Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study
Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study
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DOI：
10.1371/journal.pmed.1002914
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发表时间：
2019-10-01
期刊：
影响因子：
15.8
通讯作者：
Kain, Kevin C.
中科院分区：
文献类型：
--
作者：
Elphinstone, Robyn E.;Weckman, Andrea M.;Kain, Kevin C.
作者简介：为什么要做这项研究？怀孕期间感染疟疾对母亲及其未出生的孩子造成严重后果。我们对疟疾导致不良出生结果的机制了解甚少，特别是早产，这是5岁以下儿童死亡的主要原因。迄今为止，预防孕妇疟疾的努力并未显示出降低与疟疾感染相关的肺结核风险。我们进行了这项研究，以评估疟疾感染，特别是在怀孕早期，是否可能改变控制胎盘生长和功能的重要因素，并确定这些因素是否导致PTB。研究人员做了什么，发现了什么？我们测量了10种不同的血管生成，炎症和/或代谢蛋白在怀孕期间纵向水平在一个大的队列的1,628马拉维妇女在疟疾感染的风险，并证明疟疾的早期感染与几个关键蛋白的变化是重要的健康怀孕。超声波测年的使用突出了早期疟疾感染对早产风险增加的贡献，以前认为早产主要发生在怀孕后期的疟疾。这些发现意味着什么？目前预防妊娠期疟疾的干预措施通常是在妊娠中期的第一次产前检查时开始的。这项研究表明，许多妇女在第一次就诊时就已经感染了疟疾，这些早期感染足以改变胎盘所必需的因素，以充分支持胎儿生长和健康的妊娠结局。这些早期感染增加了早产的风险，这表明预防妊娠期疟疾的干预措施可能需要在妊娠早期开始，以减少与疟疾相关的不良出生outcomes.Background妊娠期疟疾与不良出生结局相关。然而，对潜在的机制仍然知之甚少。血管生成、代谢和炎症途径的严格调节对于健康怀孕至关重要。我们假设疟疾破坏了这些导致早产（PTB）的途径。方法和发现我们对2011年7月21日至2013年3月18日在马拉维进行的妊娠期疟疾预防随机试验进行了二次分析。我们在一组HIV阴性女性（n = 1，628）中纵向评估了妊娠期间血管生成、代谢和炎症途径的循环介质，这些女性的中位年龄为21岁[18，25]，其中562人（35%）为早孕。超声测定妊娠日期，并在第13 - 23周（访视1）、第28 - 33周（访视2）和/或第34 - 36周（访视3）分析样本。疟疾流行率高; 70%（n = 1，138）在妊娠过程中至少有一次PCR阳性恶性疟原虫感染和/或胎盘组织学阳性。整个队列中早产的风险为20%（n = 304/1506）。妊娠24周前患疟疾的妇女患结核病的风险更高（24% vs 18%，p = 0.005;校正相对风险[aRR] 1.30，95%置信区间[CI] 1.04 - 1.63，p = 0.021）;而那些在24周前疟疾呈阳性的人患肺结核的风险更大（28% vs 17%，p = 0.02; aRR为1.67，95% CI 1.20 - 2.30，p = 0.002）。使用线性混合效应模型，妊娠24周前的疟疾与炎症反应动力学的改变有关。（C反应蛋白[CRP]、几丁质酶3样蛋白-1 [CHI3L1]、白细胞介素18结合蛋白[IL-18 BP]、可溶性肿瘤坏死因子受体II [sTNFRII]、可溶性细胞间粘附分子-1 [sICAM-1]）、血管生成在妊娠过程中，可溶性内皮糖蛋白[sEng]和代谢介质（瘦素，血管生成素样3 [Angptl3]）的水平升高（chi（2）> 13.0，p
Author summaryWhy was this study done? Malaria infection during pregnancy has serious consequences for the mother and her unborn child. We have a poor understanding of the mechanisms by which malaria causes adverse birth outcomes, especially preterm birth (PTB), a leading cause of death in children less than 5 years of age. Efforts to date to prevent malaria in pregnant women have not been shown to reduce the risk of PTB associated with malaria infection. We conducted this study to assess if malaria infection, especially early in pregnancy, might alter important factors that control placental growth and function and determine if these lead to PTB. What did the researchers do and find? We measured levels of 10 different angiogenic, inflammatory, and/or metabolic proteins longitudinally during pregnancy in a large cohort of 1,628 Malawian women at risk of malaria infection and demonstrate that early infection with malaria is associated with changes in several key proteins that are important for healthy pregnancies. The use of ultrasound dating highlighted the contribution of early malaria infection to an increased risk of delivering preterm, previously thought to occur primarily from malaria late in pregnancy. What do these findings mean? Current interventions to prevent malaria in pregnancy are usually initiated at the first antenatal visit in the second trimester. This study demonstrates that many women are already malaria-infected at this first visit and that these early infections are sufficient to alter factors essential for the placenta to adequately support fetal growth and healthy pregnancy outcomes. These early infections increase the risk of delivering preterm, indicating that interventions to prevent malaria in pregnancy may need to be started earlier in pregnancy in order to reduce malaria-associated adverse birth outcomes.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 (chi(2) > 13.0, p