frame inherent in the HDSS, whether at individual, household/compound or neighbourhood level.

Coverage of malaria protection in pregnant women in sub-Saharan Africa: a synthesis and analysis of national survey data

Summary Background Insecticide-treated nets and intermittent preventive treatment with sulfadoxine–pyrimethamine are recommended for the control of malaria during pregnancy in endemic areas in Africa, but there has been no analysis of coverage data at a subnational level. We aimed to synthesise data from national surveys about these interventions, accounting for disparities in malaria risk within national borders. Methods We extracted data for specific strategies for malaria control in pregnant women from national malaria policies from endemic countries in Africa. We identified the most recent national household cluster-sample surveys recording intermittent preventive treatment with sulfadoxine–pyrimethamine and use of insecticide-treated nets. We reconciled data to subnational administrative units to construct a model to estimate the number of pregnant women covered by a recommended intervention in 2007. Findings 45 (96%) of 47 countries surveyed had a policy for distribution of insecticide-treated nets for pregnant women; estimated coverage in 2007 was 4·7 million (17%) of 27·7 million pregnancies at risk of malaria in 32 countries with data. 39 (83%) of 47 countries surveyed had an intermittent preventive treatment policy; in 2007, an estimated 6·4 million (25%) of 25·6 million pregnant women received at least one dose of treatment and 19·8 million (77%) visited an antenatal clinic (31 countries). Estimated coverage was lowest in areas of high-intensity transmission of malaria. Interpretation Despite success in a few countries, coverage of insecticide-treated nets and intermittent preventive treatment in pregnant African women is inadequate; increased efforts towards scale-up are needed. Funding The Malaria in Pregnancy Consortium and Wellcome Trust.