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Supplementary report provided to the WHO/GMP Guideline Development Group on Malaria Chemoprevention for “Section 4.2.5 Post-discharge malaria chemoprevention (PDMC)” of the WHO Guidelines for malaria, 3 June2022.

Report considered by the WHO/GMP Guideline Development Group on Malaria Chemoprevention for “Section 4.2.5 Post-discharge malaria chemoprevention (PDMC)” of the WHO Guidelines for malaria, 3 June2022.

Supplementary report provided to the WHO/GMP Guideline Development Group on Malaria Chemoprevention for “Section 4.2.5 Post-discharge malaria chemoprevention (PDMC)” of the WHO Guidelines for malaria, 3 June 2022.

Report considered by the WHO/GMP Guideline Development Group on Malaria Chemoprevention for “Section 4.2.1 Intermittent preventive treatment of malaria in pregnancy (IPTp)” of the WHO Guidelines for malaria, 3 June 2022.

Background Plasmodium falciparum resistance to sulphadoxine-pyrimethamine (SP) threatens the efficacy of intermittent preventive treatment (IPTp) for malaria in pregnancy in Africa. We conducted a meta-analysis to assess the impact of SP resistance on IPTp-SP effectiveness. Methods We searched databases (1990 to March-01-2018) for clinical studies (aggregated data) or surveys (individual-participant data) containing information on low birthweight (LBW, primary outcome) and malaria by IPTp-SP dose, and for studies reporting SP-resistance molecular markers. We performed random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarized dose-response data (Relative-Risk-Reduction:RRR) and multivariate meta-regression to explore modifying effects of SP-resistance (dhps substitutions A437G, K540E, A581G). Findings Of 1097 records, 57 studies were included in the aggregated-data meta-analysis (59,457 births). The RRR for LBW declined with increasing prevalence of Pfdhps-K540E (P-trend=0.0060) but not with Pfdhps-A437G (P-trend=0.35). The RRR in areas of high (Pfdhps-K540E >90%, n=11), moderate (Central/West Africa:Pfdhps-A437G≥90% or East/southern Africa:Pfdhps-K540E 30-90%, n=16) and low SP-resistances (n=30) were 7% (95% CI 0-13), 21% (14-29) and 27% (21-33) respectively (P-trend=0.0054, I2=69.5%). In the individual-participant analysis of 13 surveys (42,394 births), IPTp-SP was associated with reduced LBW in areas with Pfdhps-K540E>90% & Pfdhps-A581G=10% (pooled Pfdhps-A581G prevalence:37%, range 29-46) (RRR=0.5%, -16-14, n=3). Interpretation The effectiveness of IPTp-SP is reduced in areas with high SP-resistance, but IPTp-SP remains associated with reduced LBW in areas where Pfdhps-K540E prevalence exceeds 90%. IPTp-SP is not effective in areas with ≥37% prevalence of the highly-resistant sextuple Pfdhps-A581G-containing genotype.

Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA's ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: -267.99 g; 95% Confidence Interval [CI]: -466.43 g, -69.55 g) and higher odds of low birthweight (< 2500 g) (Odds Ratio [OR] 5.41; 95% CI: 0.99,29.52) and small-for-gestational-age (OR: 3.65; 95% CI: 1.01,13.38). In two distinct malaria-endemic African settings, parasites harboring 3D7-like variants of VAR2CSA were associated with worse birth outcomes, supporting differential effects of infection with specific parasite strains. The immense diversity coupled with differential clinical effects of this diversity suggest that an effective VAR2CSA-based vaccine may require multivalent activity.

Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose.

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.

To assess risk factors for anemia in late pregnancy, we studied healthy pregnant women with a singleton uncomplicated pregnancy of > or = 32 weeks attending the prenatal clinic in the Provincial Hospital in Kisumu, Kenya. Between June 1996 and December 1998, 4,608 pregnant women had a blood sample collected for hemoglobin (Hb) measurement, malaria smear, and testing for human immunodeficiency virus (HIV). The mean +/- standard deviation of Hb was 9.58 +/- 1.8 g/dL; 21% had malaria in their blood; and 25% of the women were HIV seropositive. Plasmodium falciparum parasitemia was more common among HIV-seropositive women in all gravidities compared with HIV-seronegative women (risk ratio, 1.71; 95% confidence interval, 1.53-1.92). In a multivariate analysis, for primi- and secundigravidae women, the factors malaria, belonging to the Luo tribe, and HIV seropositivity were significantly associated with any anemia (Hb < 11 g/dL), and HIV seropositivity and documented fever were associated with severe anemia (Hb < 7 g/dL). In women of higher gravidities, HIV seropositivity was the only statistically significant factor associated with any anemia or with severe anemia. Asymptomatic HIV seropositivity is an important risk factor to be considered in the differential diagnosis of maternal anemia, independent of P. falciparum parasitemia

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia