Browsing by Author "ter Kuile, Feiko O."

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    The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy
    (Elsevier, 2021-11) Tran, Vanessa; Weckman, Andrea M.; Crowley, Valerie M.; Cahill, Lindsay S.; Zhong, Kathleen; Cabrera, Ana; Elphinstone, Robyn E.; Pearce, Victoria; Madanitsa, Mwayiwawo; Kalilani-Phiri, Linda; Mwapasa, Victor; Khairallah, Carole; Conroy, Andrea L.; ter Kuile, Feiko O.; Sled, John G.; Kain, Kevin C.; Pediatrics, School of Medicine
    Background: Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes. Methods: Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1+/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes. Findings: Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1+/-), to worsen birth outcomes by impeding vascular remodeling required for placental function. Interpretation: Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes.
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    Economic evaluation of postdischarge malaria chemoprevention in preschool children treated for severe anaemia in Malawi, Kenya, and Uganda: A cost-effectiveness analysis
    (Elsevier, 2022-10-01) Kühl, Melf-Jakob; Gondwe, Thandile; Dhabangi, Aggrey; Kwambai, Titus K.; Mori, Amani T.; Opoka, Robert; John, C. Chandy; Idro, Richard; ter Kuile, Feiko O.; Phiri, Kamija S.; Robberstad, Bjarne; Pediatrics, School of Medicine
    Background: Children hospitalised with severe anaemia in malaria-endemic areas are at a high risk of dying or being readmitted within six months of discharge. A trial in Kenya and Uganda showed that three months of postdischarge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) substantially reduced this risk. The World Health Organization recently included PDMC in its malaria chemoprevention guidelines. We conducted a cost-effectiveness analysis of community-based PDMC delivery (supplying all three PDMC-DP courses to caregivers at discharge to administer at home), facility-based PDMC delivery (monthly dispensing of PDMC-DP at the hospital), and the standard of care (no PDMC). Methods: We combined data from two recently completed trials; one placebo-controlled trial in Kenya and Uganda collecting efficacy data (May 6, 2016 until November 15, 2018; n=1049), and one delivery mechanism trial from Malawi collecting adherence data (March 24, 2016 until October 3, 2018; n=375). Cost data were collected alongside both trials. Three Markov decision models, one each for Malawi, Kenya, and Uganda, were used to compute incremental cost-effectiveness ratios expressed as costs per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty. Findings: Both PDMC strategies were cost-saving in each country, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care. The estimated incremental cost savings for community-based PDMC compared to the standard of care were US$ 22·10 (Malawi), 38·52 (Kenya), and 26·23 (Uganda) per child treated. The incremental effectiveness gain using either PDMC strategy varied between 0·3 and 0·4 QALYs. Community-based PDMC was less costly and more effective than facility-based PDMC. These results remained robust in sensitivity analyses. Interpretation: PDMC under implementation conditions is cost-saving. Caregivers receiving PDMC at discharge is a cost-effective delivery strategy for implementation in malaria-endemic southeastern African settings.
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    Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort study
    (Elsevier, 2023) Wright, Julie K.; Weckman, Andrea M.; Ngai, Michelle; Stefanova, Veselina; Zhong, Kathleen; McDonald, Chloe R.; Elphinstone, Robyn E.; Conroy, Andrea L.; Coburn, Bryan A.; Madanitsa, Mwayi; Taylor, Steve M.; ter Kuile, Feiko O.; Kain, Kevin C.; Pediatrics, School of Medicine
    Background: Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. Methods: We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. Findings: Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p <0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p = 0.006) and 1.63 (1.07-2.47, p = 0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p <0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p <0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p <0.001). Interpretation: Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth.
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    Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study
    (PLOS, 2021-09-28) Weckman, Andrea M.; Conroy, Andrea L.; Madanitsa, Mwayiwawo; Gnaneswaran, Bruno; McDonald, Chloe R.; Kalilani-Phiri, Linda; Chandna, Jaya; Ali, Doreen; Mwapasa, Victor; Khairallah, Carole; Thwai, Kyaw Lay; Meshnick, Steven R.; Taylor, Steve M.; ter Kuile, Feiko O.; Kain, Kevin C.; Gladstone, Melissa; Pediatrics, School of Medicine
    Background: Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. Methods and findings: Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. Conclusions: This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.