Prophylaxis Against Malaria to Enhance Child Development (PROTECT Study)
Condition: Neurobehavioral Manifestations
MeSH terms: Malaria; Neurobehavioral Manifestations
Study type: Observational

Summary: 
      Each year, ~85.3 million pregnant women are at risk of becoming infected with Plasmodium
      falciparum(1). Among women in sub-Saharan Africa, most of whom have some degree of clinical
      immunity to malaria, malaria infection in pregnancy leads to placental malaria (PM), often
      without clinical symptoms in the mother. The systemic and placental changes that occur with
      malaria in pregnancy can adversely affect the developing fetal brain, an fetal brain injury
      strongly affects long-term childhood neurodevelopmental (ND) and behavior but there are no
      published studies to date on the impact of malaria in pregnancy on childhood ND. This study,
      conducted in Uganda, will address the effects of malaria in pregnancy and childhood ND and
      define mechanisms by which malaria may lead to ND impairment including micronutrient
      deficiencies. ND outcomes will be measured by the following neuropsychological and behavioral
      tests: Mullen Scales of Early Learning, the Color Object Association Test, the Early
      Childhood Vigilance Test, the Behavior Rating Scales, the Behavior Related inventory of
      Executive Function and the Child Behavior Checklist. These tests will be given at 12, 24, 36,
      and 60 months of age. This study will be nested in an ongoing Ugandan IRB approved
      interventional trial (PROMOTE-II) (NCT02163447). Blood sampling is being conducted in the
      PROMOTE-II protocol for research purposes. Some of that blood will be used to test for
      micronutrient deficiencies as well as other immune responses to malaria.
    

Detailed description: 
      The PROMOTE-II randomized clinical trial in Tororo, Uganda, led by investigators from
      Makerere University in Uganda and the University of California-San Francisco (UCSF), provides
      an ideal setting to assess the effects of malaria prevention in pregnant women and their
      children on childhood ND. In PROMOTE-II Project 1,300 pregnant HIV-uninfected women will be
      randomized at 12-20 weeks of gestation to malaria prophylaxis with 3 doses of
      sulfadoxine-pyrimethamine (current standard of care), 3 doses of
      dihydroartemisinin-piperaquine (DP), or monthly DP. Their children will be randomized to
      receive DP prophylaxis monthly or every 3 months from 2 to 24 months age. The children will
      be followed for malaria episodes from birth to age 36 months. The proposed prospective study
      of child ND, the Prophylaxis against malaria To Enhance Child developmenT (PROTECT) study,
      will be nested within the PROMOTE-II Project 1 cohort. It is hypothesized that mothers on SP
      and mothers and children on less frequent prophylaxis will have more malaria episodes. The
      investigators predict that child ND will improve with more effective prophylaxis.

      The central hypotheses of this study are that malaria prevention in pregnant women and their
      children improves child ND through 1) prevention of placental sequestration and inflammation
      and of consequent micronutrient deficiency in the fetus, and 2) reduction of systemic
      inflammation and endothelial activation that can lead to micronutrient deficiency and anemia
      during pregnancy and in early childhood and thus to alteration of brain structures
      particularly sensitive to such deficiencies (e.g., the hippocampus, myelin and the frontal
      lobe). The collaborative team, which has expertise in malaria in pregnant women and children,
      malaria pathogenesis, micronutrient deficiency, fetal and child neurodevelopment, and
      modeling of complex disease pathways, is well qualified to undertake the proposed research.

      The specific aims of the study are:

      Aim 1. Determine the effect of malaria prevention in pregnant women and their children on
      child ND. Hypotheses: 1) Long-term child ND improves with more effective chemoprevention in
      pregnant women and in their children. 2) The effect of malaria prevention on child ND
      persists through 36 months of age. Child ND will be assessed with a testing battery validated
      in previous studies by this group in Ugandan children. The investigators will test these
      hypotheses by comparing child ND at 12, 24, 36 and 60 months of age between treatment groups.

      Aim 2. Identify the major mechanisms by which malaria prevention in pregnant women and
      children affects child ND. Hypotheses: 1) Malaria prevention in pregnant women affects child
      ND through prevention of placental sequestration and inflammation, with consequent prevention
      of prematurity, intrauterine growth retardation and fetal micronutrient deficiency. 2)
      Malaria prevention in pregnant women and in their children after birth improves child ND
      through reduction of systemic inflammation, endothelial activation, micronutrient deficiency
      and anemia, but the relative contributions of the factors differ in pregnant women compared
      to children. The investigators will test these hypotheses by conducting path analysis to
      determine if networks that include these paths explain a significant proportion of the
      difference in child ND between treatment groups.
    

Intervention name(s): No intervention in PROTECT
Intervention type(s): Other
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        300 Ugandan Children already enrolled in PROMOTE II study
      
Keywords: malaria; infant; pregnancy; prophylaxis; dihyroartemisinin-piperaquine; sulfadoxine-pyrimethamine; behavior; neurodevelopment; cognitive