Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.
ABSTRACT: 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.
Project description:Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).
Project description:BACKGROUND:The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region. METHODS:Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach. RESULTS:Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials. DISCUSSION/ CONCLUSIONS:The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.
Project description:BACKGROUND:Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. METHODS:This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5-50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. FINDINGS:Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; -10·2%, IQR -143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; -6·0%, IQR -126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). INTERPRETATION:Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. FUNDING:Bill & Melinda Gates Foundation, European Research Council.
Project description:BACKGROUND:In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP. METHODS AND FINDINGS:This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI -3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90-1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92-1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71-1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%-12.63%]; all women: RR = 1.19 [95% CI 1.07-1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04-1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02-1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01-4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design. CONCLUSIONS:Scheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery. TRIAL REGISTRATION:Pan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930.
Project description:One of the fundamental steps toward malaria control is the use of antimalarial drugs. The success of antimalarial treatment can be affected by the presence of drug-resistant populations of Plasmodium falciparum. To assess resistance, we used molecular methods to examine 351 P. falciparum isolates collected from 4 sentinel sites in Mozambique for K13, pfmdr1, pfcrt, and pfdhps polymorphisms and for plasmepsin2 (pfpm2) and pfmdr1 copy numbers. We found multiple copies of pfpm2 in 1.1% of isolates. All isolates carried K13 wild-type alleles (3D7-like), except 4 novel polymorphisms (Leu619Leu, Phe656Ile, Val666Val, Gly690Gly). Prevalence of isolates with pfcrt mutant (K76T) allele was low (2.3%). Prevalence of isolates with pfdhps mutant alleles (A437G and K540E) was >80%, indicating persistence of sulfadoxine/pyrimethamine resistance; however, markers of artemisinin were absent, and markers of piperaquine resistance were low. Piperaquine resistance isolates may spread in Mozambique as dihydroartemisinin/piperaquine drug pressure increases.
Project description:Background:In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria. Methods:We compared genotypes using sequencing, fluorescent microsphere, and quantitative polymerase chain reaction assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP. Results:Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, P < .001; 93.9% vs 59.2%, P < .001; and 87.7% vs 75.4%, P = .03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/mL. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5-mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, P = .001). Conclusions:IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.
Project description:Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.An open-label, randomized controlled trial.Tororo, Uganda, a rural area with intense, year-round, malaria transmission.Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P?<?0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P?=?0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P?=?0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.
Project description:In malaria endemic areas, schoolchildren usually have asymptomatic malaria infections and consequently remain untreated. Therefore, intermittent preventive treatment with sulfadoxine-pyrimethamine in schoolchildren would be a plausible strategy in malaria stable transmission areas to prevent anaemia and malnutrition. However, in contrast to infancy and pregnancy, antimalaria intermittent preventive treatment in children has been barely investigated. As the implementation of intermittent preventive treatment may be challenged by sulfadoxine-pyrimethamine resistance, sulfadoxine-pyrimethamine combined with piperaquine may be a better alternative than sulfadoxine-pyrimethamine monotherapy. A clinical trial is being conducted to assess the efficacy and safety of intermittent preventive treatments versus controls in Democratic Republic of Congo (DRCongo) schoolchildren and their impact on sulfadoxine-pyrimethamine resistance.A phase IIIb, randomised, controlled trial will enroll asymptomatic schoolchildren. For interventions, sulfadoxine-pyrimethamine is compared to sulfadoxine-pyrimethamine plus piperaquine and to a control group. The two treatments are given four-monthly from baseline for a year as a single dose for sulfadoxine-pyrimethamine and two doses at 24-hour intervals for piperaquine. All participants receive praziquantel and albendazole as mass-treatment for helminthiasis at enrolment. The primary endpoint is haemoglobin concentration change at 12 months follow-up. Secondary endpoints are malaria parasite load and malaria prevalence, at baseline and at month 12. Malaria and helminthiasis incidence will be monitored throughout the study. Statistical analysis will use multilevel modelling due to repeated measurements and clustering effect of participants.The very few studies on intermittent preventive treatment in schoolchildren in malaria stable transmission areas have contradictory results. This randomised controlled trial is unique in comparing efficacy and safety of a prophylactic combination therapy to monotherapy or a control group after 12 months follow-up. Resistance markers for sulfadoxine-pyrimethamine (including break through parasitaemias) will also be recorded. Its uniqueness lies also in the fact that we use piperaquine, a long acting antimalarial, in combination with sulfadoxine-pyrimethamine. Artemisinin derivatives have been excluded as it is part of the treatment policies in virtually all malaria endemic countries. Our findings may, therefore, contribute to the public health of youngsters who fail to thrive and grow due to multiple morbidities.NCT01722539; PACTR201211000449323.
Project description:Background:Dihydroartemisinin-piperaquine (DHA-PQ) is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine (PQ) exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. Methods:Human immunodeficiency virus-uninfected pregnant women (n = 300) were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks' gestation and randomized to sulfadoxine-pyrimethamine every 8 weeks, DHA-PQ every 8 weeks, or DHA-PQ every 4 weeks during pregnancy. Pharmacokinetic sampling for PQ was performed every 4 weeks, and an intensive pharmacokinetic substudy was performed in 30 women at 28 weeks' gestation. Concentration-effect relationships were assessed between exposure to PQ; the prevalence of Plasmodium falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birth weight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed. Results:Model-defined PQ target venous plasma concentrations of 13.9 ng/mL provided 99% protection from P. falciparum infection during pregnancy. Each 10-day increase in time above target PQ concentrations was associated with reduced odds of placental parasitemia, preterm birth, and low birth weight, though increases in PQ concentrations were associated with QT interval prolongation. Modeling suggests that daily or weekly administration of lower dosages of PQ, compared to standard dosing, will maintain PQ trough levels above target concentrations with reduced PQ peak levels, potentially limiting toxicity. Conclusions:The protective efficacy of IPTp with DHA-PQ was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative DHA-PQ IPTp dosing strategies are warranted. Clinical Trials Registration:NCT02163447.
Project description:BACKGROUND:Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP. METHODS AND FINDINGS:We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy. CONCLUSIONS:Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy. TRIAL REGISTRATION:ClinicalTrials.gov number NCT02163447.