Browsing by Author "Taylor, Steve M."

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    Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study
    (Public Library of Science, 2019-10-01) Elphinstone, Robyn E.; Weckman, Andrea M.; McDonald, Chloe R.; Tran, Vanessa; Zhong, Kathleen; Madanitsa, Mwayiwawo; Kalilani-Phiri, Linda; Khairallah, Carole; Taylor, Steve M.; Meshnick, Steven R.; Mwapasa, Victor; Ter Kuile, Feiko O.; Conroy, Andrea L.; Kain, Kevin C.; Pediatrics, School of Medicine
    Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB). Methods and findings We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04–1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20–2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy. Conclusions Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic 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.
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    Predictors of Plasmodium falciparum Infection in the First Trimester Among Nulliparous Women From Kenya, Zambia, and the Democratic Republic of the Congo
    (Oxford University Press, 2022) Leuba, Sequoia I.; Westreich, Daniel; Bose, Carl L.; Powers, Kimberly A.; Olshan, Andy; Taylor, Steve M.; Tshefu, Antoinette; Lokangaka, Adrien; Carlo, Waldemar A.; Chomba, Elwyn; Liechty, Edward A.; Bucher, Sherri L.; Esamai, Fabian; Jessani, Saleem; Saleem, Sarah; Goldenberg, Robert L.; Moore, Janet; Nolen, Tracy; Hemingway-Foday, Jennifer; McClure, Elizabeth M.; Koso-Thomas, Marion; Derman, Richard J.; Hoffman, Matthew; Bauserman, Melissa; Pediatrics, School of Medicine
    Background: Malaria can have deleterious effects early in pregnancy, during placentation. However, malaria testing and treatment are rarely initiated until the second trimester, leaving pregnancies unprotected in the first trimester. To inform potential early intervention approaches, we sought to identify clinical and demographic predictors of first-trimester malaria. Methods: We prospectively recruited women from sites in the Democratic Republic of the Congo (DRC), Kenya, and Zambia who participated in the ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) trial. Nulliparous women were tested for first-trimester Plasmodium falciparum infection by quantitative polymerase chain reaction. We evaluated predictors using descriptive statistics. Results: First-trimester malaria prevalence among 1513 nulliparous pregnant women was 6.3% (95% confidence interval [CI], 3.7%-8.8%] in the Zambian site, 37.8% (95% CI, 34.2%-41.5%) in the Kenyan site, and 62.9% (95% CI, 58.6%-67.2%) in the DRC site. First-trimester malaria was associated with shorter height and younger age in Kenyan women in site-stratified analyses, and with lower educational attainment in analyses combining all 3 sites. No other predictors were identified. Conclusions: First-trimester malaria prevalence varied by study site in sub-Saharan Africa. The absence of consistent predictors suggests that routine parasite screening in early pregnancy may be needed to mitigate first-trimester malaria in high-prevalence settings.