Preventing growth restriction and preterm birth in countries with a high infectious disease burden

IMPROVE was a double-blind randomised, partly placebo-controlled trial in Kenya, Tanzania, and Malawi that compared monthly intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) vs dihydroartemisinin-piperaquine (DP) alone, or DP combined with a single course of azithromycin (AZ). SP was superior to DP and DP+AZ at improving maternal weight gain and fetal growth, despite having inferior antimalarial activity relative to DP.

We hypothesize that the mechanism for observed protection against low birthweight may be through reduced burden of infections, bacterial load, inflammation, and/or the modulation of microbiomes to improve nutrient uptake (intestinal) and/or reduce diversity (vaginal). We propose to test this hypothesis by characterizing the intestinal and vaginal microbiomes associated with improved growth and/or decreased systemic inflammation. Specifically, we plan to:

(1) Compare the impact of IPTp with SP vs DP vs DP+AZ on the intestinal microbiome and on levels of intestinal inflammation using paired stool samples (collected prior to dosing at enrolment and near-to-delivery) from 152 women in Tanzania and Malawi. This will enable us to identify bacterial families and genera associated with improved nutrient uptake and reduced inflammation, and then correlate these findings with improved maternal and fetal growth and reduced biomarkers of intestinal inflammation (calprotectin, lipocalin2, myeloperoxidase and dual oxidase 2).

(2) Compare the impact of IPTp on the vaginal microbiome with SP vs DP vs DP+AZ using paired swabs from the same time points in 162 women and assessing the Lactobacillus-dominated environment and the prevalence of bacteria associated with preterm birth.

(3) Compare the impact of IPTp on levels of maternal systemic inflammation and the potential inverse relationship with levels of growth hormone and insulin-like growth factors in the maternal circulation. In the trial, fetal growth and maternal weight gain were associated with malaria infection and sexually transmitted or reproductive tract infections.

We will analyzse plasma samples collected at trial enrolment (16 to 28 weeks, mean 24.2 weeks) and currently stored in Tanzania to measure cytokines (IL-6, IL-8, IL-1b and TNFa), growth hormone and insulin-like growth factors.

(4) Compare the effects of different IPTp regimens between microbiomes of individual women and across treatment groups to determine whether bacteria with similar functional capabilities are affected in similar ways (co-variation).