Post-discharge malaria chemoprevention in children admitted with severe anaemia in malaria-endemic settings in Africa: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia. METHODS: This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791. FINDINGS: Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I2=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias. INTERPRETATION: In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity. FUNDING: The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.

Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.

BACKGROUND: Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine. METHODS: We defined treatment as random assignment to sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine before pooling individual participant-level data from 1617 HIV-uninfected pregnant women in Kenya (one trial; n=806) and Uganda (two trials; n=811). We quantified the relative effect of treatment on birthweight (primary outcome) attributed to preventing placental malaria infection (mediator). We estimated antimalarial (indirect) and non-malarial (direct) effects of IPTp on birth outcomes using causal mediation analyses, accounting for confounders. We used two-stage individual participant data meta-analyses to calculate pooled-effect sizes. FINDINGS: Overall, birthweight was higher among neonates of women randomly assigned to sulfadoxine-pyrimethamine compared with women assigned to dihydroartemisinin-piperaquine (mean difference 69 g, 95% CI 26 to 112), despite placental malaria infection being lower in the dihydroartemisinin-piperaquine group (relative risk [RR] 0·64, 95% CI 0·39 to 1·04). Mediation analyses showed sulfadoxine-pyrimethamine conferred a greater non-malarial effect than did dihydroartemisinin-piperaquine (mean difference 87 g, 95% CI 43 to 131), whereas dihydroartemisinin-piperaquine conferred a slightly larger antimalarial effect than did sulfadoxine-pyrimethamine (8 g, -9 to 26), although more frequent dosing increased the antimalarial effect (31 g, 3 to 60). INTERPRETATION: IPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation, and Worldwide Antimalarial Resistance Network.

First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age

While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth. Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site). Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high. ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

Intermittent screening and treatment with dihydroartemisinin-piperaquine and intermittent preventive therapy with sulfadoxine-pyrimethamine have similar effects on malaria antibody in pregnant Malawian women.

In a randomised trial comparing intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine (DP) and intermittent preventive therapy against malaria in pregnancy (IPT) with sulfadoxine-pyrimethamine (SP) in Malawi, the impacts of IST-DP and IPT-SP on the development and maintenance of malaria antibody immunity were compared. Pregnant Malawian women were randomised to receive IST-DP or IPT-SP. In a nested study, paired enrolment and delivery plasma samples from 681 women were assayed for antibodies against recombinant antigens and for IgG and opsonising antibodies to antigens found on infected erythrocytes (IEs). At delivery, antibody responses did not differ between study arms. Between enrolment and delivery, antibodies to recombinant antigens decreased, whereas antibodies to IEs including opsonising antibodies remained stable. Overall, changes in antibody responses over pregnancy did not differ by treatment arm. Stratifying by gravidity, antibody to schizont extract decreased more in multigravidae receiving IST-DP than IPT-SP. There was minimal impact of treatment arm on the development and maintenance of malaria immunity. While antibodies to recombinant antigens declined between enrolment and delivery, antibodies directed against IEs tended to be more stable, suggesting longer-lasting protection.Clinical trial registration: Pa n African Clinical Trials Registry (PACTR201103000280319) 14/03/2011. URL: http://www.isrctn.com/ISRCTN69800930 .

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24-0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31-1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27-3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77-1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79-1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37-1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy.

Burden of malaria at community level in children less than 5 years of age in Togo.

A community-based baseline cross-sectional survey was conducted in three districts in Togo in September 2004 as part of a multidisciplinary evaluation of the impact of the Togo National Integrated Child Health Campaign. During this campaign, long-lasting-insecticide-treated bed nets (LLITNs) were distributed to households with children between 9 months and 5 years of age throughout the country in December 2004. The pre-intervention survey provided baseline malaria and anemia prevalence in children < 5 years of age during peak malaria transmission. Of 2,532 enrolled children from 1,740 households, 62.2% (1,352/2,172) were parasitemic and 84.4% (2,129/2,524) were anemic (hemoglobin < 11 g/dL). Moderate-to-severe anemia (< 8.0 g/dL) was found in 21.7% (543/2,524), with a peak prevalence in children 6-17 months of age and was strongly correlated with parasitemia (OR = 2.3, 95% CI: 1.8-2.5). Net ownership (mainly untreated) was 225/2,532 (8.9%). Subsequent nation-wide introduction of LLITNs and the introduction of artemisinin-based combination therapy have the potential to markedly reduce this burden of malaria.

Sulfadoxine-pyrimethamine in treatment of malaria in Western Kenya: increasing resistance and underdosing.

Between 1993 and 1999, we monitored the efficacy of sulfadoxine-pyrimethamine in 1175 children aged <24 months receiving 2789 treatments for falciparum malaria in western Kenya using a widely deployed age-based dose regimen: infants, 125 plus 6.25 mg (sulfadoxine plus pyrimethamine); children aged 12 to 23 months; 250 plus 12.5 mg. Cumulative treatment failure by day 7, defined as early clinical failure by day 3 or presence of parasitemia on day 7, increased from 18% in 1993 to 1994 to 22% in 1997 to 1998 (P-trend test = 0.20). Based on body weight, the median dose received was 20 plus 1.00 mg/kg, and 73% of the treatments were given at lower than the recommended target dose of 25 plus 1.25 mg/kg. Underdosing accounted for 26% of cumulative treatment failures. After the dose was increased in 1998 (median, 36 plus 1.8 mg/kg), only 4.2% of patients received less than 25 plus 1.25 mg/kg and there was no association with treatment failure. However, the proportion of cumulative treatment failure continued to increase to 27% by 1999 (P-trend test = 0.03). These results raise concern about the longevity of sulfadoxine-pyrimethamine in these settings. Underdosing may have contributed to the rate at which sulfadoxine-pyrimethamine resistance developed in this area. Treatment guidelines should ensure that adequate doses are given from the initial deployment of antimalarials onward.

Increased efficacy of sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria among children with sickle cell trait in Western Kenya.

The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2-3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36-0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome.