Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial

Abstract

Background: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized.

Methods: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age.

Results: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes.

Conclusions: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

Keywords: chemoprevention; development; malaria; pregnancy.

Figure 1.

Flow diagram of enrollment and testing of study participants. *An additional child was assigned monthly dihydroartemisinin-piperaquine but withdrew from study before neurocognitive assessments. Abbreviations: C, could not comply with study protocol; DC, declined participation; DE, death; DP, dihydroartemisinin-piperaquine; HIV, human immunodeficiency virus; L, could not be located; M, moved out of study area; SP, sulfadoxine-pyrimethamine; W, withdrew consent.

Figure 2.

Cognitive outcomes at 12, 24, and 36 months, according to malaria chemoprevention regimen. Mean and 95% confidence interval for each chemoprevention regimens are shown. Within each assessment and time point, a regimen pair with significantly different means at a significance level of .05 is shown with a bracket with the corresponding Tukey P values adjusted for multiple comparisons. Abbreviations: 3DP, 3 doses of dihydroartemisinin-piperaquine; COAT, Color Object Association Test; DP3, dihydroartemisinin-piperaquine every 3 months; ECVT, Early Childhood Vigilance Test; MDP, monthly dihydroartemisinin-piperaquine; SP, 3 doses of sulfadoxine-pyrimethamine.

Figure 3.

Behavioral and executive function scores at 24 and 36 months, according to malaria chemoprevention regimen. Mean and 95% confidence interval for each chemoprevention regimen are shown. Within each assessment and time point, a regimen pair with significantly different means at a significance level of .05 is shown with a bracket, along with the corresponding Tukey P values adjusted for multiple comparisons. Abbreviations: 3DP, 3 doses of dihydroartemisinin-piperaquine; BRIEF, Behavior Rating Inventory for Executive Function; CBCL, Child Behavior Checklist; DP3, dihydroartemisinin-piperaquine every 3 months; MDP, monthly dihydroartemisinin-piperaquine; SP, 3 doses of sulfadoxine-pyrimethamine.

Figure 4.

Bayley cognitive, language, and motor composite scores at 12, 24, and 36 months, according to malaria risk factors. Mean and 95% confidence interval for each risk factor are shown. First column: malaria in pregnancy (MIP) assessed by loop-mediated isothermal amplification (LAMP). Second column: timing of MIP assessed by LAMP. Third column: presence of placental malaria. Fourth column: presence of clinical malaria in the child in the first 12 months of life. Within each assessment and time point, a regimen pair with significantly different means at a significance level of .05 is shown with a bracket, along with the corresponding Tukey P values adjusted for multiple comparisons. Abbreviations: CM, clinical malaria; MIP, malaria in pregnancy; PM, placental malaria.

Figure 5.

Behavioral and executive function scores at 24 and 36 months, according to malaria risk factors. Mean and 95% confidence interval for each risk factor are shown. First column: malaria in pregnancy (MIP) assessed by loop-mediated isothermal amplification (LAMP). Second column: timing of MIP assessed by LAMP. Third column: presence of placental malaria. Fourth column: presence of clinical malaria in the child in the first 12 months of life. Within each assessment and time point, a regimen pair with significantly different means at a significance level of .05 is shown with a bracket, along with the corresponding Tukey P values adjusted for multiple comparisons. Abbreviations: BRIEF, Behavior Rating Inventory for Executive Function; CBCL, Child Behavior Checklist; CM, clinical malaria; MIP, malaria in pregnancy; PM, placental malaria.