Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study.
BACKGROUND: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 lea...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-10-01
|
| Series: | PLoS Medicine |
| Online Access: | https://doi.org/10.1371/journal.pmed.1002914 |
| _version_ | 1819040893289627648 |
|---|---|
| author | Robyn E Elphinstone Andrea M Weckman Chloe R McDonald Vanessa Tran Kathleen Zhong Mwayiwawo Madanitsa Linda Kalilani-Phiri Carole Khairallah Steve M Taylor Steven R Meshnick Victor Mwapasa Feiko O Ter Kuile Andrea L Conroy Kevin C Kain |
| author_facet | Robyn E Elphinstone Andrea M Weckman Chloe R McDonald Vanessa Tran Kathleen Zhong Mwayiwawo Madanitsa Linda Kalilani-Phiri Carole Khairallah Steve M Taylor Steven R Meshnick Victor Mwapasa Feiko O Ter Kuile Andrea L Conroy Kevin C Kain |
| author_sort | Robyn E Elphinstone |
| collection | DOAJ |
| description | BACKGROUND: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. |
| first_indexed | 2024-12-21T09:16:20Z |
| format | Article |
| id | doaj.art-669bbf685ae747cda33e31edc93cd1d6 |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-12-21T09:16:20Z |
| publishDate | 2019-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-669bbf685ae747cda33e31edc93cd1d62022-12-21T19:09:09ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762019-10-011610e100291410.1371/journal.pmed.1002914Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study.Robyn E ElphinstoneAndrea M WeckmanChloe R McDonaldVanessa TranKathleen ZhongMwayiwawo MadanitsaLinda Kalilani-PhiriCarole KhairallahSteve M TaylorSteven R MeshnickVictor MwapasaFeiko O Ter KuileAndrea L ConroyKevin C KainBACKGROUND: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.https://doi.org/10.1371/journal.pmed.1002914 |
| spellingShingle | Robyn E Elphinstone Andrea M Weckman Chloe R McDonald Vanessa Tran Kathleen Zhong Mwayiwawo Madanitsa Linda Kalilani-Phiri Carole Khairallah Steve M Taylor Steven R Meshnick Victor Mwapasa Feiko O Ter Kuile Andrea L Conroy Kevin C Kain Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. PLoS Medicine |
| title | Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. |
| title_full | Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. |
| title_fullStr | Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. |
| title_full_unstemmed | Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. |
| title_short | Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. |
| title_sort | early malaria infection dysregulation of angiogenesis metabolism and inflammation across pregnancy and risk of preterm birth in malawi a cohort study |
| url | https://doi.org/10.1371/journal.pmed.1002914 |
| work_keys_str_mv | AT robyneelphinstone earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT andreamweckman earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT chloermcdonald earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT vanessatran earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT kathleenzhong earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT mwayiwawomadanitsa earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT lindakalilaniphiri earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT carolekhairallah earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT stevemtaylor earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT stevenrmeshnick earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT victormwapasa earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT feikooterkuile earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT andrealconroy earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy AT kevinckain earlymalariainfectiondysregulationofangiogenesismetabolismandinflammationacrosspregnancyandriskofpretermbirthinmalawiacohortstudy |